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1
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Borrego-Ruiz A, Borrego JJ. The Bidirectional Interplay Between Substances of Abuse and Gut Microbiome Homeostasis. Life (Basel) 2025; 15:834. [PMID: 40566488 PMCID: PMC12194791 DOI: 10.3390/life15060834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2025] [Revised: 05/17/2025] [Accepted: 05/21/2025] [Indexed: 06/28/2025] Open
Abstract
Specific gut microorganisms and their metabolic by-products have been identified as key regulators of host physiology, contributing to the modulation of the immune system, inflammatory processes, brain function, and behavior, which highlights the gut microbiome as a potential modulator of the neurobiological mechanisms involved in substance use disorders. This narrative review provides an updated overview of how drugs of abuse influence the composition and dynamics of the human gut microbiome and how bacterial dysbiosis may be a contributing factor to substance use disorders by modulating the communication between the gut and the brain. Thus, by examining commonly abused substances such as alcohol, psychostimulants, opioids, cannabinoids, and nicotine, this review aimed to deepen the understanding of the bidirectional relationship between the gut microbiome and substance use. There is evidence indicating that gut microbiome alterations may influence addiction through changes in gut-brain signaling. Furthermore, changes in the gut microbiome and its metabolites may not only result from substance use disorders, but could also modulate behavioral responses to drugs of abuse. Although the exact mechanisms by which the gut microbiome modulates behavioral responses to drugs of abuse are not fully understood, microbial products such as short-chain fatty acids, tryptophan metabolites, bile acids, and neurotransmitters have been suggested to play a role in this process by influencing the blood-brain barrier permeability, host immune activation, neural signaling, and gene expression. Therefore, manipulating the gut microbiome or its by-products may represent a promising approach for enhancing substance use disorder treatments, identifying individuals at increased risk of pathological drug use, and elucidating its role in substance-related behaviors.
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Affiliation(s)
- Alejandro Borrego-Ruiz
- Departamento de Psicología Social y de las Organizaciones, Universidad Nacional de Educación a Distancia (UNED), 28040 Madrid, Spain
| | - Juan J. Borrego
- Departamento de Microbiología, Universidad de Málaga, 29071 Málaga, Spain;
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Gao Y, Kong D, Sun JX, Ma ZX, Wang GQ, Ma XF, Sun L, Luo HY, Xu Y, Wang KH. Intestinal barrier damage caused by addictive substance use disorder. Eur J Med Res 2025; 30:226. [PMID: 40176069 PMCID: PMC11963533 DOI: 10.1186/s40001-025-02446-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Accepted: 03/10/2025] [Indexed: 04/04/2025] Open
Abstract
Addictive substance use disorder has a wide range of effects on the intestinal barrier, including damage to the biological, chemical, mechanical, and immune barriers. Damage to the intestinal barrier caused by addictive substance use disorder allows harmful substances and bacteria to cross the intestinal barrier into the circulatory system, leading to systemic inflammatory responses and immune imbalances. In addition, the interaction between the gut flora and the central nervous system is recognized as an important component of the gut-brain axis. Gut barrier damage leads to dysbiosis, which in turn affects brain function by activating immune cells and releasing inflammatory factors. This may lead to altered mood and cognitive function, increased addictive substance cravings, and dependence. Recent research has indicated that reshaping the gut-brain axis and adjusting the composition and abundance of gut microbiota holds promise in alleviating withdrawal symptoms with addictive substance dependence. This article reviews the effects of addictive substance use disorder on the intestinal barrier and explores the possibility of improving addictive substance dependence by treating gut barrier damage.
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Affiliation(s)
- Yan Gao
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, 650504, China
| | - Deshenyue Kong
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, 650504, China
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Jia-Xue Sun
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, 650504, China
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Zhong-Xu Ma
- Third People's Hospital of Kunming City, Kunming, 650041, China
| | - Guang-Qing Wang
- Drug Rehabilitation Administration of Yunnan Province, Kunming, 650032, China
| | - Xing-Feng Ma
- Drug Rehabilitation Administration of Yunnan Province, Kunming, 650032, China
| | - Liang Sun
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China
| | - Hua-You Luo
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
| | - Yu Xu
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, 650504, China.
- Department of Gastrointestinal and Hernia Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, 650032, China.
| | - Kun-Hua Wang
- Yunnan Technological Innovation Centre of Drug Addiction Medicine, Yunnan University, Kunming, 650504, China.
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Saeedi N, Pourabdolhossein F, Dadashi M, Suha A, Janahmadi M, Behzadi G, Hosseinmardi N. Faecal Microbiota Transplantation Modulates Morphine Addictive-Like Behaviours Through Hippocampal Metaplasticity. Addict Biol 2025; 30:e70034. [PMID: 40237231 PMCID: PMC12000926 DOI: 10.1111/adb.70034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2024] [Revised: 02/11/2025] [Accepted: 04/03/2025] [Indexed: 04/18/2025]
Abstract
The microbiota-gut-brain axis has been implicated in the pathology of substance use disorders (SUDs). In light of the brain's capability to reorganize itself in response to intrinsic and extrinsic stimuli, opioid-induced dysbiosis is likely to contribute to addictive behaviour through modulating neuroplasticity. In this study, a faecal microbiota transplantation (FMT) from a saline-donor was performed on morphine-treated rats to evaluate the effects of gut microbiota on morphine-induced metaplasticity and addictive behaviours. Male Wistar rats were treated with subcutaneous injections of 10 mg/kg morphine sulphate every 12 h for 9 days in an effort to induce dependence. The withdrawal syndrome was precipitated by injecting naloxone (1.5 mg/kg, ip) after the final dose of morphine. The tolerance was induced by repeated morphine injections over a period of 7 days (10 mg/kg, once a day, ip). FMT was applied daily through gavage of processed faeces 1 week before and during the morphine treatment. Field potential recordings (i.e., fEPSP) were carried out to assess short-term and long-term synaptic plasticity in the CA1 area of the hippocampus following Schaffer-collateral stimulation. Animals subjected to FMT exhibited significant reductions in naloxone-precipitated withdrawal syndrome (one-way ANOVA, p < 0.05). Tolerance to the analgesic effects of morphine was not affected by FMT (two-way ANOVA, p > 0.05). Following high-frequency stimulation (HFS) to induce long-term potentiation (LTP), a greater fEPSP slope was observed in morphine-treated animals (unpaired t test, p < 0.05). FMT from saline-donor rats diminished morphine-induced augmented LTP (unpaired t test, p < 0.05). These results highlighted the alleviating effects of FMT from saline-donors on morphine-induced metaplasticity and dependence potentially by modulating the dysbiosis of gut microbiota.
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Affiliation(s)
- Negin Saeedi
- Department of Physiology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | | | - Masoud Dadashi
- Department of Microbiology, School of MedicineAlborz University of Medical SciencesKarajIran
| | - Ali Jaafari Suha
- Department of Physiology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Mahyar Janahmadi
- Neurophysiology Research Center, Department of Physiology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Gila Behzadi
- Neurophysiology Research Center, Department of Physiology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Narges Hosseinmardi
- Neurophysiology Research Center, Department of Physiology, School of MedicineShahid Beheshti University of Medical SciencesTehranIran
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Szymczak-Pajor I, Drzewoski J, Kozłowska M, Krekora J, Śliwińska A. The Gut Microbiota-Related Antihyperglycemic Effect of Metformin. Pharmaceuticals (Basel) 2025; 18:55. [PMID: 39861118 PMCID: PMC11768994 DOI: 10.3390/ph18010055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Revised: 12/26/2024] [Accepted: 12/30/2024] [Indexed: 01/27/2025] Open
Abstract
It is critical to sustain the diversity of the microbiota to maintain host homeostasis and health. Growing evidence indicates that changes in gut microbial biodiversity may be associated with the development of several pathologies, including type 2 diabetes mellitus (T2DM). Metformin is still the first-line drug for treatment of T2DM unless there are contra-indications. The drug primarily inhibits hepatic gluconeogenesis and increases the sensitivity of target cells (hepatocytes, adipocytes and myocytes) to insulin; however, increasing evidence suggests that it may also influence the gut. As T2DM patients exhibit gut dysbiosis, the intestinal microbiome has gained interest as a key target for metabolic diseases. Interestingly, changes in the gut microbiome were also observed in T2DM patients treated with metformin compared to those who were not. Therefore, the aim of this review is to present the current state of knowledge regarding the association of the gut microbiome with the antihyperglycemic effect of metformin. Numerous studies indicate that the reduction in glucose concentration observed in T2DM patients treated with metformin is due in part to changes in the biodiversity of the gut microbiota. These changes contribute to improved intestinal barrier integrity, increased production of short-chain fatty acids (SCFAs), regulation of bile acid metabolism, and enhanced glucose absorption. Therefore, in addition to the well-recognized reduction of gluconeogenesis, metformin also appears to exert its glucose-lowering effect by influencing gut microbiome biodiversity. However, we are only beginning to understand how metformin acts on specific microorganisms in the intestine, and further research is needed to understand its role in regulating glucose metabolism, including the impact of this remarkable drug on specific microorganisms in the gut.
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Affiliation(s)
- Izabela Szymczak-Pajor
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland;
| | - Józef Drzewoski
- Central Teaching Hospital of the Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland; (J.D.); (J.K.)
| | - Małgorzata Kozłowska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland;
| | - Jan Krekora
- Central Teaching Hospital of the Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland; (J.D.); (J.K.)
| | - Agnieszka Śliwińska
- Department of Nucleic Acid Biochemistry, Medical University of Lodz, 251 Pomorska Str., 92-213 Lodz, Poland;
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Aluthge N, Adams S, Davila CA, Gocchi Carrasco NR, Chiou KS, Abadie R, Bennett SJ, Dombrowski K, Major AM, Valentín-Acevedo A, West JT, Wood C, Fernando SC. Gut microbiota profiling in injection drug users with and without HIV-1 infection in Puerto Rico. Front Microbiol 2024; 15:1470037. [PMID: 39697649 PMCID: PMC11652967 DOI: 10.3389/fmicb.2024.1470037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/23/2024] [Indexed: 12/20/2024] Open
Abstract
Introduction The full extent of interactions between human immunodeficiency virus (HIV) infection, injection drug use, and the human microbiome is unclear. In this study, we examined the microbiomes of HIV-positive and HIV-negative individuals, both drug-injecting and non-injecting, to identify bacterial community changes in response to HIV and drug use. We utilized a well-established cohort of people who inject drugs in Puerto Rico, a region with historically high levels of injection drug use and an HIV incidence rate disproportionately associated with drug use. Methods Using amplicon-based 16S rDNA sequencing, we identified amplicon sequence variants (ASVs) that demonstrated significant variations in the composition of microbial communities based on HIV status and drug use. Results and discussion Our findings indicate that the HIV-positive group exhibited a higher abundance of ASVs belonging to the genera Prevotella, Alloprevotella, Sutterella, Megasphaera, Fusobacterium, and Mitsuokella. However, Bifidobacteria and Lactobacillus ASVs were more abundant in injectors than in non-injectors. We examined the effect of drug use on the gut microbiome in both HIV-infected and non-infected patients, and found that multiple drug use significantly affected the microbial community composition. Analysis of differential of bacterial taxa revealed an enrichment of Bifidobacterium spp., Faecalibacterium spp., and Lactobacillus spp. in the multiple drug-injecting group. However, in the non-injecting group, Parabacteroides spp., Prevotella spp., Paraprevotella spp., Sutterella spp., and Lachnoclostridium spp. The presence of multiple drug-injecting groups was observed to be more prevalent. Our findings provide detailed insight into ASV-level changes in the microbiome in response to HIV and drug use, suggesting that the effect of HIV status and drug injection may have different effects on microbiome composition and in modulating gut bacterial populations.
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Affiliation(s)
- Nirosh Aluthge
- Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE, United States
| | - Seidu Adams
- Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE, United States
| | - Carmen A. Davila
- Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE, United States
| | | | - Kathy S. Chiou
- Department of Psychology, University of Nebraska-Lincoln, Lincoln, NE, United States
| | - Roberto Abadie
- Department of Kinesiology, University of Wisconsin-Madison, Madison, WI, United States
| | - Sydney J. Bennett
- Department of Biological Science, University of Nebraska-Lincoln, Lincoln, NE, United States
| | | | - Angel M. Major
- Department of Microbiology and Immunology, Universidad Central del Caribe, Bayamon, Puerto Rico
| | - Aníbal Valentín-Acevedo
- Department of Microbiology and Immunology, Universidad Central del Caribe, Bayamon, Puerto Rico
| | - John T. West
- Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, United States
| | - Charles Wood
- Department of Interdisciplinary Oncology, Louisiana State University Health Sciences Center, Louisiana Cancer Research Center, New Orleans, LA, United States
| | - Samodha C. Fernando
- Department of Animal Science, University of Nebraska-Lincoln, Lincoln, NE, United States
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Barkus A, Baltrūnienė V, Baušienė J, Baltrūnas T, Barkienė L, Kazlauskaitė P, Baušys A. The Gut-Brain Axis in Opioid Use Disorder: Exploring the Bidirectional Influence of Opioids and the Gut Microbiome-A Comprehensive Review. Life (Basel) 2024; 14:1227. [PMID: 39459527 PMCID: PMC11508959 DOI: 10.3390/life14101227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/15/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024] Open
Abstract
Opioid Use Disorder is a chronic condition characterized by compulsive opioid use despite negative consequences, resulting in severe health risks such as overdose and contraction of infectious diseases. High dropout rates in opioid agonist therapy highlight the need for more effective relapse prevention strategies. Animal and clinical studies indicate that opioids influence gut microbiota, which in turn plays a critical role in addiction development and alters behavioral responses to opioids. This study provides a comprehensive review of the literature on the effects of opioids on the gut microbiome and explores the potential of microbiome manipulation as a therapeutic target in opioid addiction.
