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Chew W, Lim YP, Lim WS, Chambers ES, Frost G, Wong SH, Ali Y. Gut-muscle crosstalk. A perspective on influence of microbes on muscle function. Front Med (Lausanne) 2023; 9:1065365. [PMID: 36698827 PMCID: PMC9868714 DOI: 10.3389/fmed.2022.1065365] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 12/20/2022] [Indexed: 01/11/2023] Open
Abstract
Our gastrointestinal system functions to digest and absorb ingested food, but it is also home to trillions of microbes that change across time, nutrition, lifestyle, and disease conditions. Largely commensals, these microbes are gaining prominence with regards to how they collectively affect the function of important metabolic organs, from the adipose tissues to the endocrine pancreas to the skeletal muscle. Muscle, as the biggest utilizer of ingested glucose and an important reservoir of body proteins, is intricately linked with homeostasis, and with important anabolic and catabolic functions, respectively. Herein, we provide a brief overview of how gut microbiota may influence muscle health and how various microbes may in turn be altered during certain muscle disease states. Specifically, we discuss recent experimental and clinical evidence in support for a role of gut-muscle crosstalk and include suggested underpinning molecular mechanisms that facilitate this crosstalk in health and diseased conditions. We end with a brief perspective on how exercise and pharmacological interventions may interface with the gut-muscle axis to improve muscle mass and function.
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Affiliation(s)
- Weixuan Chew
- Nutrition, Metabolism and Health Programme, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore,Centre for Microbiome Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
| | - Yen Peng Lim
- Institute of Geriatrics and Active Aging, Tan Tock Seng Hospital, Singapore, Singapore,Department of Nutrition and Dietetics, Tan Tock Seng Hospital, National Healthcare Group, Singapore, Singapore
| | - Wee Shiong Lim
- Nutrition, Metabolism and Health Programme, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore,Centre for Microbiome Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore,Institute of Geriatrics and Active Aging, Tan Tock Seng Hospital, Singapore, Singapore
| | - Edward S. Chambers
- Section for Nutrition Research, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Gary Frost
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, United Kingdom
| | - Sunny Hei Wong
- Nutrition, Metabolism and Health Programme, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore,Centre for Microbiome Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore,Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, National Healthcare Group, Singapore, Singapore
| | - Yusuf Ali
- Nutrition, Metabolism and Health Programme, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore,Centre for Microbiome Medicine, Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore,Singapore General Hospital, Singapore Eye Research Institute (SERI), Singapore, Singapore,Clinical Research Unit, Khoo Teck Puat Hospital, National Healthcare Group, Singapore, Singapore,*Correspondence: Yusuf Ali ✉
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Understanding the molecular basis of anorexia and tissue wasting in cancer cachexia. Exp Mol Med 2022; 54:426-432. [PMID: 35388147 PMCID: PMC9076846 DOI: 10.1038/s12276-022-00752-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 12/15/2021] [Accepted: 01/16/2022] [Indexed: 02/07/2023] Open
Abstract
Cancer cachexia syndrome is a major cause of morbidity and mortality in cancer patients in the advanced stage. It is a devastating disorder characterized by nutritional impairment, weakness, and wasting, and it affects treatment success and quality of life. Two major symptoms of cancer cachexia are anorexia and weight loss. Weight loss in cachexia is not reversed through increased food intake, suggesting that anorexia and weight loss in cancer patients are regulated by independent molecular mechanisms. Although the wasting phenotype mostly occurs in skeletal muscle and adipose tissue, other organs, such as the brain, liver, pancreas, heart, and gut, are also involved in cachexia. Thus, cachexia is a multiorgan syndrome. Although the molecular basis of cancer cachexia-induced weight loss is known, the mechanism underlying anorexia is poorly understood. Here, we highlight our recent discovery of a new anorexia mechanism by which a tumor-derived humoral factor induces cancer anorexia by regulating feeding-related neuropeptide hormones in the brain. Furthermore, we elucidated the process through which anorexia precedes tissue wasting in cachexia. This review article aims to provide an overview of the key molecular mechanisms of anorexia and tissue wasting caused by cancer cachexia. Tumors can release factors that cause anorexia and weight loss in cancer patients, negatively impacting quality of life and treatment success. Patients with this condition, known as cachexia, can lose their appetite and be unable to gain weight even if they eat more. Although cancer cachexia directly causes the death of up to 20% of cancer patients, the mechanisms are poorly understood. Eunbyul Yeom and Kweon Yu at The Korea Research Institute of Bioscience and Biotechnology, Daejon, South Korea have reviewed the causes of cancer cachexia, highlighting their recent discovery that tumors produce a signaling molecule that induces anorexia by disrupting hunger signaling in the brain. Improving our understanding of the mechanisms underlying cancer cachexia may help in development of treatments.
