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Lupu VV, Ghiciuc CM, Stefanescu G, Mihai CM, Popp A, Sasaran MO, Bozomitu L, Starcea IM, Adam Raileanu A, Lupu A. Emerging role of the gut microbiome in post-infectious irritable bowel syndrome: A literature review. World J Gastroenterol 2023; 29:3241-3256. [PMID: 37377581 PMCID: PMC10292139 DOI: 10.3748/wjg.v29.i21.3241] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/04/2023] [Accepted: 05/08/2023] [Indexed: 06/01/2023] Open
Abstract
Post-infectious irritable bowel syndrome (PI-IBS) is a particular type of IBS, with symptom onset after an acute episode of infectious gastroenteritis. Despite infectious disease resolution and clearance of the inciting pathogen agent, 10% of patients will develop PI-IBS. In susceptible individuals, the exposure to pathogenic organisms leads to a marked shift in the gut microbiota with prolonged changes in host-microbiota interactions. These changes can affect the gut-brain axis and the visceral sensitivity, disrupting the intestinal barrier, altering neuromuscular function, triggering persistent low inflammation, and sustaining the onset of IBS symptoms. There is no specific treatment strategy for PI-IBS. Different drug classes can be used to treat PI-IBS similar to patients with IBS in general, guided by their clinical symptoms. This review summarizes the current evidence for microbial dysbiosis in PI-IBS and analyzes the available data regarding the role of the microbiome in mediating the central and peripheral dysfunctions that lead to IBS symptoms. It also discusses the current state of evidence on therapies targeting the microbiome in the management of PI-IBS. The results of microbial modulation strategies used in relieving IBS symptomatology are encouraging. Several studies on PI-IBS animal models reported promising results. However, published data that describe the efficacy and safety of microbial targeted therapy in PI-IBS patients are scarce. Future research is required.
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Affiliation(s)
- Vasile Valeriu Lupu
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Cristina Mihaela Ghiciuc
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Gabriela Stefanescu
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | | | - Alina Popp
- Faculty of General Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest 020021, Romania
| | - Maria Oana Sasaran
- Faculty of General Medicine, “George Emil Palade” University of Medicine, Pharmacy, Science and Technology, Targu Mures 540142, Romania
| | - Laura Bozomitu
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Iuliana Magdalena Starcea
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Anca Adam Raileanu
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Ancuta Lupu
- Faculty of General Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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Li Y, Zhu Y, Chu B, Liu N, Chen S, Wang J, Zou Y. Map of Enteropathogenic Escherichia coli Targets Mitochondria and Triggers DRP-1-Mediated Mitochondrial Fission and Cell Apoptosis in Bovine Mastitis. Int J Mol Sci 2022; 23:ijms23094907. [PMID: 35563295 PMCID: PMC9105652 DOI: 10.3390/ijms23094907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 02/05/2023] Open
Abstract
Bovine mastitis seriously affects bovine health and dairy product quality. Escherichia coli is the most important pathogen in the environment and dairy products. Enteropathogenic Escherichia coli (EPEC) is a zoonotic pathogen, which seriously threatens the health of people and dairy cows. We recently reported that E. coli can induce endogenous apoptosis in bovine mammary epithelial cells. However, the mechanism of EPEC-damaged mitochondria and -induced bovine mastitis is unclear. In this study, we found that EPEC can induce DRP-1-dependent mitochondrial fission and apoptosis. This was verified by the application of Mdivi, a DRP-1 inhibitor. Meanwhile, in order to verify the role of the Map virulence factor in EPEC-induced bovine mastitis, we constructed a map mutant, complementary strain, and recombinant plasmid MapHis. In the present study, we find that Map induced DRP-1-mediated mitochondrial fission, resulting in mitochondrial dysfunction and apoptosis. These inferences were further verified in vivo by establishing a mouse mastitis model. After the map gene was knocked out, breast inflammation and apoptosis in mice were significantly alleviated. All results show that EPEC targets mitochondria by secreting the Map virulence factor to induce DRP-1-mediated mitochondrial fission, mitochondrial dysfunction, and endogenous apoptosis in bovine mastitis.
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Affiliation(s)
| | | | | | | | | | - Jiufeng Wang
- Correspondence: (J.W.); (Y.Z.); Tel.: +86-10-6273-1094 (J.W.)
| | - Yunjing Zou
- Correspondence: (J.W.); (Y.Z.); Tel.: +86-10-6273-1094 (J.W.)