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Affiliation(s)
- Artūras Barkus
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
- Laboratory of Experimental Surgery and Oncology, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
| | - Vaida Baltrūnienė
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
- Laboratory of Experimental Surgery and Oncology, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
| | - Justė Baušienė
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
- Laboratory of Experimental Surgery and Oncology, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
| | - Tomas Baltrūnas
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
- Laboratory of Experimental Surgery and Oncology, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
| | - Lina Barkienė
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
- Laboratory of Experimental Surgery and Oncology, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
| | - Paulina Kazlauskaitė
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
- Laboratory of Experimental Surgery and Oncology, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
| | - Augustinas Baušys
- Department of Pathology and Forensic Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
- Laboratory of Experimental Surgery and Oncology, Faculty of Medicine, Vilnius University, 03101 Vilnius, Lithuania
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7
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Han C, Manners MT, Robinson SA. Sex differences in opioid response: a role for the gut microbiome? Front Pharmacol 2024; 15:1455416. [PMID: 39268474 PMCID: PMC11390522 DOI: 10.3389/fphar.2024.1455416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/14/2024] [Indexed: 09/15/2024] Open
Abstract
Opioid drugs have been long known to induce different responses in males compared to females, however, the molecular mechanisms underlying these effects are yet to be fully characterized. Recent studies have established a link between the gut microbiome and behavioral responses to opioids. Chronic opioid use is associated with gut dysbiosis, or microbiome disruptions, which is thought to contribute to altered opioid analgesia and reward processing. Gut microbiome composition and functioning have also been demonstrated to be influenced by sex hormones. Despite this, there is currently very little work investigating whether sex differences in the gut microbiome mediate sex-dependent responses to opioids, highlighting a critical gap in the literature. Here, we briefly review the supporting evidence implicating a potential role for the gut microbiome in regulating sexually dimorphic opioid response and identify areas for future research.
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Affiliation(s)
- Caitlin Han
- Department of Psychology, Williams College, Williamstown, MA, United States
| | - Melissa T. Manners
- Department of Biological and Biomedical Sciences, Rowan University, Glassboro, NJ, United States
| | - Shivon A. Robinson
- Department of Psychology, Williams College, Williamstown, MA, United States
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Coluzzi F, Scerpa MS, Loffredo C, Borro M, Pergolizzi JV, LeQuang JA, Alessandri E, Simmaco M, Rocco M. Opioid Use and Gut Dysbiosis in Cancer Pain Patients. Int J Mol Sci 2024; 25:7999. [PMID: 39063241 PMCID: PMC11276997 DOI: 10.3390/ijms25147999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 07/11/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
Opioids are commonly used for the management of severe chronic cancer pain. Their well-known pharmacological effects on the gastrointestinal system, particularly opioid-induced constipation (OIC), are the most common limiting factors in the optimization of analgesia, and have led to the wide use of laxatives and/or peripherally acting mu-opioid receptor antagonists (PAMORAs). A growing interest has been recently recorded in the possible effects of opioid treatment on the gut microbiota. Preclinical and clinical data, as presented in this review, showed that alterations of the gut microbiota play a role in modulating opioid-mediated analgesia and tolerability, including constipation. Moreover, due to the bidirectional crosstalk between gut bacteria and the central nervous system, gut dysbiosis may be crucial in modulating opioid reward and addictive behavior. The microbiota may also modulate pain regulation and tolerance, by activating microglial cells and inducing the release of inflammatory cytokines and chemokines, which sustain neuroinflammation. In the subset of cancer patients, the clinical meaning of opioid-induced gut dysbiosis, particularly its possible interference with the efficacy of chemotherapy and immunotherapy, is still unclear. Gut dysbiosis could be a new target for treatment in cancer patients. Restoring the physiological amount of specific gut bacteria may represent a promising therapeutic option for managing gastrointestinal symptoms and optimizing analgesia for cancer patients using opioids.
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Affiliation(s)
- Flaminia Coluzzi
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, 00189 Rome, Italy
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Maria Sole Scerpa
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Chiara Loffredo
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Marina Borro
- Department of Neuroscience, Mental Health and Sense Organs NESMOS, Sapienza University of Rome, 00185 Rome, Italy
| | | | | | - Elisa Alessandri
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
| | - Maurizio Simmaco
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
- Department of Neuroscience, Mental Health and Sense Organs NESMOS, Sapienza University of Rome, 00185 Rome, Italy
| | - Monica Rocco
- Department of Medical-Surgical Sciences and Translational Medicine, Sapienza University of Rome, 00189 Rome, Italy
- Unit of Anaesthesia, Intensive Care, and Pain Medicine, Sant’Andrea University Hospital, 00189 Rome, Italy
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Muchhala KH, Kallurkar PS, Kang M, Koseli E, Poklis JL, Xu Q, Dewey WL, Fettweis JM, Jimenez NR, Akbarali HI. The role of morphine- and fentanyl-induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota-gut-brain axis. FASEB J 2024; 38:e23603. [PMID: 38648368 PMCID: PMC11047137 DOI: 10.1096/fj.202301590rr] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 03/22/2024] [Accepted: 03/26/2024] [Indexed: 04/25/2024]
Abstract
Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis.
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Affiliation(s)
- Karan H. Muchhala
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Prajkta S. Kallurkar
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Minho Kang
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Eda Koseli
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Justin L. Poklis
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Qingguo Xu
- Department of Pharmaceutics, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, United States
| | - William L. Dewey
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
| | - Jennifer M. Fettweis
- Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Nicole R. Jimenez
- Department of Microbiology and Immunology, School of Medicine, Virginia Commonwealth University, Richmond, VA, United States
| | - Hamid I. Akbarali
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States
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10
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Zelicha H, Yang J, Henning SM, Huang J, Lee RP, Thames G, Livingston EH, Heber D, Li Z. Effect of cinnamon spice on continuously monitored glycemic response in adults with prediabetes: a 4-week randomized controlled crossover trial. Am J Clin Nutr 2024; 119:649-657. [PMID: 38290699 DOI: 10.1016/j.ajcnut.2024.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Revised: 01/03/2024] [Accepted: 01/09/2024] [Indexed: 02/01/2024] Open
Abstract
BACKGROUND Previous clinical studies showing that cinnamon spice lowers blood glucose concentrations had inconsistent results. OBJECTIVES To determine the effect of daily cinnamon spice supplementation in an amount commonly used for seasoning on glucose concentrations in adults with obesity and prediabetes. METHODS Following a 2-wk run-in period of maintaining a low polyphenol/fiber diet, 18 participants with obesity and prediabetes underwent a 10-wk randomized, controlled, double-blind, crossover trial (mean age 51.1 y; mean fasting plasma glucose 102.9 mg/dL). The participants were randomly assigned to take cinnamon (4 g/d) or placebo for 4-wk, followed by a 2-wk washout period, and then crossed over to the other intervention for an additional 4-wk. Glucose changes were measured with continuous glucose monitoring. Oral glucose tolerance testing immediately following ingestion of cinnamon or placebo was performed at 4-time points to assess their acute effects both at the baseline and end of each intervention phase. Digestive symptom logs were obtained daily. RESULTS There were 694 follow-up days with 66,624 glucose observations. When compared with placebo, 24-h glucose concentrations were significantly lower when cinnamon was administered [mixed-models; effect size (ES) = 0.96; 95 % confidence interval (CI): -2.9, -1.5; P < 0.001]. Similarly, the mean net-area-under-the-curve (netAUC) for glucose was significantly lower than for placebo when cinnamon was given (over 24 h; ES = -0.66; 95 % CI: 2501.7, 5412.1, P = 0.01). Cinnamon supplementation resulted in lower glucose peaks compared with placebo (Δpeak 9.56 ± 9.1 mg/dL compared with 11.73 ± 8.0 mg/dL; ES = -0.57; 95 % CI: 0.8, 3.7, P = 0.027). Glucose-dependent-insulinotropic-polypeptide concentrations increased during oral glucose tolerance testing + cinnamon testing (mixed-models; ES = 0.51; 95 % CI: 1.56, 100.1, P = 0.04), whereas triglyceride concentrations decreased (mixed-models; ES = 0.55; 95 % CI: -16.0, -1.6, P = 0.02). Treatment adherence was excellent in both groups (cinnamon: 97.6 ± 3.4 % compared with placebo: 97.9 ± 3.7 %; ES = -0.15; 95 % CI: -1.8, 0.2, P = 0.5). No differences were found in digestive symptoms (abdominal pain, borborygmi, bloating, excess flatus, and stools/day) between cinnamon and placebo groups. CONCLUSIONS Cinnamon, a widely available and low-cost supplement, may contribute to better glucose control when added to the diet in people who have obesity-related prediabetes. This trial was registered at clinicaltrials.gov as NCT04342624.
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Affiliation(s)
- Hila Zelicha
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA, United States
| | - Jieping Yang
- Department of Medicine, Center for Human Nutrition, David Geffen School of Medicine, Los Angeles, United States
| | - Susanne M Henning
- Department of Medicine, Center for Human Nutrition, David Geffen School of Medicine, Los Angeles, United States
| | - Jianjun Huang
- Department of Medicine, Center for Human Nutrition, David Geffen School of Medicine, Los Angeles, United States
| | - Ru-Po Lee
- Department of Medicine, Center for Human Nutrition, David Geffen School of Medicine, Los Angeles, United States
| | - Gail Thames
- Department of Medicine, Center for Human Nutrition, David Geffen School of Medicine, Los Angeles, United States
| | - Edward H Livingston
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA, United States
| | - David Heber
- Department of Medicine, Center for Human Nutrition, David Geffen School of Medicine, Los Angeles, United States
| | - Zhaoping Li
- Department of Medicine, Center for Human Nutrition, David Geffen School of Medicine, Los Angeles, United States.
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11
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Young P, Elghawy O, Mock J, Wynter E, Gentzler RD, Martin LW, Novicoff W, Hall R. Impact of Opioid Use on Duration of Therapy and Overall Survival for Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors. Curr Oncol 2024; 31:260-273. [PMID: 38248102 PMCID: PMC10814484 DOI: 10.3390/curroncol31010017] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 12/27/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
Immune checkpoint inhibitors (ICI) have significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). We evaluated the effect of opioid use on outcomes in patients receiving ICI either alone or with chemotherapy. We conducted a retrospective review of 209 patients with advanced NSCLC who received an ICI at the University of Virginia between 1 February 2015 and 1 January 2020. We performed univariate and multivariate analyses to evaluate the impact of opioid use on duration of therapy (DOT) and overall survival (OS). Patients with no or low opioid use (n = 172) had a median DOT of 12.2 months (95% CI: 6.9-17.4) compared to 1.9 months (95% CI: 1.8-2.0) for those with high opioid use (n = 37, HR 0.26 95% CI: 0.17-0.40, p < 0.001). Patients with no or low opioid use had a median OS of 22.6 months (95% CI: 14.8-30.4) compared to 3.8 months (95% CI: 2.7-4.9) for those with high opioid use (HR 0.26 95% CI: 0.17-0.40 p < 0.001). High opioid use was associated with a shorter DOT and worse OS. This difference remained significant when accounting for possible confounding variables. These data warrant investigation of possible mechanistic interactions between opioids, tumor progression, and ICIs, as well as prospective evaluation of opioid-sparing pain management strategies, where possible.
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Affiliation(s)
- Philip Young
- Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA 22903, USA; (P.Y.); (R.D.G.)
| | - Omar Elghawy
- School of Medicine, University of Virginia, Charlottesville, VA 22903, USA;
| | - Joseph Mock
- Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA 22903, USA; (P.Y.); (R.D.G.)
| | - Emmett Wynter
- Department of Medicine, University of Virginia, Charlottesville, VA 22903, USA
| | - Ryan D. Gentzler
- Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA 22903, USA; (P.Y.); (R.D.G.)
| | - Linda W. Martin
- Department of Surgery, Division of Thoracic and Cardiovascular Surgery, University of Virginia, Charlottesville, VA 22903, USA
| | - Wendy Novicoff
- Department of Public Health Sciences and Orthopedic Surgery, University of Virginia, Charlottesville, VA 22903, USA
| | - Richard Hall
- Department of Medicine, Division of Hematology/Oncology, University of Virginia, Charlottesville, VA 22903, USA; (P.Y.); (R.D.G.)
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12
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Duffy EP, Bachtell RK, Ehringer MA. Opioid trail: Tracking contributions to opioid use disorder from host genetics to the gut microbiome. Neurosci Biobehav Rev 2024; 156:105487. [PMID: 38040073 PMCID: PMC10836641 DOI: 10.1016/j.neubiorev.2023.105487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 12/03/2023]
Abstract
Opioid use disorder (OUD) is a worldwide public health crisis with few effective treatment options. Traditional genetics and neuroscience approaches have provided knowledge about biological mechanisms that contribute to OUD-related phenotypes, but the complexity and magnitude of effects in the brain and body remain poorly understood. The gut-brain axis has emerged as a promising target for future therapeutics for several psychiatric conditions, so characterizing the relationship between host genetics and the gut microbiome in the context of OUD will be essential for development of novel treatments. In this review, we describe evidence that interactions between host genetics, the gut microbiome, and immune signaling likely play a key role in mediating opioid-related phenotypes. Studies in humans and model organisms consistently demonstrated that genetic background is a major determinant of gut microbiome composition. Furthermore, the gut microbiome is susceptible to environmental influences such as opioid exposure. Additional work focused on gene by microbiome interactions will be necessary to gain improved understanding of their effects on OUD-related behaviors.
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Affiliation(s)
- Eamonn P Duffy
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA; Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
| | - Ryan K Bachtell
- Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA; Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, CO, USA
| | - Marissa A Ehringer
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, USA; Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA
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13
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Taboun ZS, Sadeghi J. The bidirectional relationship between opioids and the gut microbiome: Implications for opioid tolerance and clinical interventions. Int Immunopharmacol 2023; 125:111142. [PMID: 37918085 DOI: 10.1016/j.intimp.2023.111142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/06/2023] [Accepted: 10/26/2023] [Indexed: 11/04/2023]
Abstract
Opioids are widely used in treating patients with acute and chronic pain; however, this class of drugs is also commonly abused. Opioid use disorder and associated overdoses are becoming more prevalent as the opioid crisis continues. Chronic opioid use is associated with tolerance, which decreases the efficacy of opioids over time, but also puts individuals at risk of fatal overdoses. Therefore, it is essential to identify strategies to reduce opioid tolerance in those that use these agents. The gut microbiome has been found to play a critical role in opioid tolerance, with opioids causing dysbiosis of the gut, and changes in the gut microbiome impacting opioid tolerance. These changes in turn have a detrimental effect on the gut microbiome, creating a positive feedback cycle. We review the bidirectional relationship between the gut microbiome and opioid tolerance, discuss the role of modulation of the gut microbiome as a potential therapeutic option in opioid-induced gut dysbiosis, and suggest opportunities for further research and clinical interventions.
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Affiliation(s)
- Zahra S Taboun
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Javad Sadeghi
- School of Engineering, University of British Columbia - Okanagan, Kelowna, British Columbia, Canada.