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Doudakmanis C, Bouliaris K, Kolla C, Efthimiou M, Koukoulis GD. Bacterial translocation in patients undergoing major gastrointestinal surgery and its role in postoperative sepsis. World J Gastrointest Pathophysiol 2021; 12:106-114. [PMID: 34877025 PMCID: PMC8611185 DOI: 10.4291/wjgp.v12.i6.106] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/14/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
Bacteria of the human intestinal microflora have a dual role. They promote digestion and are part of a defense mechanism against pathogens. These bacteria could become potential pathogens under certain circumstances. The term “bacterial translocation” describes the passage of bacteria of the gastrointestinal tract through the intestinal mucosa barrier to mesenteric lymph nodes and other organs. In some cases, the passage of bacteria and endotoxins could result in blood stream infections and in multiple organ failure. Open elective abdominal surgery more frequently results in malfunction of the intestinal barrier and subsequent bacterial translocation and blood stream infections than laparoscopic surgery. Postoperative sepsis is a common finding in patients who have undergone non-elective abdominal surgeries, including trauma patients treated with laparotomy. Postoperative sepsis is an emerging issue, as it changes the treatment plan in surgical patients and prolongs hospital stay. The association between bacterial translocation and postoperative sepsis could provide novel treatment options.
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Affiliation(s)
- Christos Doudakmanis
- Department of General Surgery, General Hospital of Larissa, Larisa 41221, Greece
| | | | - Christina Kolla
- Department of General Surgery, General Hospital of Larissa, Larisa 41221, Greece
| | - Matthaios Efthimiou
- Department of General Surgery, General Hospital of Larissa, Larisa 41221, Greece
| | - Georgios D Koukoulis
- Department of General Surgery, General Hospital of Larissa, Larisa 41221, Greece
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Yang W, Huang J, Wu H, Wang Y, Du Z, Ling Y, Wang W, Wu Q, Gao W. Molecular mechanisms of cancer cachexia‑induced muscle atrophy (Review). Mol Med Rep 2020; 22:4967-4980. [PMID: 33174001 PMCID: PMC7646947 DOI: 10.3892/mmr.2020.11608] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 09/09/2020] [Indexed: 12/20/2022] Open
Abstract
Muscle atrophy is a severe clinical problem involving the loss of muscle mass and strength that frequently accompanies the development of numerous types of cancer, including pancreatic, lung and gastric cancers. Cancer cachexia is a multifactorial syndrome characterized by a continuous decline in skeletal muscle mass that cannot be reversed by conventional nutritional therapy. The pathophysiological characteristic of cancer cachexia is a negative protein and energy balance caused by a combination of factors, including reduced food intake and metabolic abnormalities. Numerous necessary cellular processes are disrupted by the presence of abnormal metabolites, which mediate several intracellular signaling pathways and result in the net loss of cytoplasm and organelles in atrophic skeletal muscle during various states of cancer cachexia. Currently, the clinical morbidity and mortality rates of patients with cancer cachexia are high. Once a patient enters the cachexia phase, the consequences are difficult to reverse and the treatment methods for cancer cachexia are very limited. The present review aimed to summarize the recent discoveries regarding the pathogenesis of cancer cachexia-induced muscle atrophy and provided novel ideas for the comprehensive treatment to improve the prognosis of affected patients.