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Mancini NL, Rajeev S, Jayme TS, Wang A, Keita ÅV, Workentine ML, Hamed S, Söderholm JD, Lopes F, Shutt TE, Shearer J, McKay DM. Crohn's Disease Pathobiont Adherent-Invasive E coli Disrupts Epithelial Mitochondrial Networks With Implications for Gut Permeability. Cell Mol Gastroenterol Hepatol 2020; 11:551-571. [PMID: 32992049 PMCID: PMC7797367 DOI: 10.1016/j.jcmgh.2020.09.013] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Revised: 09/21/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Adherent-invasive Escherichia coli are implicated in inflammatory bowel disease, and mitochondrial dysfunction has been observed in biopsy specimens from patients with inflammatory bowel disease. As a novel aspect of adherent-invasive E coli-epithelial interaction, we hypothesized that E coli (strain LF82) would elicit substantial disruption of epithelial mitochondrial form and function. METHODS Monolayers of human colon-derived epithelial cell lines were exposed to E coli-LF82 or commensal E coli and RNA sequence analysis, mitochondrial function (adenosine triphosphate synthesis) and dynamics (mitochondrial network imaging, immunoblotting for fission and fusion proteins), and epithelial permeability (transepithelial resistance, flux of fluorescein isothiocyanate-dextran and bacteria) were assessed. RESULTS E coli-LF82 significantly affected epithelial expression of ∼8600 genes, many relating to mitochondrial function. E coli-LF82-infected epithelia showed swollen mitochondria, reduced mitochondrial membrane potential and adenosine triphosphate, and fragmentation of the mitochondrial network: events not observed with dead E coli-LF82, medium from bacterial cultures, or control E coli. Treatment with Mitochondrial Division Inhibitor 1 (Mdivi1, inhibits dynamin-related peptide 1, guanosine triphosphatase principally responsible for mitochondrial fission) or P110 (prevents dynamin-related peptide 1 binding to mitochondrial fission 1 protein) partially reduced E coli-LF82-induced mitochondrial fragmentation in the short term. E coli-LF82-infected epithelia showed loss of the long isoform of optic atrophy factor 1, which mediates mitochondrial fusion. Mitochondrial Division Inhibitor 1 reduced the magnitude of E coli-LF82-induced increased transepithelial flux of fluorescein isothiocyanate dextran. By 8 hours after infection, increased cytosolic cytochrome C and DNA fragmentation were apparent without evidence of caspase-3 or apoptosis inducing factor activation. CONCLUSIONS Epithelial mitochondrial fragmentation caused by E coli-LF82 could be targeted to maintain cellular homeostasis and mitigate infection-induced loss of epithelial barrier function. Data have been deposited in NCBI's Gene Expression Omnibus and are accessible through GEO series accession numbers GSE154121 and GSE154122 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE154121).
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Affiliation(s)
- Nicole L Mancini
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Sruthi Rajeev
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Timothy S Jayme
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Arthur Wang
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Åsa V Keita
- Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | | | - Samira Hamed
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada
| | - Johan D Söderholm
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Surgery, County Council of Östergötland, Linköping, Sweden
| | - Fernando Lopes
- Institute of Parasitology, Faculty of Agriculture and Environmental Sciences, Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | - Timothy E Shutt
- Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, Alberta, Canada
| | - Jane Shearer
- Department of Biochemistry and Molecular Biology, Faculty of Kinesiology, University of Calgary, Alberta, Canada
| | - Derek M McKay
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Alberta, Canada.
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Abstract
Irritable bowel syndrome (IBS) is a multifactorial functional disorder with no clearly defined etiology or pathophysiology. Modern culture-independent techniques have improved the understanding of the gut microbiota’s composition and demonstrated that an altered gut microbiota profile might be found in at least some subgroups of IBS patients. Research on IBS from a microbial perspective is gaining momentum and advancing. This review will therefore highlight potential links between the gut microbiota and IBS by discussing the current knowledge of the gut microbiota; it will also illustrate bacterial-host interactions and how alterations to these interactions could exacerbate, induce or even help alleviate IBS.
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Affiliation(s)
- Sean M P Bennet
- Departments of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lena Ohman
- Departments of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Simren
- Departments of Internal Medicine and Clinical Nutrition, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Beatty JK, Bhargava A, Buret AG. Post-infectious irritable bowel syndrome: Mechanistic insights into chronic disturbances following enteric infection. World J Gastroenterol 2014; 20:3976-3985. [PMID: 24744587 PMCID: PMC3983453 DOI: 10.3748/wjg.v20.i14.3976] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2013] [Revised: 01/09/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is a commonly encountered chronic functional gastrointestinal (GI) disorder. Approximately 10% of IBS patients can trace the onset of their symptoms to a previous a bout of infectious dysentery. The appearance of new IBS symptoms following an infectious event is defined as post-infectious-IBS. Indeed, with the World Health Organization estimating between 2 and 4 billion cases annually, infectious diarrheal disease represents an incredible international healthcare burden. Additionally, compounding evidence suggests many commonly encountered enteropathogens as unique triggers behind IBS symptom generation and underlying pathophysiological features. A growing body of work provides evidence supporting a role for pathogen-mediated modifications in the resident intestinal microbiota, epithelial barrier integrity, effector cell functions, and innate and adaptive immune features, all proposed physiological manifestations that can underlie GI abnormalities in IBS. Enteric pathogens must employ a vast array of machinery to evade host protective immune mechanisms, and illicit successful infections. Consequently, the impact of infectious events on host physiology can be multidimensional in terms of anatomical location, functional scope, and duration. This review offers a unique discussion of the mechanisms employed by many commonly encountered enteric pathogens that cause acute disease, but may also lead to the establishment of chronic GI dysfunction compatible with IBS.