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14
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Kolli U, Jalodia R, Moidunny S, Singh PK, Ban Y, Tao J, Cantu GN, Valdes E, Ramakrishnan S, Roy S. Multi-omics analysis revealing the interplay between gut microbiome and the host following opioid use. Gut Microbes 2023; 15:2246184. [PMID: 37610102 PMCID: PMC10448978 DOI: 10.1080/19490976.2023.2246184] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 07/18/2023] [Accepted: 08/04/2023] [Indexed: 08/24/2023] Open
Abstract
Opioid crisis is an ongoing epidemic since the past several decades in the United States. Opioid use-associated microbial dysbiosis is emerging as a key regulator of intestinal homeostasis and behavioral responses to opioid. However, the mechanistic insight into the role of microbial community in modulating host response is unavailable. To uncover the role of opioid-induced dysbiosis in disrupting intestinal homeostasis we utilized whole genome sequencing, untargeted metabolomics, and mRNA sequencing to identify changes in microbiome, metabolome, and host transcriptome respectively. Morphine treatment resulted in significant expansion of Parasuterella excrementihominis, Burkholderiales bacterium 1_1_47, Enterococcus faecalis, Enterorhabdus caecimuris and depletion of Lactobacillus johnsonii. These changes correlated with alterations in lipid metabolites and flavonoids. Significant alteration in microbial metabolism (metabolism of lipids, amino acids, vitamins and cofactors) and increased expression of virulence factors and biosynthesis of lipopolysaccharides (LPS) and lipoteichoic acid (LTA) were observed in microbiome of morphine-treated animals. In concurrence with changes in microbiome and metabolome extensive changes in innate and adaptive immune response, lipid metabolism, and gut barrier dysfunction were observed in the host transcriptome. Microbiome depleted mice displayed lower levels of inflammation, immune response and tissue destruction compared to mice harboring a dysbiotic microbiome in response to morphine treatment, thus establishing dysbiotic microbiome as mediator of morphine gut pathophysiology. Integrative analysis of multi-omics data highlighted the associations between Parasutterella excrementihominis, Burkholderiales bacterium 1_1_47, Enterococcus faecalis, Enterorhabdus caecimuris and altered levels of riboflavin, flavonoids, and lipid metabolites including phosphocholines, carnitines, bile acids, and ethanolamines with host gene expression changes involved in inflammation and barrier integrity of intestine. Omic analysis also highlighted the role of probiotic bacteria Lactobacillus johnsonii, metabolites flavonoids and riboflavin that were depleted with morphine as important factors for intestinal homeostasis. This study presents for the first time ever an interactive view of morphine-induced changes in microbial metabolism, strain level gut microbiome analysis and comprehensive view of changes in gut transcriptome. We also identified areas of potential therapeutic interventions to limit microbial dysbiosis and present a unique resource to the opioid research community.
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Affiliation(s)
- Udhghatri Kolli
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Richa Jalodia
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Shamsudheen Moidunny
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Praveen Kumar Singh
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Yuguang Ban
- Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Fl, USA
| | - Junyi Tao
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Eridania Valdes
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sundaram Ramakrishnan
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sabita Roy
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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15
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Ma L, La X, Zhang B, Xu W, Tian C, Fu Q, Wang M, Wu C, Chen Z, Chang H, Li JA. Total Astragalus saponins can reverse type 2 diabetes mellitus-related intestinal dysbiosis and hepatic insulin resistance in vivo. Front Endocrinol (Lausanne) 2023; 14:1190827. [PMID: 38053727 PMCID: PMC10694298 DOI: 10.3389/fendo.2023.1190827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 10/31/2023] [Indexed: 12/07/2023] Open
Abstract
Objective Intestinal flora homeostasis in rats with type 2 diabetes mellitus (T2DM) was evaluated to explore the effects of total Astragalus saponins (TAS) on hepatic insulin resistance (IR). Methods Six-week-old male Sprague-Dawley rats were fed high-fat and high-sugar diet for 4 weeks and intraperitoneally injected with streptozotocin to induce T2DM, and they were then randomly divided into control, model, metformin, and TAS groups. Stool, serum, colon, and liver samples were collected after 8 weeks of drug administration for relevant analyses. Results TAS reduced fasting blood glucose, 2-hour postprandial blood glucose, area under the curve of oral glucose tolerance test, glycated serum protein, homeostasis model assessment of insulin resistance, total cholesterol, triglyceride, and low-density lipoprotein cholesterol levels in T2DM rats but increased insulin, C-peptide, and high-density lipoprotein cholesterol levels. Moreover, TAS improved the morphology and structure of liver and colon tissues and improved the composition of the intestinal microbiome and bacterial community structure at different taxonomic levels. In addition, TAS increased the protein expression of hepatic IRS-1, PI3K, PDK1, and p-AKT and decreased the protein expression of p-GSK-3β. Meanwhile, TAS increased the mRNA expression of liver PDK1, PI3K, and GS and decreased the mRNA expression of GSK-3β. Conclusion TAS can ameliorate T2DM-related abnormal glucose and blood lipid metabolism, intestinal dysbiosis, and IR.
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Affiliation(s)
- Leilei Ma
- School of Public Health, North China University of Science and Technology, Tangshan, China
- He Bei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Xiaojin La
- He Bei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Biwei Zhang
- School of Public Health, North China University of Science and Technology, Tangshan, China
- He Bei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Wenxuan Xu
- He Bei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Chunyu Tian
- He Bei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Qianru Fu
- He Bei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Meng Wang
- He Bei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Chenxi Wu
- He Bei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Zhen Chen
- Oriental Herbs Korlatolt felelossegu tarsasag, Budapest, Hungary
| | - Hong Chang
- He Bei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
| | - Ji-an Li
- School of Public Health, North China University of Science and Technology, Tangshan, China
- He Bei Key Laboratory of Integrated Traditional Chinese and Western Medicine for Diabetes and Its Complications, College of Traditional Chinese Medicine, North China University of Science and Technology, Tangshan, China
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16
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Mathrani A, Lu LW, Sequeira-Bisson IR, Silvestre MP, Hoggard M, Barnett D, Fogelholm M, Raben A, Poppitt SD, Taylor MW. Gut microbiota profiles in two New Zealand cohorts with overweight and prediabetes: a Tū Ora/PREVIEW comparative study. Front Microbiol 2023; 14:1244179. [PMID: 38033566 PMCID: PMC10687470 DOI: 10.3389/fmicb.2023.1244179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 10/20/2023] [Indexed: 12/02/2023] Open
Abstract
Obesity-related metabolic diseases such as type 2 diabetes (T2D) are major global health issues, affecting hundreds of millions of people worldwide. The underlying factors are both diverse and complex, incorporating biological as well as cultural considerations. A role for ethnicity - a measure of self-perceived cultural affiliation which encompasses diet, lifestyle and genetic components - in susceptibility to metabolic diseases such as T2D is well established. For example, Asian populations may be disproportionally affected by the adverse 'TOFI' (Thin on the Outside, Fat on the Inside) profile, whereby outwardly lean individuals have increased susceptibility due to excess visceral and ectopic organ fat deposition. A potential link between the gut microbiota and metabolic disease has more recently come under consideration, yet our understanding of the interplay between ethnicity, the microbiota and T2D remains incomplete. We present here a 16S rRNA gene-based comparison of the fecal microbiota of European-ancestry and Chinese-ancestry cohorts with overweight and prediabetes, residing in New Zealand. The cohorts were matched for mean fasting plasma glucose (FPG: mean ± SD, European-ancestry: 6.1 ± 0.4; Chinese-ancestry: 6.0 ± 0.4 mmol/L), a consequence of which was a significantly higher mean body mass index in the European group (BMI: European-ancestry: 37.4 ± 6.8; Chinese-ancestry: 27.7 ± 4.0 kg/m2; p < 0.001). Our findings reveal significant microbiota differences between the two ethnicities, though we cannot determine the underpinning factors. In both cohorts Firmicutes was by far the dominant bacterial phylum (European-ancestry: 93.4 ± 5.5%; Chinese-ancestry: 79.6 ± 10.4% of 16S rRNA gene sequences), with Bacteroidetes and Actinobacteria the next most abundant. Among the more abundant (≥1% overall relative sequence abundance) genus-level taxa, four zero-radius operational taxonomic units (zOTUs) were significantly higher in the European-ancestry cohort, namely members of the Subdoligranulum, Blautia, Ruminoclostridium, and Dorea genera. Differential abundance analysis further identified a number of additional zOTUs to be disproportionately overrepresented across the two ethnicities, with the majority of taxa exhibiting a higher abundance in the Chinese-ancestry cohort. Our findings underscore a potential influence of ethnicity on gut microbiota composition in the context of individuals with overweight and prediabetes.
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Affiliation(s)
- Akarsh Mathrani
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
| | - Louise W. Lu
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
- Human Nutrition Unit, University of Auckland, Auckland, New Zealand
| | - Ivana R. Sequeira-Bisson
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
- Human Nutrition Unit, University of Auckland, Auckland, New Zealand
| | - Marta P. Silvestre
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
- Human Nutrition Unit, University of Auckland, Auckland, New Zealand
- Centro de Investigação em Tecnologias e Serviços de Saúde (CINTESIS), NOVA University of Lisbon, Lisbon, Portugal
| | - Michael Hoggard
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
| | - Daniel Barnett
- Department of Statistics, University of Auckland, Auckland, New Zealand
| | - Mikael Fogelholm
- Department of Food and Nutrition, Faculty of Agriculture and Forestry, University of Helsinki, Helsinki, Finland
| | - Anne Raben
- Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Copenhagen University Hospital – Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Sally D. Poppitt
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
- Human Nutrition Unit, University of Auckland, Auckland, New Zealand
- Department of Medicine, University of Auckland, Auckland, New Zealand
| | - Michael W. Taylor
- School of Biological Sciences, University of Auckland, Auckland, New Zealand
- High-Value Nutrition National Science Challenge, Auckland, New Zealand
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17
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Pavlo Petakh, Kamyshna I, Kamyshnyi A. Effects of metformin on the gut microbiota: A systematic review. Mol Metab 2023; 77:101805. [PMID: 37696355 PMCID: PMC10518565 DOI: 10.1016/j.molmet.2023.101805] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 09/04/2023] [Accepted: 09/07/2023] [Indexed: 09/13/2023] Open
Abstract
BACKGROUND The gut microbiota is increasingly recognized as a crucial factor in human health and disease. Metformin, a commonly prescribed medication for type 2 diabetes, has been studied for its potential impact on the gut microbiota in preclinical models. However, the effects of metformin on the gut microbiota in humans remain uncertain. SCOPE OF REVIEW We conducted a systematic review of clinical trials and observational studies to assess the existing knowledge on the impact of metformin on the gut microbiota in humans. The review focused on changes in bacterial composition and diversity following metformin treatment. MAJOR CONCLUSIONS Thirteen studies were included in the analysis. The results revealed alterations in the abundance of bacterial genera from various phyla, suggesting that metformin may selectively influence certain groups of bacteria in the gut microbiota. However, the effects on gut microbiota diversity were inconsistent across populations, with conflicting findings on changes in alpha and beta diversity measures. Overall, the use of metformin was associated with changes in the abundance of specific bacterial genera within the gut microbiota of human populations. However, the effects on gut microbiota diversity were not consistent, highlighting the need for further research to understand the underlying mechanisms and clinical significance of these changes.
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Affiliation(s)
- Pavlo Petakh
- Department of Biochemistry and Pharmacology, Uzhhorod National University, Uzhhorod, Ukraine; Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine.
| | - Iryna Kamyshna
- Department of Medical Rehabilitation, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Aleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine.
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18
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Yan P, Ma H, Tian W, Liu J, Yan X, Ma L, Wei S, Zhu J, Zhu Y, Lai J. Methadone maintenance treatment is more effective than compulsory detoxification in addressing gut microbiota dysbiosis caused by heroin abuse. Front Microbiol 2023; 14:1283276. [PMID: 37954240 PMCID: PMC10635210 DOI: 10.3389/fmicb.2023.1283276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 10/09/2023] [Indexed: 11/14/2023] Open
Abstract
Introduction Heroin use disorder (HUD) is commonly accompanied by gut dysbiosis, but the roles of gut microbiota in HUD treatment, such as compulsory detoxification and methadone maintenance treatment (MMT), remain poorly understood. Methods In this study, we performed 16 s rDNA and whole metagenome sequencing to analyze the gut microbial profiles of HUD patients undergoing heroin addiction, heroin withdrawal (compulsory detoxification), and MMT. Results Our findings revealed that, compared to healthy controls, microbial diversity was significantly decreased in HUD patients who were in a state of heroin addiction and withdrawal, but not in those receiving MMT. We observed significant alterations in 10 bacterial phyla and 20 bacterial families in HUD patients, while MMT partially restored these changes. Whole metagenome sequencing indicated gut microbiota functions were significantly disrupted in HUD patients experiencing heroin addiction and withdrawal, but MMT was found to almost reverse these dysfunctions. In addition, we identified 24 featured bacteria at the genus level that could be used to effectively distinguish between healthy individuals and those with heroin addiction, heroin withdrawal, or receiving MMT. Furthermore, we found the relative abundance of Actinomyces, Turicibacter and Weissella were positively associated with the Hamilton Depression Scale score in different states of HUD patients. Discussion This study provides evidence from the gut microbiota perspective that MMT is a more effective approach than compulsory detoxification for HUD treatment.
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Affiliation(s)
- Peng Yan
- NHC Key Laboratory of Forensic Science, College of Forensic Science, Xi’an Jiaotong University, Xi’an, China
- National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China
| | - Haotian Ma
- NHC Key Laboratory of Forensic Science, College of Forensic Science, Xi’an Jiaotong University, Xi’an, China
- National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China
| | - Wenrong Tian
- NHC Key Laboratory of Forensic Science, College of Forensic Science, Xi’an Jiaotong University, Xi’an, China
- National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China
| | - Jincen Liu
- NHC Key Laboratory of Forensic Science, College of Forensic Science, Xi’an Jiaotong University, Xi’an, China
- National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China
| | - Xinyue Yan
- NHC Key Laboratory of Forensic Science, College of Forensic Science, Xi’an Jiaotong University, Xi’an, China
- National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China
| | - Lei Ma
- NHC Key Laboratory of Forensic Science, College of Forensic Science, Xi’an Jiaotong University, Xi’an, China
- National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China
| | - Shuguang Wei
- NHC Key Laboratory of Forensic Science, College of Forensic Science, Xi’an Jiaotong University, Xi’an, China
- National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China
| | - Jie Zhu
- NHC Key Laboratory of Forensic Science, College of Forensic Science, Xi’an Jiaotong University, Xi’an, China
- National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China
| | - Yongsheng Zhu
- NHC Key Laboratory of Forensic Science, College of Forensic Science, Xi’an Jiaotong University, Xi’an, China
- National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China
| | - Jianghua Lai
- NHC Key Laboratory of Forensic Science, College of Forensic Science, Xi’an Jiaotong University, Xi’an, China
- National Biosafety Evidence Foundation, Bio-evidence Sciences Academy, Western China Science and Technology Innovation Harbor, Xi'an Jiaotong University, Xi'an, China
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19
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Petakh P, Kamyshna I, Kamyshnyi A. Unveiling the potential pleiotropic effects of metformin in treating COVID-19: a comprehensive review. Front Mol Biosci 2023; 10:1260633. [PMID: 37881440 PMCID: PMC10595158 DOI: 10.3389/fmolb.2023.1260633] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 09/28/2023] [Indexed: 10/27/2023] Open
Abstract
This review article explores the potential of metformin, a medication commonly used for type 2 diabetes, as an antiviral and anti-inflammatory agent in the context of coronavirus disease 2019 (COVID-19). Metformin has demonstrated inhibitory effects on the growth of SARS-CoV-2 in cell culture models and has shown promising results in reducing viral load and achieving undetectable viral levels in clinical trials. Additionally, metformin exhibits anti-inflammatory properties by reducing the production of pro-inflammatory cytokines and modulating immune cell function, which may help prevent cytokine storms associated with severe COVID-19. The drug's ability to regulate the balance between pro-inflammatory Th17 cells and anti-inflammatory Treg cells suggests its potential in mitigating inflammation and restoring T cell functionality. Furthermore, metformin's modulation of the gut microbiota, particularly changes in bacterial taxa and the production of short-chain fatty acids, may contribute to its therapeutic effects. The interplay between metformin, bile acids, the gut microbiome, glucagon-like peptide-1 secretion, and glycemic control has implications for the management of diabetes and potential interventions in COVID-19. By refreshing the current evidence, this review highlights the potential of metformin as a therapeutic option in the management of COVID-19, while also exploring its effects on the gut microbiome and immunometabolism.