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Affiliation(s)
- Wei Yang
- Department of Oncology, The Third Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518000, P.R. China
| | - Jianhui Huang
- Department of Oncology, Lishui Municipal Central Hospital, Lishui, Zhejiang 323000, P.R. China
| | - Hui Wu
- Department of Clinical Medicine, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Yuqing Wang
- Department of Clinical Medicine, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Zhiyin Du
- Department of Clinical Medicine, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Yuanbo Ling
- Department of Clinical Medicine, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Weizhuo Wang
- Department of Clinical Medicine, Anhui University of Science and Technology, Huainan, Anhui 232001, P.R. China
| | - Qian Wu
- Department of Oncology, The Third Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518000, P.R. China
| | - Wenbin Gao
- Department of Oncology, The Third Affiliated Hospital of Shenzhen University, Shenzhen, Guangdong 518000, P.R. China
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Rohm M, Zeigerer A, Machado J, Herzig S. Energy metabolism in cachexia. EMBO Rep 2019; 20:embr.201847258. [PMID: 30890538 DOI: 10.15252/embr.201847258] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 01/11/2019] [Accepted: 02/05/2019] [Indexed: 12/26/2022] Open
Abstract
Cachexia is a wasting disorder that accompanies many chronic diseases including cancer and results from an imbalance of energy requirements and energy uptake. In cancer cachexia, tumor-secreted factors and/or tumor-host interactions cause this imbalance, leading to loss of adipose tissue and skeletal and cardiac muscle, which weakens the body. In this review, we discuss how energy enters the body and is utilized by the different organs, including the gut, liver, adipose tissue, and muscle, and how these organs contribute to the energy wasting observed in cachexia. We also discuss futile cycles both between the organs and within the cells, which are often used to fine-tune energy supply under physiologic conditions. Ultimately, understanding the complex interplay of pathologic energy-wasting circuits in cachexia can bring us closer to identifying effective treatment strategies for this devastating wasting disease.
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Affiliation(s)
- Maria Rohm
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.,Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
| | - Anja Zeigerer
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.,Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
| | - Juliano Machado
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany.,Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany
| | - Stephan Herzig
- Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Neuherberg, Germany .,Joint Heidelberg-IDC Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, Heidelberg, Germany.,Chair Molecular Metabolic Control, Technical University Munich, Munich, Germany
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Ono Y, Sakamoto K. Lipopolysaccharide inhibits myogenic differentiation of C2C12 myoblasts through the Toll-like receptor 4-nuclear factor-κB signaling pathway and myoblast-derived tumor necrosis factor-α. PLoS One 2017; 12:e0182040. [PMID: 28742154 PMCID: PMC5524356 DOI: 10.1371/journal.pone.0182040] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 07/11/2017] [Indexed: 12/21/2022] Open
Abstract
Background Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or with various endogenous diseases that are associated with metabolic endotoxemia. Involuntary loss of skeletal muscle, termed muscle wasting, is commonly observed in these conditions, suggesting that circulating LPS might play an essential role in its development. Although impairment of muscle regeneration is an important determinant of skeletal muscle wasting, it is unclear whether LPS affects this process and, if so, by what mechanism. Here, we used the C2C12 myoblast cell line to investigate the effects of LPS on myogenesis. Methods C2C12 myoblasts were grown to 80% confluence and induced to differentiate in the absence or presence of LPS (0.1 or 1 μg/mL); TAK-242 (1 μM), a specific inhibitor of Toll-like receptor 4 (TLR4) signaling; and a tumor necrosis factor (TNF)-α neutralizing antibody (5 μg/mL). Expression of a skeletal muscle differentiation marker (myosin heavy chain II), two essential myogenic regulatory factors (myogenin and MyoD), and a muscle negative regulatory factor (myostatin) was analyzed by western blotting. Nuclear factor-κB (NF-κB) DNA-binding activity was measured using an enzyme-linked immunosorbent assay. Results LPS dose-dependently and significantly decreased the formation of multinucleated myotubes and the expression of myosin heavy chain II, myogenin, and MyoD, and increased NF-κB DNA-binding activity and myostatin expression. The inhibitory effect of LPS on myogenic differentiation was reversible, suggesting that it was not caused by nonspecific toxicity. Both TAK-242 and anti-TNF-α reduced the LPS-induced increase in NF-κB DNA-binding activity, downregulation of myogenic regulatory factors, and upregulation of myostatin, thereby partially rescuing the impairment of myogenesis. Conclusions Our data suggest that LPS inhibits myogenic differentiation via a TLR4–NF-κB-dependent pathway and an autocrine/paracrine TNF-α-induced pathway. These pathways may be involved in the development of muscle wasting caused by sepsis or metabolic endotoxemia.