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Buret AG, Bhargava A. Modulatory mechanisms of enterocyte apoptosis by viral, bacterial and parasitic pathogens. Crit Rev Microbiol 2013; 40:1-17. [PMID: 23297858 DOI: 10.3109/1040841x.2012.746952] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Natarajan SK, Becker DF. Role of apoptosis-inducing factor, proline dehydrogenase, and NADPH oxidase in apoptosis and oxidative stress. ACTA ACUST UNITED AC 2012; 2012:11-27. [PMID: 22593641 DOI: 10.2147/chc.s4955] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Flavoproteins catalyze a variety of reactions utilizing flavin mononucleotide or flavin adenine dinucleotide as cofactors. The oxidoreductase properties of flavoenzymes implicate them in redox homeostasis, oxidative stress, and various cellular processes, including programmed cell death. Here we explore three critical flavoproteins involved in apoptosis and redox signaling, ie, apoptosis-inducing factor (AIF), proline dehydrogenase, and NADPH oxidase. These proteins have diverse biochemical functions and influence apoptotic signaling by unique mechanisms. The role of AIF in apoptotic signaling is two-fold, with AIF changing intracellular location from the inner mitochondrial membrane space to the nucleus upon exposure of cells to apoptotic stimuli. In the mitochondria, AIF enhances mitochondrial bioenergetics and complex I activity/assembly to help maintain proper cellular redox homeostasis. After translocating to the nucleus, AIF forms a chromatin degrading complex with other proteins, such as cyclophilin A. AIF translocation from the mitochondria to the nucleus is triggered by oxidative stress, implicating AIF as a mitochondrial redox sensor. Proline dehydrogenase is a membrane-associated flavoenzyme in the mitochondrion that catalyzes the rate-limiting step of proline oxidation. Upregulation of proline dehydrogenase by the tumor suppressor, p53, leads to enhanced mitochondrial reactive oxygen species that induce the intrinsic apoptotic pathway. NADPH oxidases are a group of enzymes that generate reactive oxygen species for oxidative stress and signaling purposes. Upon activation, NADPH oxidase 2 generates a burst of superoxide in neutrophils that leads to killing of microbes during phagocytosis. NADPH oxidases also participate in redox signaling that involves hydrogen peroxide-mediated activation of different pathways regulating cell proliferation and cell death. Potential therapeutic strategies for each enzyme are also highlighted.
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Affiliation(s)
- Sathish Kumar Natarajan
- Department of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE
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Cotton JA, Beatty JK, Buret AG. Host parasite interactions and pathophysiology in Giardia infections. Int J Parasitol 2011; 41:925-33. [PMID: 21683702 DOI: 10.1016/j.ijpara.2011.05.002] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Revised: 05/13/2011] [Accepted: 05/14/2011] [Indexed: 12/13/2022]
Abstract
Giardia is a protozoan parasite of the small intestine, and a leading cause of diarrhoeal disease worldwide in a variety of animals, including humans. The host-parasite interaction and pathophysiological processes of giardiasis remain incompletely understood. Current research suggests that Giardia-induced diarrhoeal disease is mediated by small intestinal malabsorption and maldigestion, chloride hypersecretion and increased rates of small intestinal transit. Small intestinal malabsorption and maldigestion results from the CD8+ lymphocyte-induced diffuse shortening of brush border microvilli. Activation of CD8+ lymphocytes occurs secondary to small intestinal barrier dysfunction, which results from heightened rates of enterocyte apoptosis and disruption of epithelial tight junctions. Both host and parasite factors contribute to the pathogenesis of giardiasis and ongoing research in this field may elucidate genotype/assemblage-specific pathogenic mechanisms. Giardia infections can result in chronic gastrointestinal disorders such as post-infectious Irritable Bowel Syndrome and symptoms may manifest at extra-intestinal sites, even though the parasite does not disseminate beyond the gastrointestinal tract. The infection can cause failure to thrive in children. Furthermore, there is now evidence suggesting that Giardia symptoms may vary between industrialised and developing areas of the world, for reasons that remain obscure. More research is needed to improve our understanding of this parasitic infection which was recently included in the World Health Organisation "Neglected Disease Initiative".
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Affiliation(s)
- James A Cotton
- Dept. of Biological Sciences, Inflammation Research Network, University of Calgary, Calgary (AB), Canada T2N 1N4
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