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Affiliation(s)
- Pavlo Petakh
- Department of Biochemistry and Pharmacology, Uzhhorod National University, Uzhhorod, Ukraine
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Iryna Kamyshna
- Department of Medical Rehabilitation, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
| | - Aleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, Ternopil, Ukraine
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20
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Muchhala K, Kang M, Koseli E, Poklis J, Xu Q, Dewey W, Fettweis J, Jimenez N, Akbarali H. The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis.. [PMID: 37503065 PMCID: PMC10371156 DOI: 10.21203/rs.3.rs-3084467/v2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/04/2024]
Abstract
Abstract
Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupt the intestinal epithelial layer and cause intestinal dysbiosis. Inhibiting opioid-induced dysbiosis can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. However, the mechanism underlying opioid-induced dysbiosis remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine exposure reduces expression of the antimicrobial peptide, Regenerating islet-derived 3 gamma (Reg3γ), in the ileum resulting in reduced intestinal antimicrobial activity against Gram-positive bacteria, L. reuteri. Fecal samples from morphine-treated mice had reduced levels of the phylum, Firmicutes, concomitant with reduced levels of short-chain fatty acid, butyrate. Fecal microbial transplant (FMT) from morphine-naïve mice restored the antimicrobial activity, the expression of Reg3γ, and prevented the increase in intestinal permeability and the development of antinociceptive tolerance in morphine-dependent mice. Similarly, oral gavage with sodium butyrate dose-dependently reduced the development of antinociceptive tolerance, and prevented the downregulation of Reg3γ and the reduction in antimicrobial activity. The alpha diversity of the microbiome was also restored by oral butyrate in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which morphine disrupts the microbiota-gut-brain axis.
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21
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Muchhala K, Kang M, Koseli E, Poklis J, Xu Q, Dewey W, Fettweis J, Jimenez N, Akbarali H. The Role of Morphine-Induced Impairment of Intestinal Epithelial Antibacterial Activity in Dysbiosis and its Impact on the Microbiota-Gut-Brain Axis. RESEARCH SQUARE 2023:rs.3.rs-3084467. [PMID: 37503065 PMCID: PMC10371156 DOI: 10.21203/rs.3.rs-3084467/v1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/29/2023]
Abstract
Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupt the intestinal epithelial layer and cause intestinal dysbiosis. Inhibiting opioid-induced dysbiosis can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. However, the mechanism underlying opioid-induced dysbiosis remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine exposure reduces expression of the antimicrobial peptide, Regenerating islet-derived 3 gamma (Reg3γ), in the ileum resulting in reduced intestinal antimicrobial activity against Gram-positive bacteria, L. reuteri. Fecal samples from morphine-treated mice had reduced levels of the phylum, Firmicutes, concomitant with reduced levels of short-chain fatty acid, butyrate. Fecal microbial transplant (FMT) from morphine-naïve mice restored the antimicrobial activity, the expression of Reg3γ, and prevented the increase in intestinal permeability and the development of antinociceptive tolerance in morphine-dependent mice. Similarly, oral gavage with sodium butyrate dose-dependently reduced the development of antinociceptive tolerance, and prevented the downregulation of Reg3γ and the reduction in antimicrobial activity. The alpha diversity of the microbiome was also restored by oral butyrate in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which morphine disrupts the microbiota-gut-brain axis.
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22
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Mathrani A, Yip W, Sequeira-Bisson IR, Barnett D, Stevenson O, Taylor MW, Poppitt SD. Effect of a 12-Week Polyphenol Rutin Intervention on Markers of Pancreatic β-Cell Function and Gut Microbiota in Adults with Overweight without Diabetes. Nutrients 2023; 15:3360. [PMID: 37571297 PMCID: PMC10420824 DOI: 10.3390/nu15153360] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2023] [Revised: 07/18/2023] [Accepted: 07/21/2023] [Indexed: 08/13/2023] Open
Abstract
Supplementation with prebiotic polyphenol rutin is a potential dietary therapy for type 2 diabetes prevention in adults with obesity, based on previous glycaemic improvement in transgenic mouse models. Gut microbiota are hypothesised to underpin these effects. We investigated the effect of rutin supplementation on pancreatic β-cell function measured as C-peptide/glucose ratio, and 16S rRNA gene-based gut microbiota profiles, in a cohort of individuals with overweight plus normoglycaemia or prediabetes. Eighty-seven participants were enrolled, aged 18-65 years with BMI of 23-35 kg/m2. This was a 12-week double-blind randomised controlled trial (RCT), with 3 treatments comprising (i) placebo control, (ii) 500 mg/day encapsulated rutin, and (iii) 500 mg/day rutin-supplemented yoghurt. A 2-h oral glucose tolerance test (OGTT) was performed at baseline and at the end of the trial, with faecal samples also collected. Compliance with treatment was high (~90%), but rutin in both capsule and dietary format did not alter pancreatic β-cell response to OGTT over 12 weeks. Gut bacterial community composition also did not significantly change, with Firmicutes dominating irrespective of treatment. Fasting plasma glucose negatively correlated with the abundance of the butyrate producer Roseburia inulinivorans, known for its anti-inflammatory capacity. This is the first RCT to investigate postprandial pancreatic β-cell function in response to rutin supplementation.
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Affiliation(s)
- Akarsh Mathrani
- School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand; (A.M.); (W.Y.); (I.R.S.-B.)
- High-Value Nutrition National Science Challenge, Auckland 1010, New Zealand
| | - Wilson Yip
- School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand; (A.M.); (W.Y.); (I.R.S.-B.)
- High-Value Nutrition National Science Challenge, Auckland 1010, New Zealand
- Human Nutrition Unit, University of Auckland, Auckland 1024, New Zealand
| | - Ivana R. Sequeira-Bisson
- School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand; (A.M.); (W.Y.); (I.R.S.-B.)
- High-Value Nutrition National Science Challenge, Auckland 1010, New Zealand
- Human Nutrition Unit, University of Auckland, Auckland 1024, New Zealand
| | - Daniel Barnett
- Department of Statistics, University of Auckland, Auckland 1010, New Zealand; (D.B.); (O.S.)
| | - Oliver Stevenson
- Department of Statistics, University of Auckland, Auckland 1010, New Zealand; (D.B.); (O.S.)
| | - Michael W. Taylor
- School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand; (A.M.); (W.Y.); (I.R.S.-B.)
- High-Value Nutrition National Science Challenge, Auckland 1010, New Zealand
| | - Sally D. Poppitt
- School of Biological Sciences, University of Auckland, Auckland 1010, New Zealand; (A.M.); (W.Y.); (I.R.S.-B.)
- High-Value Nutrition National Science Challenge, Auckland 1010, New Zealand
- Human Nutrition Unit, University of Auckland, Auckland 1024, New Zealand
- Department of Medicine, University of Auckland, Auckland 1010, New Zealand
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23
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Satish S, Abu Y, Gomez D, Kumar Dutta R, Roy S. HIV, opioid use, and alterations to the gut microbiome: elucidating independent and synergistic effects. Front Immunol 2023; 14:1156862. [PMID: 37168868 PMCID: PMC10164749 DOI: 10.3389/fimmu.2023.1156862] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 03/22/2023] [Indexed: 05/13/2023] Open
Abstract
Background The microbiome is essential to immune development, defense against pathogens, and modulation of inflammation. Microbial dysbiosis has been reported in various diseases including human immunodeficiency virus (HIV) and opioid use disorder (OUD). Notably, people living with HIV (PLWH) have been reported to both have higher rates of OUD and use opioids at higher rates than the general public. Thus, studying gut microbial alterations in people living with HIV and with OUD could elucidate mechanisms pertaining to how these conditions both shape and are shaped by the microbiome. However, to date few studies have investigated how HIV and OUD in combination impact the microbiome. Aim of review Here, we review previous studies outlining interactions between HIV, opioid use, and microbial dysbiosis and describe attempts to treat this dysbiosis with fecal microbial transplantation, probiotics, and dietary changes. Key scientific concepts of review While the limited number of studies prevent overgeneralizations; accumulating data suggest that HIV and opioid use together induce distinct alterations in the gut microbiome. Among the three existing preclinical studies of HIV and opioid use, two studies reported a decrease in Lachnospiraceae and Ruminococcaceae, and one study reported a decrease in Muribaculaceae in the combined HIV and opioid group relative to HIV-alone, opioid-alone, or control groups. These bacteria are known to modulate immune function, decrease colonic inflammation, and maintain gut epithelial barrier integrity in healthy individuals. Accordingly, modulation of the gut microbiome to restore gut homeostasis may be attempted to improve both conditions. While mixed results exist regarding treating dysbiosis with microbial restoration in PLWH or in those with opioid dependency, larger well-defined studies that can improve microbial engraftment in hosts hold much promise and should still be explored.
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Affiliation(s)
- Sanjana Satish
- Department of Medical Education, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Yaa Abu
- Department of Medical Education, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Daniel Gomez
- Department of Medical Education, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Rajib Kumar Dutta
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Sabita Roy
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
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24
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Lin Y, Xu Z, Yeoh YK, Tun HM, Huang W, Jiang W, Chan FKL, Ng SC. Combing fecal microbial community data to identify consistent obesity-specific microbial signatures and shared metabolic pathways. iScience 2023; 26:106476. [PMID: 37096041 PMCID: PMC10122048 DOI: 10.1016/j.isci.2023.106476] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 01/14/2023] [Accepted: 03/20/2023] [Indexed: 03/31/2023] Open
Abstract
Obesity is associated with altered gut microbiome composition but data across different populations remain inconsistent. We meta-analyzed publicly available 16S-rRNA sequence datasets from 18 different studies and identified differentially abundant taxa and functional pathways of the obese gut microbiome. Most differentially abundant genera (Odoribacter, Oscillospira, Akkermansia, Alistipes, and Bacteroides) were depleted in obesity, indicating a deficiency of commensal microbes in the obese gut microbiome. From microbiome functional pathways, elevated lipid biosynthesis and depleted carbohydrate and protein degradation suggested metabolic adaptation to high-fat, low-carbohydrate, and low-protein diets in obese individuals. Machine learning models trained on the 18 studies were modest in predicting obesity with a median AUC of 0.608 using 10-fold cross-validation. The median AUC increased to 0.771 when models were trained in eight studies designed for investigating obesity-microbiome association. By meta-analyzing obesity-associated microbiota signatures, we identified obesity-associated depleted taxa that may be exploited to mitigate obesity and related metabolic diseases.
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Affiliation(s)
- Yu Lin
- Microbiota I-Center (MagIC), Hong Kong SAR, China
- Center for Gut Microbiota Research, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Zhilu Xu
- Microbiota I-Center (MagIC), Hong Kong SAR, China
- Center for Gut Microbiota Research, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yun Kit Yeoh
- Microbiota I-Center (MagIC), Hong Kong SAR, China
- Center for Gut Microbiota Research, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Microbiology, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hein Min Tun
- Microbiota I-Center (MagIC), Hong Kong SAR, China
- Jockey Club School of Public Health and Primary Care, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wenli Huang
- Microbiota I-Center (MagIC), Hong Kong SAR, China
- Center for Gut Microbiota Research, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wei Jiang
- Microbiota I-Center (MagIC), Hong Kong SAR, China
- Center for Gut Microbiota Research, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Francis Ka Leung Chan
- Microbiota I-Center (MagIC), Hong Kong SAR, China
- Center for Gut Microbiota Research, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
| | - Siew Chien Ng
- Microbiota I-Center (MagIC), Hong Kong SAR, China
- Center for Gut Microbiota Research, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Hong Kong SAR, China
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25
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McLeod A, Wolf P, Chapkin RS, Davidson LA, Ivanov I, Berbaum M, Williams LR, Gaskins HR, Ridlon J, Sanchez-Flack J, Blumstein L, Schiffer L, Hamm A, Cares K, Antonic M, Bernabe BP, Fitzgibbon M, Tussing-Humphreys L. Design of the Building Research in CRC prevention (BRIDGE-CRC) trial: a 6-month, parallel group Mediterranean diet and weight loss randomized controlled lifestyle intervention targeting the bile acid-gut microbiome axis to reduce colorectal cancer risk among African American/Black adults with obesity. Trials 2023; 24:113. [PMID: 36793105 PMCID: PMC9930092 DOI: 10.1186/s13063-023-07115-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 01/23/2023] [Indexed: 02/17/2023] Open
Abstract
BACKGROUND Among all racial/ethnic groups, people who identify as African American/Blacks have the second highest colorectal cancer (CRC) incidence in the USA. This disparity may exist because African American/Blacks, compared to other racial/ethnic groups, have a higher prevalence of risk factors for CRC, including obesity, low fiber consumption, and higher intakes of fat and animal protein. One unexplored, underlying mechanism of this relationship is the bile acid-gut microbiome axis. High saturated fat, low fiber diets, and obesity lead to increases in tumor promoting secondary bile acids. Diets high in fiber, such as a Mediterranean diet, and intentional weight loss may reduce CRC risk by modulating the bile acid-gut microbiome axis. The purpose of this study is to test the impact of a Mediterranean diet alone, weight loss alone, or both, compared to typical diet controls on the bile acid-gut microbiome axis and CRC risk factors among African American/Blacks with obesity. Because weight loss or a Mediterranean diet alone can reduce CRC risk, we hypothesize that weight loss plus a Mediterranean diet will reduce CRC risk the most. METHODS This randomized controlled lifestyle intervention will randomize 192 African American/Blacks with obesity, aged 45-75 years to one of four arms: Mediterranean diet, weight loss, weight loss plus Mediterranean diet, or typical diet controls, for 6 months (48 per arm). Data will be collected at baseline, mid-study, and study end. Primary outcomes include total circulating and fecal bile acids, taurine-conjugated bile acids, and deoxycholic acid. Secondary outcomes include body weight, body composition, dietary change, physical activity, metabolic risk, circulating cytokines, gut microbial community structure and composition, fecal short-chain fatty acids, and expression levels of genes from exfoliated intestinal cells linked to carcinogenesis. DISCUSSION This study will be the first randomized controlled trial to examine the effects of a Mediterranean diet, weight loss, or both on bile acid metabolism, the gut microbiome, and intestinal epithelial genes associated with carcinogenesis. This approach to CRC risk reduction may be especially important among African American/Blacks given their higher risk factor profile and increased CRC incidence. TRIAL REGISTRATION ClinicalTrials.gov NCT04753359 . Registered on 15 February 2021.