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Affiliation(s)
- Yuko Ono
- Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima, Japan
- Emergency and Critical Care Medical Center, Fukushima Medical University Hospital, Fukushima, Japan
| | - Kazuho Sakamoto
- Department of Pharmacology, School of Medicine, Fukushima Medical University, Fukushima, Japan
- * E-mail:
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Murine model of chemotherapy-induced extraintestinal pathogenic Escherichia coli translocation. Infect Immun 2015; 83:3243-56. [PMID: 26034214 DOI: 10.1128/iai.00684-15] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 05/28/2015] [Indexed: 11/20/2022] Open
Abstract
Escherichia coli is a major cause of life-threatening infections in patients with neutropenia, particularly those receiving chemotherapy for the treatment of cancer. In most cases, these infections originate from opportunistic strains living within the patient's gastrointestinal tract which then translocate to major organ systems. There are no animal models that faithfully recapitulate these infections, and, as such, the host or bacterial factors that govern this process remain unidentified. We present here a novel model of chemotherapy-induced bacterial translocation of E. coli. Oral gavage of BALB/c mice with a clinical isolate of extraintestinal pathogenic E. coli (ExPEC) leads to stable and long-term colonization of the murine intestine. Following the induction of neutropenia with the chemotherapeutic drug cyclophosphamide, ExPEC translocates from the intestine to the lungs, liver, spleen, and kidneys with concomitant morbidity in infected animals. Translocation can also occur in mice bearing mammary tumors, even in the absence of chemotherapy. Translocation of ExPEC is also associated with an increase of the diversity of bacterial DNA detected in the blood. This is the first report of a chemotherapy-based animal model of ExPEC translocation in cancerous mice, a system that can be readily used to identify important virulence factors for this process.
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Abstract
PURPOSE OF REVIEW Interleukin-6 (IL-6) has emerged as a cytokine involved in cachexia progression with some cancers. This review will present the recent breakthroughs in animal models and humans related to targeting IL-6 as a cancer cachexia therapy. RECENT FINDINGS IL-6 can target adipose, skeletal muscle, gut, and liver tissue, which can all affect cachectic patient recovery. IL-6 trans-signaling through the soluble IL-6R has the potential to amplify IL-6 signaling in the cachectic patient. In the skeletal muscle, chronic IL-6 exposure induces proteasome and autophagy protein degradation pathways that lead to wasting. IL-6 is also indirectly associated with AMP-activated kinase (AMPK) and nuclear factor kappa B (NF-κB) activation. Several mouse cancer models have clearly demonstrated that blocking IL-6 and associated signaling can attenuate cachexia progression. Additionally, pharmaceuticals targeting IL-6 and associated signaling can relieve some cachectic symptoms in cancer patients. Research with cachectic mice has demonstrated that exercise and nutraceutical administration can interact with chronic IL-6 signaling during cachexia progression. SUMMARY IL-6 remains a promising therapeutic strategy for attenuating cachexia progression with many types of cancer. However, improvement of this treatment will require a better understanding of the indirect and direct effects of IL-6 as well as its tissue-specific actions in the cancer patient.
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Affiliation(s)
- Aditi A Narsale
- Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, SC 29208
- Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208
| | - James A. Carson
- Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, SC 29208
- Center for Colon Cancer Research, University of South Carolina, Columbia, SC 29208
- Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208
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Jiang Y, Guo C, Zhang D, Zhang J, Wang X, Geng C. The altered tight junctions: an important gateway of bacterial translocation in cachexia patients with advanced gastric cancer. J Interferon Cytokine Res 2014; 34:518-25. [PMID: 24720758 DOI: 10.1089/jir.2013.0020] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED Tight junctions (TJs) are the structural basis for the intestinal epithelium barrier. Increased intestinal permeability caused by variations in TJ proteins may result in bacterial translocation (BT). There is increasing evidence that BT might contribute to the occurrence and development of cancer cachexia, but the details are not known. Aims, we undertook further investigations into the pathway of BT in cancer cachexia. RESULTS BT-positive patients had a higher level of claudins-2 (CL-2, P=0.035) and a lower level of occludin (P=0.038) and Zonula occluden-1 (P=0.01) than BT-negative patients. Moreover, the levels of IL-6, TNF-α, and IFN-γ in BT-positive cachexia patients were higher compared with BT-negative cachexia patients (P<0.001, P=0.01, P<0.001) and BT-positive noncachexia patients (P<0.001, P=0.025, P<0.001). In the BT-positive cachexia patients, the local concentration of IL-6, TNF-α, and IFN-γ, in the middle colic vein, was higher than in the peripheral venous (P=0.04, P=0.03, P=0.038). In addition, endotoxin was detected within the small intestinal wall, and the concentration of endotoxin decreased from the mucosal side to the serosal side gradually in BT-positive patients. This study suggests that the altered TJs could be an important gateway of BT in gastric cancer cachexia and local cytokines could play a more important role than systemic cytokines in the process.
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Affiliation(s)
- Yingjian Jiang
- 1 Department of General Surgery, The Affiliated Hospital of Medical College, Qingdao University , Qingdao, P.R. China
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