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Affiliation(s)
- Andrew McLeod
- grid.185648.60000 0001 2175 0319Institute for Health Research and Policy, University of Illinois Chicago (UIC), Chicago, IL USA
| | - Patricia Wolf
- grid.169077.e0000 0004 1937 2197Department of Nutrition Science, Purdue University, West Lafayette, IN USA
| | - Robert S. Chapkin
- grid.264756.40000 0004 4687 2082Department of Nutrition, Program in Integrative Nutrition & Complex Diseases, and Center for Environmental Health Research, Texas A&M University, College Station, TX USA
| | - Laurie A. Davidson
- grid.264756.40000 0004 4687 2082Department of Nutrition, Program in Integrative Nutrition & Complex Diseases, and Center for Environmental Health Research, Texas A&M University, College Station, TX USA
| | - Ivan Ivanov
- grid.264756.40000 0004 4687 2082Department of Nutrition, Program in Integrative Nutrition & Complex Diseases, and Center for Environmental Health Research, Texas A&M University, College Station, TX USA ,grid.264756.40000 0004 4687 2082Department of Veterinary Physiology & Pharmacology, and Center for Environmental Health Research, Texas A&M University, College Station, TX USA
| | - Michael Berbaum
- grid.185648.60000 0001 2175 0319Institute for Health Research and Policy, University of Illinois Chicago (UIC), Chicago, IL USA
| | - Lauren R. Williams
- grid.185648.60000 0001 2175 0319Mile Square Health Center, University of Illinois Chicago, Chicago, IL USA
| | - H. Rex Gaskins
- grid.35403.310000 0004 1936 9991Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL USA ,grid.35403.310000 0004 1936 9991Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL USA ,grid.35403.310000 0004 1936 9991Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL USA ,grid.35403.310000 0004 1936 9991Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL USA ,grid.35403.310000 0004 1936 9991Department of Biomedical and Translational Sciences, University of Illinois Urbana-Champaign, Urbana, IL USA ,grid.35403.310000 0004 1936 9991Department of Pathobiology, University of Illinois Urbana-Champaign, Urbana, IL USA
| | - Jason Ridlon
- grid.35403.310000 0004 1936 9991Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL USA ,grid.35403.310000 0004 1936 9991Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL USA ,grid.35403.310000 0004 1936 9991Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL USA ,grid.35403.310000 0004 1936 9991Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL USA
| | - Jen Sanchez-Flack
- grid.185648.60000 0001 2175 0319Institute for Health Research and Policy, University of Illinois Chicago (UIC), Chicago, IL USA ,grid.185648.60000 0001 2175 0319Department of Pediatrics, University of Illinois Chicago, Chicago, IL USA ,grid.185648.60000 0001 2175 0319University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL USA
| | - Lara Blumstein
- grid.185648.60000 0001 2175 0319Institute for Health Research and Policy, University of Illinois Chicago (UIC), Chicago, IL USA
| | - Linda Schiffer
- grid.185648.60000 0001 2175 0319Institute for Health Research and Policy, University of Illinois Chicago (UIC), Chicago, IL USA
| | - Alyshia Hamm
- grid.185648.60000 0001 2175 0319Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL USA
| | - Kate Cares
- grid.185648.60000 0001 2175 0319Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL USA
| | - Mirjana Antonic
- grid.185648.60000 0001 2175 0319Institute for Health Research and Policy, University of Illinois Chicago (UIC), Chicago, IL USA
| | - Beatriz Penalver Bernabe
- grid.185648.60000 0001 2175 0319Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL USA
| | - Marian Fitzgibbon
- Institute for Health Research and Policy, University of Illinois Chicago (UIC), Chicago, IL, USA. .,Department of Pediatrics, University of Illinois Chicago, Chicago, IL, USA. .,University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, USA.
| | - Lisa Tussing-Humphreys
- Institute for Health Research and Policy, University of Illinois Chicago (UIC), Chicago, IL, USA. .,University of Illinois Cancer Center, University of Illinois Chicago, Chicago, IL, USA. .,Department of Kinesiology and Nutrition, University of Illinois Chicago, Chicago, IL, USA.
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26
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Zádori ZS, Király K, Al-Khrasani M, Gyires K. Interactions between NSAIDs, opioids and the gut microbiota - Future perspectives in the management of inflammation and pain. Pharmacol Ther 2023; 241:108327. [PMID: 36473615 DOI: 10.1016/j.pharmthera.2022.108327] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022]
Abstract
The composition of intestinal microbiota is influenced by a number of factors, including medications, which may have a substantial impact on host physiology. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics are among those widely used medications that have been shown to alter microbiota composition in both animals and humans. Although much effort has been devoted to identify microbiota signatures associated with these medications, much less is known about the underlying mechanisms. Mucosal inflammation, changes in intestinal motility, luminal pH and bile acid metabolism, or direct drug-induced inhibitory effect on bacterial growth are all potential contributors to NSAID- and opioid-induced dysbiosis, however, only a few studies have addressed directly these issues. In addition, there is a notable overlap between the microbiota signatures of these drugs and certain diseases in which they are used, such as spondyloarthritis (SpA), rheumatoid arthritis (RA) and neuropathic pain associated with type 2 diabetes (T2D). The aims of the present review are threefold. First, we aim to provide a comprehensive up-to-date summary on the bacterial alterations caused by NSAIDs and opioids. Second, we critically review the available data on the possible underlying mechanisms of dysbiosis. Third, we review the current knowledge on gut dysbiosis associated with SpA, RA and neuropathic pain in T2D, and highlight the similarities between them and those caused by NSAIDs and opioids. We posit that drug-induced dysbiosis may contribute to the persistence of these diseases, and may potentially limit the therapeutic effect of these medications by long-term use. In this context, we will review the available literature data on the effect of probiotic supplementation and fecal microbiota transplantation on the therapeutic efficacy of NSAIDs and opioids in these diseases.
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Affiliation(s)
- Zoltán S Zádori
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.
| | - Kornél Király
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Mahmoud Al-Khrasani
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
| | - Klára Gyires
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary
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27
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Lin L, Lin J, Qiu J, Wei F, Bai X, Ma W, Zeng J, Lin D. Gut microbiota alterations may increase the risk of prescription opioid use, but not vice versa: A two-sample bi-directional Mendelian randomization study. Front Microbiol 2022; 13:994170. [PMID: 36483210 PMCID: PMC9722965 DOI: 10.3389/fmicb.2022.994170] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 11/01/2022] [Indexed: 11/23/2022] Open
Abstract
INTRODUCTION Gut microbiota alterations are strongly associated with prescription opioid use (POU) and multisite chronic pain (MCP). However, whether or not these associations are causal remains unknown. Therefore, we aim to explore the causal relationships between them comprehensively. METHODS A two-sample bi-directional Mendelian randomization was conducted to assess the potential associations between gut microbiota and POU/MCP using summary level Genome-wide association studies (GWASs) that were based on predominantly European ancestry. RESULTS Potential causal effects were identified between seven host genetic-driven traits of gut microbiota on POU, including Adlercreutzia, Allisonella, Dialister, Anaerofilum, Anaerostipes, ChristensenellaceaeR.7group, and LachnospiraceaeNC2004group at the genus level (p < 0.05) by the Inverse-variance weighted method, with significant causal effects of ChristensenellaceaeR.7group and Allisonella on POU (p < 0.025). A total of five genetically greater abundance of gut microbiota traits were identified to be possibly related to the level of MCP (p < 0.05), including genus ErysipelotrichaceaeUCG003, family Clostridiaceae1, order Gastranaerophilales, order Actinomycetales, and family Actinomycetaceae. In the other direction, no clear evidence was found to support a significant causal relationship between POU and gut microbiota, as well as MCP and gut microbiota. In addition, evidence was also provided for the relationship between triacylglycerols and diacylglycerol elevation, and an increased risk of POU and MCP. No evidence was found across various sensitivity analyses, including reverse causality, pleiotropy, and heterogeneity. CONCLUSION The findings from this study provide robust evidence that gut microbiota alterations may be a risk of POU/MCP, but not vice versa.
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Affiliation(s)
- Liling Lin
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianwei Lin
- Big Data Laboratory, Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, Guangdong, China
| | - Junxiong Qiu
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Feng Wei
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaohui Bai
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weiying Ma
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jingxian Zeng
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Daowei Lin
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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Lin L, Lin J, Qiu J, Wei F, Bai X, Ma W, Zeng J, Lin D. Gut microbiota alterations may increase the risk of prescription opioid use, but not vice versa: A two-sample bi-directional Mendelian randomization study. Front Microbiol 2022; 13:994170. [PMID: 36483210 DOI: 10.3389/fmicb.2022.994170.pmid:] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 11/01/2022] [Indexed: 10/04/2024] Open
Abstract
INTRODUCTION Gut microbiota alterations are strongly associated with prescription opioid use (POU) and multisite chronic pain (MCP). However, whether or not these associations are causal remains unknown. Therefore, we aim to explore the causal relationships between them comprehensively. METHODS A two-sample bi-directional Mendelian randomization was conducted to assess the potential associations between gut microbiota and POU/MCP using summary level Genome-wide association studies (GWASs) that were based on predominantly European ancestry. RESULTS Potential causal effects were identified between seven host genetic-driven traits of gut microbiota on POU, including Adlercreutzia, Allisonella, Dialister, Anaerofilum, Anaerostipes, ChristensenellaceaeR.7group, and LachnospiraceaeNC2004group at the genus level (p < 0.05) by the Inverse-variance weighted method, with significant causal effects of ChristensenellaceaeR.7group and Allisonella on POU (p < 0.025). A total of five genetically greater abundance of gut microbiota traits were identified to be possibly related to the level of MCP (p < 0.05), including genus ErysipelotrichaceaeUCG003, family Clostridiaceae1, order Gastranaerophilales, order Actinomycetales, and family Actinomycetaceae. In the other direction, no clear evidence was found to support a significant causal relationship between POU and gut microbiota, as well as MCP and gut microbiota. In addition, evidence was also provided for the relationship between triacylglycerols and diacylglycerol elevation, and an increased risk of POU and MCP. No evidence was found across various sensitivity analyses, including reverse causality, pleiotropy, and heterogeneity. CONCLUSION The findings from this study provide robust evidence that gut microbiota alterations may be a risk of POU/MCP, but not vice versa.
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Affiliation(s)
- Liling Lin
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jianwei Lin
- Big Data Laboratory, Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, Guangdong, China
| | - Junxiong Qiu
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Feng Wei
- Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaohui Bai
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Weiying Ma
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jingxian Zeng
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Daowei Lin
- Department of Anesthesiology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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Wang N, Chen L, Yi K, Zhang B, Li C, Zhou X. The effects of microbiota on reproductive health: A review. Crit Rev Food Sci Nutr 2022; 64:1486-1507. [PMID: 36066460 DOI: 10.1080/10408398.2022.2117784] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Reproductive issues are becoming an increasing global problem. There is increasing interest in the relationship between microbiota and reproductive health. Stable microbiota communities exist in the gut, reproductive tract, uterus, testes, and semen. Various effects (e.g., epigenetic modifications, nervous system, metabolism) of dysbiosis in the microbiota can impair gamete quality; interfere with zygote formation, embryo implantation, and embryo development; and increase disease susceptibility, thus adversely impacting reproductive capacity and pregnancy. The maintenance of a healthy microbiota can protect the host from pathogens, increase reproductive potential, and reduce the rates of adverse pregnancy outcomes. In conclusion, this review discusses microbiota in the male and female reproductive systems of multiple animal species. It explores the effects and mechanisms of microbiota on reproduction, factors that influence microbiota composition, and applications of microbiota in reproductive disorder treatment and detection. The findings support novel approaches for managing reproductive diseases through microbiota improvement and monitoring. In addition, it will stimulate further systematic explorations of microbiota-mediated effects on reproduction.
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Affiliation(s)
- Nan Wang
- College of Animal Sciences, Jilin University, Changchun, China
| | - Lu Chen
- College of Animal Sciences, Jilin University, Changchun, China
| | - Kangle Yi
- Hunan Institute of Animal and Veterinary Science, Changsha, China
| | - Baizhong Zhang
- Hunan Institute of Animal and Veterinary Science, Changsha, China
| | - Chunjin Li
- College of Animal Sciences, Jilin University, Changchun, China
| | - Xu Zhou
- College of Animal Sciences, Jilin University, Changchun, China
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Substance use, microbiome and psychiatric disorders. Pharmacol Biochem Behav 2022; 219:173432. [PMID: 35905802 DOI: 10.1016/j.pbb.2022.173432] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 04/29/2022] [Accepted: 07/20/2022] [Indexed: 11/21/2022]
Abstract
Accumulating evidence from several studies has shown association between substance use, dysregulation of the microbiome and psychiatric disorders such as depression, anxiety, and psychosis. Many of the abused substances such as cocaine and alcohol have been shown to alter immune signaling pathways and cause inflammation in both the periphery and the central nervous system (CNS). In addition, these substances of abuse also alter the composition and function of the gut microbiome which is known to play important roles such as the synthesis of neurotransmitters and metabolites, that affect the CNS homeostasis and consequent behavioral outcomes. The emerging interactions between substance use, microbiome and CNS neurochemical alterations could contribute to the development of psychiatric disorders. This review provides an overview of the associative effects of substance use such as alcohol, cocaine, methamphetamine, nicotine and opioids on the gut microbiome and psychiatric disorders involving anxiety, depression and psychosis. Understanding the relationship between substance use, microbiome and psychiatric disorders will provide insights for potential therapeutic targets, aimed at mitigating these adverse outcomes.
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Long-Term Effects of Developmental Exposure to Oxycodone on Gut Microbiota and Relationship to Adult Behaviors and Metabolism. mSystems 2022; 7:e0033622. [PMID: 35862801 PMCID: PMC9426609 DOI: 10.1128/msystems.00336-22] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Opioid drugs are commonly prescribed analgesic to pregnant women. Direct exposure to such drugs may slow gut motility, alter gut permeability, and affect the gut microbiome. While such drugs affect gut microbiome in infants, no study to date has determined whether developmental exposure to such drugs results in longstanding effects on gut microbiota and correspondingly on host responses. We hypothesized developmental exposure to oxycodone (OXY) leads to enduring effects on gut microbiota and such changes are associated with adult neurobehavioral and metabolic changes. Female mice were treated daily with 5 mg OXY/kg or saline solution (control [CTL]) for 2 weeks prior to breeding and then throughout gestation. Male and female offspring pups were weaned, tested with a battery of behavioral and metabolic tests, and fecal boli were collected adulthood (120 days of age). In females, relative abundance of Butyricimonas spp., Bacteroidetes, Anaeroplasma spp., TM7, Enterococcus spp., and Clostridia were greater in OXY versus CTL individuals. In males, relative abundance of Coriobacteriaceae, Roseburia spp., Sutterella spp., and Clostridia were elevated in OXY exposed individuals. Bacterial changes were also associated with predictive metabolite pathway alterations that also varied according to sex. In males and females, affected gut microbiota correlated with metabolic but not behavioral alterations. The findings suggest that developmental exposure to OXY leads to lasting effects on adult gut microbiota that might affect host metabolism, possibly through specific bacterial metabolites or other bacterial-derived products. Further work is needed to characterize how developmental exposure to OXY affects host responses through the gut microbiome. IMPORTANCE This is the first work to show in a rodent model that in utero exposure to an opioid drug can lead to longstanding effects on the gut microbiota when examined at adulthood. Further, such bacterial changes are associated with metabolic host responses. Given the similarities between rodent and human microbiomes, it raises cause for concern that similar effects may become evident in children born to mothers taking oxycodone and other opioid drugs.
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McEachron KR, Nalluri H, Beilman GJ, Kirchner VA, Pruett TL, Freeman ML, Trikudanathan G, Staley C, Bellin MD. Decreased Intestinal Microbiota Diversity Is Associated With Increased Gastrointestinal Symptoms in Patients With Chronic Pancreatitis. Pancreas 2022; 51:649-656. [PMID: 36099525 PMCID: PMC9547966 DOI: 10.1097/mpa.0000000000002096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Chronic pancreatitis (CP) is characterized by abdominal pain, recurrent hospitalizations, frequent exposure to antibiotics, nutritional deficiencies, and chronic opioid use. Data describing the gut microbial community structure of patients with CP is limited. We aimed to compare gut microbiota of a group of patients with severe CP being considered for total pancreatectomy with islet autotransplantation (TPIAT) with those of healthy controls and to associate these differences with severity of clinical symptoms. METHODS We collected stool from healthy donors (n = 14) and patients with CP (n = 20) undergoing workup for TPIAT, in addition to clinical metadata and a validated abdominal symptoms severity survey. RESULTS Patients with CP had significantly lower alpha diversity than healthy controls ( P < 0.001). There was a significantly increased mean relative abundance of Faecalibacterium in healthy controls compared with patients with CP ( P = 0.02). Among participants with CP, those with lower alpha diversity reported worse functional abdominal symptoms ( P = 0.006). CONCLUSIONS These findings indicate that changes in gut microbial community structure may contribute to gastrointestinal symptoms and provide basis for future studies on whether enrichment of healthy commensal bacteria such as Faecalibacterium could provide clinically meaningful improvements in outcomes for CP patients undergoing TPIAT.
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Interrelations between Gut Microbiota Composition, Nutrient Intake and Diabetes Status in an Adult Japanese Population. J Clin Med 2022; 11:jcm11113216. [PMID: 35683603 PMCID: PMC9181032 DOI: 10.3390/jcm11113216] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 05/29/2022] [Accepted: 05/30/2022] [Indexed: 01/27/2023] Open
Abstract
Upon food digestion, the gut microbiota plays a pivotal role in energy metabolism, thus affecting the development of type 2 diabetes (DM). We aimed to examine the influence of the composition of selected nutrients consumed on the association between the gut microbiota and DM. This cross-sectional study of a general population was conducted on 1019 Japanese volunteers. Compared with non-diabetic subjects, diabetic subjects had larger proportions of the genera Bifidobacterium and Streptococcus but smaller proportions of the genera Roseburia and Blautia in their gut microbiotas. The genera Streptococcus and Roseburia were positively correlated with the amounts of energy (p = 0.027) and carbohydrate and fiber (p = 0.007 and p = 0.010, respectively) consumed, respectively. In contrast, the genera Bifidobacterium and Blautia were not correlated with any of the selected nutrients consumed. Cluster analyses of these four genera revealed that the Blautia-dominant cluster was most negatively associated with DM, whereas the Bifidobacterium-dominant cluster was positively associated with DM (vs. the Blautia-dominant cluster; odds ratio 3.97, 95% confidence interval 1.68-9.35). These results indicate the possible involvement of nutrient factors in the association between the gut microbiota and DM. Furthermore, independent of nutrient factors, having a Bifidobacterium-dominant gut microbiota may be a risk factor for DM compared to having a Blautia-dominant gut microbiota in a general Japanese population.
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Opioid Use, Gut Dysbiosis, Inflammation, and the Nervous System. J Neuroimmune Pharmacol 2022; 17:76-93. [PMID: 34993905 DOI: 10.1007/s11481-021-10046-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 12/17/2021] [Indexed: 12/29/2022]
Abstract
Opioid use disorder (OUD) is defined as the chronic use or misuse of prescribed or illicitly obtained opioids and is characterized by clinically significant impairment. The etiology of OUD is multifactorial as it is influenced by genetics, environmental factors, stress response and behavior. Given the profound role of the gut microbiome in health and disease states, in recent years there has been a growing interest to explore interactions between the gut microbiome and the central nervous system as a causal link and potential therapeutic source for OUD. This review describes the role of the gut microbiome and opioid-induced immunopathological disturbances at the gut epithelial surface, which collectively contribute to OUD and perpetuate the vicious cycle of addiction and relapse.
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Simpson S, Mclellan R, Wellmeyer E, Matalon F, George O. Drugs and Bugs: The Gut-Brain Axis and Substance Use Disorders. J Neuroimmune Pharmacol 2022; 17:33-61. [PMID: 34694571 PMCID: PMC9074906 DOI: 10.1007/s11481-021-10022-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 09/06/2021] [Indexed: 02/07/2023]
Abstract
Substance use disorders (SUDs) represent a significant public health crisis. Worldwide, 5.4% of the global disease burden is attributed to SUDs and alcohol use, and many more use psychoactive substances recreationally. Often associated with comorbidities, SUDs result in changes to both brain function and physiological responses. Mounting evidence calls for a precision approach for the treatment and diagnosis of SUDs, and the gut microbiome is emerging as a contributor to such disorders. Over the last few centuries, modern lifestyles, diets, and medical care have altered the health of the microbes that live in and on our bodies; as we develop, our diets and lifestyle dictate which microbes flourish and which microbes vanish. An increase in antibiotic treatments, with many antibiotic interventions occurring early in life during the microbiome's normal development, transforms developing microbial communities. Links have been made between the microbiome and SUDs, and the microbiome and conditions that are often comorbid with SUDs such as anxiety, depression, pain, and stress. A better understanding of the mechanisms influencing behavioral changes and drug use is critical in developing novel treatments for SUDSs. Targeting the microbiome as a therapeutic and diagnostic tool is a promising avenue of exploration. This review will provide an overview of the role of the gut-brain axis in a wide range of SUDs, discuss host and microbe pathways that mediate changes in the brain's response to drugs, and the microbes and related metabolites that impact behavior and health within the gut-brain axis.
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Affiliation(s)
- Sierra Simpson
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US.
| | - Rio Mclellan
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
| | - Emma Wellmeyer
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
| | - Frederic Matalon
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
| | - Olivier George
- Department of Psychiatry, University of California San Diego, La Jolla, San Diego, CA, 92093, US
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Ren M, Lotfipour S. Dose- and Sex-Dependent Bidirectional Relationship between Intravenous Fentanyl Self-Administration and Gut Microbiota. Microorganisms 2022; 10:microorganisms10061127. [PMID: 35744645 PMCID: PMC9229572 DOI: 10.3390/microorganisms10061127] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/26/2022] [Accepted: 05/28/2022] [Indexed: 01/27/2023] Open
Abstract
Gut bacteria influence neural circuits in addiction-related behaviors. Given the association between opioid use, gastrointestinal distress, and microbial dysbiosis in humans and mice, we test the hypothesis that interactions between gut bacteria and the brain mediate the rewarding and reinforcing properties of fentanyl. We implant rats with intravenous catheters in preparation for fentanyl intravenous self-administration (IVSA) on an escalating schedule of reinforcement to determine factors that influence fentanyl intake, including sex, dose, and gut microbiota. Our data show the impact of fentanyl IVSA on gut microbiota diversity, as well as the role of gut microbiota on fentanyl IVSA, in Sprague Dawley rats in a sex- and dose-dependent manner (n = 10–16/group). We found that the diversity of gut microbiota within females dose-dependently predicts progressive but not fixed ratio schedules of fentanyl IVSA. Depending on sex and fentanyl dose, alpha diversity (richness and evenness measured with Shannon index) is either increased or decreased following fentanyl IVSA and predicts progressive ratio breakpoint. Our findings collectively suggest a role of gut bacteria in drug-related behavior, including motivation and reinforcement. This work provides feasibility for an intravenous fentanyl self-administration model and uncovers potential factors mediating drug use, which may lead to the development of effective addiction interventions.
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Affiliation(s)
- Michelle Ren
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697, USA;
- Correspondence:
| | - Shahrdad Lotfipour
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University of California Irvine, Irvine, CA 92697, USA;
- Department of Emergency Medicine, School of Medicine, University of California Irvine, Irvine, CA 92697, USA
- Department of Pathology and Laboratory Medicine, School of Medicine, University of California Irvine, Irvine, CA 92697, USA
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Herlihy B, Roy S. Gut-Microbiome Implications in Opioid Use Disorder and Related Behaviors. ADVANCES IN DRUG AND ALCOHOL RESEARCH 2022; 2:10311. [PMID: 38390617 PMCID: PMC10880781 DOI: 10.3389/adar.2022.10311] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/25/2022] [Indexed: 02/24/2024]
Abstract
Substance use disorder (SUD) is a prevalent disease that has caused hundreds of thousands of deaths and affected the lives of even more. Despite its global impact, there is still no known cure for SUD, or the psychological symptoms associated with drug use. Many of the behavioral consequences of drug use prevent people from breaking the cycle of addiction or cause them to relapse back into the cycle due to the physical and psychological consequences of withdrawal. Current research is aimed at understanding the cause of these drug related behaviors and therapeutically targeting them as a mechanism to break the addiction cycle. Research on opioids suggests that the changes in the microbiome during drug use modulated drug related behaviors and preventing these microbial changes could attenuate behavioral symptoms. This review aims to highlight the relationship between the changes in the microbiome and behavior during opioid treatment, as well as highlight the additional research needed to understand the mechanism in which the microbiome modulates behavior to determine the best therapeutic course of action.
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Affiliation(s)
- Bridget Herlihy
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
- Department of Neuroscience, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Sabita Roy
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, United States
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Intestinal AMPK modulation of microbiota mediates crosstalk with brown fat to control thermogenesis. Nat Commun 2022; 13:1135. [PMID: 35241650 PMCID: PMC8894485 DOI: 10.1038/s41467-022-28743-5] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 02/02/2022] [Indexed: 01/28/2023] Open
Abstract
The energy-dissipating capacity of brown adipose tissue through thermogenesis can be targeted to improve energy balance. Mammalian 5'-AMP-activated protein kinase, a key nutrient sensor for maintaining cellular energy status, is a known therapeutic target in Type II diabetes. Despite its well-established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine remain largely unexplored. Here we show that AMPKα1 deficiency in the intestine results in weight gain and impaired glucose tolerance under high fat diet feeding, while metformin administration fails to ameliorate these metabolic disorders in intestinal AMPKα1 knockout mice. Further, AMPKα1 in the intestine communicates with brown adipose tissue to promote thermogenesis. Mechanistically, we uncover a link between intestinal AMPKα1 activation and BAT thermogenic regulation through modulating anti-microbial peptide-controlled gut microbiota and the metabolites. Our findings identify AMPKα1-mediated mechanisms of intestine-BAT communication that may partially underlie the therapeutic effects of metformin.
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He D, Han H, Fu X, Liu A, Zhan Y, Qiu H, Ma L, Zhang X, Wang X. Metformin Reduces Blood Glucose in Treatment-Naive Type 2 Diabetes by Altering the Gut Microbiome. Can J Diabetes 2022; 46:150-156. [PMID: 35148952 DOI: 10.1016/j.jcjd.2021.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 08/05/2021] [Accepted: 08/05/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Our aim in this study was to better understand the causality of metformin and gut microbiome in the treatment of type 2 diabetes (T2D). METHODS This study was conducted on individuals with newly diagnosed and treatment-naive T2D. We used 16S rRNA sequencing to assess the effect of metformin on composition and diversity of the gut microbiota. We also compared the differences in relative abundance of gut microbiome at the genus level in patients with treatment-naive T2D before and after 2 months of metformin treatment. Spearman's rank correlation coefficient analysis was used to identify genus abundance in relation to blood glucose and related factors. RESULTS Metformin significantly reduced blood glucose and levels of the related factors in treatment-naive individuals with T2D after 2 months of treatment. The 16S rRNA sequencing showed that metformin treatment altered composition and diversity of gut microbiome. Megamonas and Klebsiella in the T2D groups were significantly higher compared with the control group. Metformin treatment caused a significant reduction in Megamonas and Klebsiella. Spearman's rank correlation coefficient analysis showed a significant positive correlation between Megamonas and blood glucose, glycated hemoglobin (A1C), serum fructosamine and alanine aminotranferase (ALT). Klebsiella showed a significant positive correlation between A1C and ALT. CONCLUSION Metformin reduces blood glucose in T2D by interacting with different gut bacteria, possibly Megamonas and Klebsiella pneumoniae.
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Affiliation(s)
- Daqiang He
- Department of Laboratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Hui Han
- Department of Endocrinology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xiaodan Fu
- Department of Endocrinology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Anbing Liu
- Department of Laboratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yuhong Zhan
- Department of Endocrinology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Haiyan Qiu
- Department of Endocrinology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Lizhen Ma
- Department of Rheumatology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xianfeng Zhang
- Department of Rheumatology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xianjun Wang
- Department of Laboratory Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
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Petakh P, Kamyshna I, Nykyforuk A, Yao R, Imbery JF, Oksenych V, Korda M, Kamyshnyi A. Immunoregulatory Intestinal Microbiota and COVID-19 in Patients with Type Two Diabetes: A Double-Edged Sword. Viruses 2022; 14:477. [PMID: 35336884 PMCID: PMC8955861 DOI: 10.3390/v14030477] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 02/06/2022] [Accepted: 02/24/2022] [Indexed: 01/09/2023] Open
Abstract
Coronavirus disease 2019, or COVID-19, is a major challenge facing scientists worldwide. Alongside the lungs, the system of organs comprising the GI tract is commonly targeted by COVID-19. The dysbiotic modulations in the intestine influence the disease severity, potentially due to the ability of the intestinal microbiota to modulate T lymphocyte functions, i.e., to suppress or activate T cell subpopulations. The interplay between the lungs and intestinal microbiota is named the gut-lung axis. One of the most usual comorbidities in COVID-19 patients is type 2 diabetes, which induces changes in intestinal microbiota, resulting in a pro-inflammatory immune response, and consequently, a more severe course of COVID-19. However, changes in the microbiota in this comorbid pathology remain unclear. Metformin is used as a medication to treat type 2 diabetes. The use of the type 2 diabetes drug metformin is a promising treatment for this comorbidity because, in addition to its hypoglycemic action, it can increase amount of intestinal bacteria that induce regulatory T cell response. This dual activity of metformin can reduce lung damage and improve the course of the COVID-19 disease.
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Affiliation(s)
- Pavlo Petakh
- Department of Biochemistry and Pharmacology, Uzhhorod National University, 88000 Uzhhorod, Ukraine; (P.P.); (A.N.)
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
| | - Iryna Kamyshna
- Department of Medical Rehabilitation, I. Horbachevsky Ternopil National Medical University, Majdan Voli 1, 46001 Ternopil, Ukraine;
| | - Andriy Nykyforuk
- Department of Biochemistry and Pharmacology, Uzhhorod National University, 88000 Uzhhorod, Ukraine; (P.P.); (A.N.)
| | - Rouan Yao
- Center of Molecular Inflammation Research, Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, 7491 Trondheim, Norway;
| | - John F. Imbery
- Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway;
| | - Valentyn Oksenych
- Institute of Clinical Medicine, University of Oslo, 0318 Oslo, Norway;
| | - Mykhaylo Korda
- Department of Medical Biochemistry, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine;
| | - Aleksandr Kamyshnyi
- Department of Microbiology, Virology, and Immunology, I. Horbachevsky Ternopil National Medical University, 46001 Ternopil, Ukraine
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Xu Z, Jiang W, Huang W, Lin Y, Chan FKL, Ng SC. Gut microbiota in patients with obesity and metabolic disorders - a systematic review. GENES & NUTRITION 2022; 17:2. [PMID: 35093025 PMCID: PMC8903526 DOI: 10.1186/s12263-021-00703-6] [Citation(s) in RCA: 114] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/23/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Previous observational studies have demonstrated inconsistent and inconclusive results of changes in the intestinal microbiota in patients with obesity and metabolic disorders. We performed a systematic review to explore evidence for this association across different geography and populations. METHODS We performed a systematic search of MEDLINE (OvidSP) and Embase (OvidSP) of articles published from Sept 1, 2010, to July 10, 2021, for case-control studies comparing intestinal microbiome of individuals with obesity and metabolic disorders with the microbiome of non-obese, metabolically healthy individuals (controls). The primary outcome was bacterial taxonomic changes in patients with obesity and metabolic disorders as compared to controls. Taxa were defined as "lean-associated" if they were depleted in patients with obesity and metabolic disorders or negatively associated with abnormal metabolic parameters. Taxa were defined as "obesity-associated" if they were enriched in patients with obesity and metabolic disorders or positively associated with abnormal metabolic parameters. RESULTS Among 2390 reports screened, we identified 110 full-text articles and 60 studies were included. Proteobacteria was the most consistently reported obesity-associated phylum. Thirteen, nine, and ten studies, respectively, reported Faecalibacterium, Akkermansia, and Alistipes as lean-associated genera. Prevotella and Ruminococcus were obesity-associated genera in studies from the West but lean-associated in the East. Roseburia and Bifidobacterium were lean-associated genera only in the East, whereas Lactobacillus was an obesity-associated genus in the West. CONCLUSIONS We identified specific bacteria associated with obesity and metabolic disorders in western and eastern populations. Mechanistic studies are required to determine whether these microbes are a cause or product of obesity and metabolic disorders.
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Affiliation(s)
- Zhilu Xu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,Center for Gut microbiota research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Microbiota Innovation Centre (MagIC Centre), Hong Kong, China
| | - Wei Jiang
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China
| | - Wenli Huang
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,Center for Gut microbiota research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Microbiota Innovation Centre (MagIC Centre), Hong Kong, China
| | - Yu Lin
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,Center for Gut microbiota research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Microbiota Innovation Centre (MagIC Centre), Hong Kong, China
| | - Francis K L Chan
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China.,Center for Gut microbiota research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Microbiota Innovation Centre (MagIC Centre), Hong Kong, China
| | - Siew C Ng
- Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, LKS Institute of Health Science, The Chinese University of Hong Kong, Hong Kong, China. .,Center for Gut microbiota research, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. .,Microbiota Innovation Centre (MagIC Centre), Hong Kong, China.
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Su L, Hong Z, Zhou T, Jian Y, Xu M, Zhang X, Zhu X, Wang J. Health improvements of type 2 diabetic patients through diet and diet plus fecal microbiota transplantation. Sci Rep 2022; 12:1152. [PMID: 35064189 PMCID: PMC8782834 DOI: 10.1038/s41598-022-05127-9] [Citation(s) in RCA: 59] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Accepted: 01/05/2022] [Indexed: 12/16/2022] Open
Abstract
Type 2 diabetes (T2D) is a major public health problem, and gut microbiota dysbiosis has been implicated in the emergence of T2D in humans. Dietary interventions can indirectly influence the health status of patients with type 2 diabetes through their modulatory effects on the intestinal microbiota. In recent years, fecal microbiota transplantation is becoming familiar as a new medical treatment that can rapidly improve intestinal health. We conducted a 90-day controlled open-label trial to evaluate the health improvement ability of a specially designed diet, and the diet combined with fecal microbiota transplantation (FMT). According to our study, both diet and diet plus FMT treatments showed great potential in controlling blood glucose and blood pressure levels. Sequencing the V4 region of 16S rRNA gene on the Illumina MiniSeq platform revealed a shift of intestinal microbial community in T2D patients, and the changes were also observed in response to the treatments. FMT changed the gut microbiota more quickly than diet. Beneficial bacterium, such as Bifidobacterium, increased along the study and was negatively correlated with blood glucose, blood pressure, blood lipid and BMI. Sulfate-reducing bacteria (SRB), Bilophila and Desulfovibrio, decreased significantly after treatment, showed a positive correlation with blood glucose indices. Thus, the specially designed diet is beneficial to improve blood glucose control in diabetic patients, it also showed the potential to reverse dyslipidemia and dysarteriotony.
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Affiliation(s)
- Lili Su
- College of Electronics and Information Engineering, School of Computer Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710048, People's Republic of China.,Guangdong Quantum Hi-Tech Microecological Medical Co., Ltd, Guangzhou, Guangdong, 510030, People's Republic of China
| | - Zhifan Hong
- Guangdong Quantum Hi-Tech Microecological Medical Co., Ltd, Guangzhou, Guangdong, 510030, People's Republic of China
| | - Tong Zhou
- Guangdong Quantum Hi-Tech Microecological Medical Co., Ltd, Guangzhou, Guangdong, 510030, People's Republic of China
| | - Yuanyuan Jian
- Guangdong Quantum Hi-Tech Microecological Medical Co., Ltd, Guangzhou, Guangdong, 510030, People's Republic of China
| | - Mei Xu
- Yunnan Richland International Hospital, Kunming, Yunnan, 650224, People's Republic of China
| | - Xuanping Zhang
- College of Electronics and Information Engineering, School of Computer Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710048, People's Republic of China
| | - Xiaoyan Zhu
- College of Electronics and Information Engineering, School of Computer Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710048, People's Republic of China
| | - Jiayin Wang
- College of Electronics and Information Engineering, School of Computer Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi, 710048, People's Republic of China.
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Vals-Delgado C, Alcala-Diaz JF, Molina-Abril H, Roncero-Ramos I, Caspers MPM, Schuren FHJ, Van den Broek TJ, Luque R, Perez-Martinez P, Katsiki N, Delgado-Lista J, Ordovas JM, van Ommen B, Camargo A, Lopez-Miranda J. An altered microbiota pattern precedes Type 2 diabetes mellitus development: From the CORDIOPREV study. J Adv Res 2022; 35:99-108. [PMID: 35024196 PMCID: PMC8721255 DOI: 10.1016/j.jare.2021.05.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 05/07/2021] [Accepted: 05/09/2021] [Indexed: 12/12/2022] Open
Abstract
Type 2 diabetes (T2DM) increases the risk of recurrence in myocardial infarction patients. A gut microbiota profile is associated to the further T2DM development. Microbiome data improved the prediction of T2DM development when added to clinical parameters. A risk score including the most predictive genera was associated with the probability of T2DM. A high risk score was associated with a higher hepatic insulin resistance and β-cell dysfunction. Introduction A distinctive gut microbiome have been linked to type 2 diabetes mellitus (T2DM). Objectives We aimed to evaluate whether gut microbiota composition, in addition to clinical biomarkers, could improve the prediction of new incident cases of diabetes in patients with coronary heart disease. Methods All the patients from the CORDIOPREV (Clinical Trials.gov.Identifier: NCT00924937) study without T2DM at baseline were included (n = 462). Overall, 107 patients developed it after a median of 60 months. The gut microbiota composition was determined by 16S rRNA gene sequencing and predictive models were created using hold-out method. Results A gut microbiota profile associated with T2DM development was determined through a microbiome-based predictive model. The addition of microbiome data to clinical parameters (variables included in FINDRISC risk score and the diabetes risk score of the American Diabetes Association, HDL, triglycerides and HbA1c) improved the prediction increasing the area under the curve from 0.632 to 0.946. Furthermore, a microbiome-based risk score including the ten most discriminant genera, was associated with the probability of develop T2DM. Conclusion These results suggest that a microbiota profile is associated to the T2DM development. An integrate predictive model of microbiome and clinical data that can improve the prediction of T2DM is also proposed, if is validated in independent populations to prevent this disease.
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Affiliation(s)
- Cristina Vals-Delgado
- Lipids and Atherosclerosis Unit, Internal Medicine Unit, Reina Sofia University Hospital, Córdoba 14004, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC)/University of Cordoba/Reina Sofia University Hospital, Córdoba 14004, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Juan F Alcala-Diaz
- Lipids and Atherosclerosis Unit, Internal Medicine Unit, Reina Sofia University Hospital, Córdoba 14004, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC)/University of Cordoba/Reina Sofia University Hospital, Córdoba 14004, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Helena Molina-Abril
- Department of Applied Mathematics I, University of Seville, Seville 41012, Spain
| | - Irene Roncero-Ramos
- Lipids and Atherosclerosis Unit, Internal Medicine Unit, Reina Sofia University Hospital, Córdoba 14004, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC)/University of Cordoba/Reina Sofia University Hospital, Córdoba 14004, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Martien P M Caspers
- Netherlands Institute for Applied Science (TNO), Research Group Microbiology & Systems Biology, Zeist NL-3704 HE, the Netherlands
| | - Frank H J Schuren
- Netherlands Institute for Applied Science (TNO), Research Group Microbiology & Systems Biology, Zeist NL-3704 HE, the Netherlands
| | - Tim J Van den Broek
- Netherlands Institute for Applied Science (TNO), Research Group Microbiology & Systems Biology, Zeist NL-3704 HE, the Netherlands
| | - Raul Luque
- Department of Cell Biology, Physiology and Immunology, University of Cordoba, Córdoba 14004, Spain
| | - Pablo Perez-Martinez
- Lipids and Atherosclerosis Unit, Internal Medicine Unit, Reina Sofia University Hospital, Córdoba 14004, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC)/University of Cordoba/Reina Sofia University Hospital, Córdoba 14004, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Niki Katsiki
- First Department of Internal Medicine, Division of Endocrinology-Metabolism, Diabetes Center, AHEPA University Hospital, Thessaloniki 546 21, Greece
| | - Javier Delgado-Lista
- Lipids and Atherosclerosis Unit, Internal Medicine Unit, Reina Sofia University Hospital, Córdoba 14004, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC)/University of Cordoba/Reina Sofia University Hospital, Córdoba 14004, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Jose M Ordovas
- Nutrition and Genomics Laboratory, J.M.-US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, United States.,IMDEA Alimentacion, Madrid, Spain
| | - Ben van Ommen
- Netherlands Institute for Applied Science (TNO), Research Group Microbiology & Systems Biology, Zeist NL-3704 HE, the Netherlands
| | - Antonio Camargo
- Lipids and Atherosclerosis Unit, Internal Medicine Unit, Reina Sofia University Hospital, Córdoba 14004, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC)/University of Cordoba/Reina Sofia University Hospital, Córdoba 14004, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain
| | - Jose Lopez-Miranda
- Lipids and Atherosclerosis Unit, Internal Medicine Unit, Reina Sofia University Hospital, Córdoba 14004, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC)/University of Cordoba/Reina Sofia University Hospital, Córdoba 14004, Spain.,CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid 28029, Spain
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Wang Z, Hou C, Chen L, Zhang M, Luo W. Potential roles of the gut microbiota in the manifestations of drug use disorders. Front Psychiatry 2022; 13:1046804. [PMID: 36590616 PMCID: PMC9795867 DOI: 10.3389/fpsyt.2022.1046804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 11/21/2022] [Indexed: 12/15/2022] Open
Abstract
Drug use disorders (DUDs) not only cause serious harm to users but also cause huge economic, security, and public health burdens to families and society. Recently, several studies have shown that gut microbiota (GM) can affect the central nervous system and brain functions. In this review, we focus on the potential role of the GM in the different stages of DUDs. First, the GM may induce individuals to seek novel substances. Second, the gut microbiota is involved in the decomposition and absorption of drugs. Symptoms of individuals who suffer from DUDs are also related to intestinal microorganisms. Third, the effects of the GM and its metabolites on drug relapse are mainly reflected in the reward effect and drug memory. In conclusion, recent studies have preliminarily explored the relationship between GM and DUDs. This review deepens our understanding of the mechanisms of DUDs and provides important information for the future development of clinical treatment for DUDs.
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Affiliation(s)
- Zhiyan Wang
- Research Center of Brain and Cognitive Neuroscience, Liaoning Normal University, Dalian, China.,Key Laboratory of Brain and Cognitive Neuroscience, Dalian, China
| | - Chengqian Hou
- Research Center of Brain and Cognitive Neuroscience, Liaoning Normal University, Dalian, China.,Key Laboratory of Brain and Cognitive Neuroscience, Dalian, China
| | - Lei Chen
- Research Center of Brain and Cognitive Neuroscience, Liaoning Normal University, Dalian, China.,Key Laboratory of Brain and Cognitive Neuroscience, Dalian, China
| | - Mingming Zhang
- Research Center of Brain and Cognitive Neuroscience, Liaoning Normal University, Dalian, China.,Key Laboratory of Brain and Cognitive Neuroscience, Dalian, China
| | - Wenbo Luo
- Research Center of Brain and Cognitive Neuroscience, Liaoning Normal University, Dalian, China.,Key Laboratory of Brain and Cognitive Neuroscience, Dalian, China
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Fik VB, Mykhalevych МM, Podolіyk МV, Tsytovskiy MN, Fedechko YM, Fedoniuk LY. DYNAMICS OF CHANGES IN THE MICROBIAL PICTURE OF THE ORAL CAVITY ON THE BACKGROUND OF CHRONIC OPIOID EXPOSURE IN THE EXPERIMENT. WIADOMOSCI LEKARSKIE (WARSAW, POLAND : 1960) 2022; 75:1991-1997. [PMID: 36129084 DOI: 10.36740/wlek202208209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
OBJECTIVE The aim is to investigate changes in the microbiota of dental biofilm at the end of the eighth, tenth and twelfth weeks of experimental opioid exposure. PATIENTS AND METHODS Materials and methods: The study was performed on 36 white outbred adult male rats, which were injected with the opioid analgesic nalbuphine in increasing doses (0,212 - 0,3 mg / kg) during 8, 10 and 12 weeks. Qualitative and quantitative composition of microbiota of dental biofilm was studied using statistical analysis. RESULTS Results: After eight weeks of opioid exposure, changes in microbiocenosis of dental biofilm of rats were caused by a significant increase in saprophytic and opportunistic microbiota and an appearance of pathogenic species of indicator microbiota with potential periodontopathogenic action. At the end of the tenth week, a significant increase in the quantitative indicators of certain species of opportunistic microbiota and increase in the quantitative composition of pathogenic bacteria were determined. After twelve week of opioid exposure, a significant increase in the quantitative indicators of pathogenic microbiota of dental biofilm was detected. CONCLUSION Conclusions: Changes in the qualitative and quantitative composition of the microbiocenosis of the dental biofilm at the end of 8, 10 and 12 weeks of opioid exposure were established, they were manifested by a significant increase in the quantitative indicators of certain species of opportunistic microorganisms and a significant increase in pathogenic microbiota in the dynamics, which led to the progression of dysbiotic changes and purulent-inflammatory process in the oral cavity of rats.
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Affiliation(s)
- Volodymyr B Fik
- DANYLO HALYTSKY LVIV NATIONAL MEDICAL UNIVERSITY, LVIV, UKRAINE
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Molavi N, Rasouli-Azad M, Mirzaei H, Matini AH, Banafshe HR, Valiollahzadeh M, Hassanzadeh M, Saghazade AR, Abbaszadeh-Mashkani S, Mamsharifi P, Ghaderi A. The Effects of Probiotic Supplementation on Opioid-Related Disorder in Patients under Methadone Maintenance Treatment Programs. Int J Clin Pract 2022; 2022:1206914. [PMID: 35685534 PMCID: PMC9159114 DOI: 10.1155/2022/1206914] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 03/11/2022] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Patients under methadone maintenance treatment programs (MMTPs) are susceptible to numerous complications (e.g., mental and metabolic disorders). This study evaluated the effects of probiotics on clinical symptoms, biomarkers of oxidative stress, inflammation, insulin resistance, and serum lipid content in patients receiving MMTPs. MATERIALS AND METHODS A randomized, double-blind, placebo-controlled trial was conducted among 70 patients receiving MMTPs to receive either 1.8 × 109 CFU/day probiotics (n = 35) or placebo (n = 35) for 12 weeks. Clinical symptoms and metabolic profiles were measured before and after the intervention in patients receiving MMTPs. RESULTS Compared with the placebo group, probiotic supplementation resulted in a significant improvement in the severity of depression (P < 0.05). In addition, probiotic administration significantly decreased fasting plasma glucose (FPG), total cholesterol, and low-density lipoprotein cholesterol (LDL cholesterol) (P < 0.05). Furthermore, probiotics resulted in a significant reduction in high-sensitivity C-reactive protein (hs-CRP) and a significant elevation in total antioxidant capacity (TAC) and total glutathione (GSH) levels (P < 0.05). CONCLUSION Treatment with probiotics for 12 weeks to patients receiving MMTPs had beneficial effects on symptoms of depression, as well as several metabolic profiles. Clinical Trial Registration: this study was registered in the Iranian website (https://www.irct.ir) for clinical trials registration (https://fa.irct.ir/trial/46363/IRCT20170420033551N9). The registration date is March 22, 2020.
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Affiliation(s)
- Nader Molavi
- Department of Addiction Studies, School of Medical, Kashan University of Medical Sciences, Kashan, Iran
| | - Morad Rasouli-Azad
- International Center for Comparative Criminology, University of Montreal, Montreal, Canada
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Amir Hassan Matini
- Department of Clinical Pathology, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamid Reza Banafshe
- Department of Addiction Studies, School of Medical, Kashan University of Medical Sciences, Kashan, Iran
- Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Majid Hassanzadeh
- Department of Addiction Studies, School of Medical, Kashan University of Medical Sciences, Kashan, Iran
| | - Ahmad Reza Saghazade
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samira Abbaszadeh-Mashkani
- Trauma Nursing Research Center, Faculty of Nursing and Midwifery, Kashan University of Medical Sciences, Kashan, Iran
| | - Peyman Mamsharifi
- Department of Psychology, Allameh Tabataba'i University, Tehran, Iran
| | - Amir Ghaderi
- Department of Addiction Studies, School of Medical, Kashan University of Medical Sciences, Kashan, Iran
- Clinical Research Development Unit-Matini/Kargarnejad Hospital, Kashan University of Medical Sciences, Kashan, Iran
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Jalodia R, Kolli U, Braniff RG, Tao J, Abu YF, Chupikova I, Moidunny S, Ramakrishnan S, Roy S. Morphine mediated neutrophil infiltration in intestinal tissue play essential role in histological damage and microbial dysbiosis. Gut Microbes 2022; 14:2143225. [PMID: 36409161 PMCID: PMC9683065 DOI: 10.1080/19490976.2022.2143225] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 09/01/2022] [Accepted: 10/17/2022] [Indexed: 11/23/2022] Open
Abstract
The gut microbial ecosystem exhibits a complex bidirectional communication with the host and is one of the key contributing factors in determining mucosal immune homeostasis or an inflammatory state. Opioid use has been established to induce gut microbial dysbiosis consistent with increased intestinal tissue inflammation. In this study, we investigated the role of infiltrated immune cells in morphine-induced intestinal tissue damage and gut microbial dysbiosis in mice. Results reveal a significant increase in chemokine expression in intestinal tissues followed by increased neutrophil infiltration post morphine treatment which is direct consequence of a dysbiotic microbiome since the effect is attenuated in antibiotics treated animals and in germ-free mice. Neutrophil neutralization using anti-Ly6G monoclonal antibody showed a significant decrease in tissue damage and an increase in tight junction protein organization. 16S rRNA sequencing on intestinal samples highlighted the role of infiltrated neutrophils in modulating microbial community structure by providing a growth benefit for pathogenic bacteria, such as Enterococcus, and simultaneously causing a significant depletion of commensal bacteria, such as Lactobacillus. Taken together, we provide the first direct evidence that neutrophil infiltration contributes to morphine-induced intestinal tissue damage and gut microbial dysbiosis. Our findings implicate that inhibition of neutrophil infiltration may provide therapeutic benefits against gastrointestinal dysfunctions associated with opioid use.
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Affiliation(s)
- Richa Jalodia
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Udhghatri Kolli
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Junyi Tao
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Yaa Fosuah Abu
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Irina Chupikova
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Shamsudheen Moidunny
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sundaram Ramakrishnan
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sabita Roy
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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Wang D, Liu J, Zhou L, Zhang Q, Li M, Xiao X. Effects of Oral Glucose-Lowering Agents on Gut Microbiota and Microbial Metabolites. Front Endocrinol (Lausanne) 2022; 13:905171. [PMID: 35909556 PMCID: PMC9326154 DOI: 10.3389/fendo.2022.905171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 06/14/2022] [Indexed: 11/30/2022] Open
Abstract
The current research and existing facts indicate that type 2 diabetes mellitus (T2DM) is characterized by gut microbiota dysbiosis and disturbed microbial metabolites. Oral glucose-lowering drugs are reported with pleiotropic beneficial effects, including not only a decrease in glucose level but also weight loss, antihypertension, anti-inflammation, and cardiovascular protection, but the underlying mechanisms are still not clear. Evidence can be found showing that oral glucose-lowering drugs might modify the gut microbiome and thereby alter gastrointestinal metabolites to improve host health. Although the connections among gut microbial communities, microbial metabolites, and T2DM are complex, figuring out how antidiabetic agents shape the gut microbiome is vital for optimizing the treatment, meaningful for the instruction for probiotic therapy and gut microbiota transplantation in T2DM. In this review, we focused on the literatures in gut microbiota and its metabolite profile alterations beneficial from oral antidiabetic drugs, trying to provide implications for future study in the developing field of these drugs, such as combination therapies, pre- and probiotics intervention in T2DM, and subjects with pregestational diabetes and gestational diabetes mellitus.
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Affiliation(s)
- Dongmei Wang
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Jieying Liu
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
- Department of Medical Research Center, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Liyuan Zhou
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Qian Zhang
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Ming Li
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
| | - Xinhua Xiao
- Department of Endocrinology, National Health Commission (NHC) Key Laboratory of Endocrinology, Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Peking Union Medical College, Beijing, China
- *Correspondence: Xinhua Xiao,
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49
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Padilla-Martinez F, Wojciechowska G, Szczerbinski L, Kretowski A. Circulating Nucleic Acid-Based Biomarkers of Type 2 Diabetes. Int J Mol Sci 2021; 23:ijms23010295. [PMID: 35008723 PMCID: PMC8745431 DOI: 10.3390/ijms23010295] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/25/2021] [Accepted: 12/26/2021] [Indexed: 11/23/2022] Open
Abstract
Type 2 diabetes (T2D) is a deficiency in how the body regulates glucose. Uncontrolled T2D will result in chronic high blood sugar levels, eventually resulting in T2D complications. These complications, such as kidney, eye, and nerve damage, are even harder to treat. Identifying individuals at high risk of developing T2D and its complications is essential for early prevention and treatment. Numerous studies have been done to identify biomarkers for T2D diagnosis and prognosis. This review focuses on recent T2D biomarker studies based on circulating nucleic acids using different omics technologies: genomics, transcriptomics, and epigenomics. Omics studies have profiled biomarker candidates from blood, urine, and other non-invasive samples. Despite methodological differences, several candidate biomarkers were reported for the risk and diagnosis of T2D, the prognosis of T2D complications, and pharmacodynamics of T2D treatments. Future studies should be done to validate the findings in larger samples and blood-based biomarkers in non-invasive samples to support the realization of precision medicine for T2D.
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Affiliation(s)
- Felipe Padilla-Martinez
- Clinical Research Centre, Medical University of Bialystok, 15276 Białystok, Poland; (F.P.-M.); (L.S.); (A.K.)
| | - Gladys Wojciechowska
- Clinical Research Centre, Medical University of Bialystok, 15276 Białystok, Poland; (F.P.-M.); (L.S.); (A.K.)
- Correspondence:
| | - Lukasz Szczerbinski
- Clinical Research Centre, Medical University of Bialystok, 15276 Białystok, Poland; (F.P.-M.); (L.S.); (A.K.)
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15276 Białystok, Poland
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, 15276 Białystok, Poland; (F.P.-M.); (L.S.); (A.K.)
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, 15276 Białystok, Poland
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50
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Cruz-Lebrón A, Johnson R, Mazahery C, Troyer Z, Joussef-Piña S, Quiñones-Mateu ME, Strauch CM, Hazen SL, Levine AD. Chronic opioid use modulates human enteric microbiota and intestinal barrier integrity. Gut Microbes 2021; 13:1946368. [PMID: 34313547 PMCID: PMC8317955 DOI: 10.1080/19490976.2021.1946368] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Over the past three decades the United States has experienced a devastating opioid epidemic. One of the many debilitating side effects of chronic opioid use is opioid-induced bowel dysfunction. We investigated the impact of methadone maintenance treatment (MMT) on the gut microbiome, the gut bacterial metabolite profile, and intestinal barrier integrity. An imbalance in key bacterial communities required for production of short-chain fatty acids (SCFAs), mucus degradation, and maintenance of barrier integrity was identified. Consistent with dysbiosis, levels of fecal SCFAs were reduced in MMT. We demonstrated that metabolites synthesized by Akkermansia muciniphila modulate intestinal barrier integrity in vitro by strengthening the pore pathway and regulating tight junction protein expression. This study provides essential information about the therapeutic potential of A. muciniphila and warrants development of new clinical strategies that aim to normalize the gut microbiome in individuals affected by chronic opioid use.
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Affiliation(s)
- Angélica Cruz-Lebrón
- Departments of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, USA
| | - Ramona Johnson
- Departments of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, USA
| | - Claire Mazahery
- Department of Pathology, Case Western Reserve University, Cleveland, USA
| | - Zach Troyer
- Departments of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, USA
| | | | - Miguel E. Quiñones-Mateu
- Department of Microbiology and Immunology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Christopher M Strauch
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, USA
| | - Stanley L. Hazen
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland, USA
| | - Alan D. Levine
- Departments of Molecular Biology and Microbiology, Case Western Reserve University, Cleveland, USA,Department of Pathology, Case Western Reserve University, Cleveland, USA,Departments of Pharmacology, Medicine, and Pediatrics, Case Western Reserve University, Cleveland, USA,CONTACT Alan D. Levine Case Western Reserve University School of Medicine (Wood W217C), 10900 Euclid Avenue, Cleveland, Ohio44106-4960
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