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Role of the Gut Microbiome in Skeletal Muscle Physiology and Pathophysiology

  • Muscle and Bone (A Bonetto and M Brotto, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review aims to summarize the recent findings about the contribution of the gut microbiome to muscle pathophysiology and discuss molecular pathways that may be involved in such process. Related findings in the context of cancer cachexia are outlined.

Recent Findings

Many bacterial metabolites have been reported to exert a beneficial or detrimental impact on muscle physiology. Most of the evidence concentrates on short-chain fatty acids (SCFAs), with an emerging role for bile acids, bacterial amino acid metabolites (bAAms), and bacterial polyphenol metabolites. Other molecular players worth considering include cytokines, hormones, lipopolysaccharides, and quorum sensing molecules.

Summary

The current literature clearly establishes the ability for the gut microbiome to modulate muscle function and mass. The understanding of the mechanisms underlying this gut-muscle axis may lead to the delivery of novel therapeutic tools to tackle muscle wasting in cancer cachexia, chronic kidney disease, liver fibrosis, and age-related sarcopenia.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Frontera WR, Ochala J. Skeletal muscle: a brief review of structure and function. Calcif Tissue Int. 2015;96(3):183–95.

    Article  CAS  PubMed  Google Scholar 

  2. Sartori R, Romanello V, Sandri M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease. Nat Commun. 2021;12(1):330. A review summarizing the main molecular pathways involved in the regulation of muscle.

  3. Lee YH, Kim SU, Song K, Park JY, Kim DY, Ahn SH, Lee BW, Kang ES, Cha BS, Han KH. Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: Nationwide surveys (KNHANES 2008-2011). Hepatology. 2016;63(3):776–86.

    Article  CAS  PubMed  Google Scholar 

  4. Prado CM, Purcell SA, Laviano A. Nutrition interventions to treat low muscle mass in cancer. J Cachexia Sarcopenia Muscle. 2020;11(2):366–80.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Prado CM, Purcell SA, Alish C, Pereira SL, Deutz NE, Heyland DK, Goodpaster BH, Tappenden KA, Heymsfield SB. Implications of low muscle mass across the continuum of care: a narrative review. Ann Med. 2018;50(8):675–93.

    Article  PubMed  Google Scholar 

  6. Maddocks M, Hopkinson J, Conibear J, Reeves A, Shaw C, Fearon KC. Practical multimodal care for cancer cachexia. Curr Opin Support Palliat Care. 2016;10(4):298–305.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Potgens SA, Sboarina M, Bindels LB. Polyunsaturated fatty acids, polyphenols, amino acids, prebiotics: can they help to tackle cancer cachexia and related inflammation? Curr Opin Clin Nutr Metab Care. 2018;21(6):458–64.

    Article  PubMed  Google Scholar 

  8. Bindels LB, Delzenne NM. Muscle wasting: the gut microbiota as a new therapeutic target? Int J Biochem Cell Biol. 2013;45(10):2186–90.

    Article  CAS  PubMed  Google Scholar 

  9. Bindels LB, Thissen JP. Nutrition in cancer patients with cachexia: a role for the gut microbiota? Clin Nutr Exp. 2016;6:74–82.

    Article  Google Scholar 

  10. Ziemons J, Smidt ML, Damink SO, Rensen SS. Gut microbiota and metabolic aspects of cancer cachexia. Best Pract Res Clin Endocrinol Metab. 2021;101508.

  11. Genton L, Cani PD, Schrenzel J. Alterations of gut barrier and gut microbiota in food restriction, food deprivation and protein-energy wasting. Clin Nutr. 2015;34(3):341–9.

    Article  CAS  PubMed  Google Scholar 

  12. Berg G, Rybakova D, Fischer D, Cernava T, Vergès MC, Charles T, et al. Microbiome definition re-visited: old concepts and new challenges. Microbiome. 2020;8(1):103.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Delzenne NM, Knudsen C, Beaumont M, Rodriguez J, Neyrinck AM, Bindels LB. Contribution of the gut microbiota to the regulation of host metabolism and energy balance: a focus on the gut-liver axis. Proc Nutr Soc. 2019:1–10.

  14. Makki K, Deehan EC, Walter J, Backhed F. The impact of dietary fiber on gut microbiota in host health and disease. Cell Host Microbe. 2018;23(6):705–15.

    Article  CAS  PubMed  Google Scholar 

  15. Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ. 2018;361:k2179. A review introducing key concepts in the gut microbiota field, how nutrition impacts the gut microbiota, and mechanisms through which the gut microbiota modulates host health.

  16. Gibson GR, Hutkins R, Sanders ME, Prescott SL, Reimer RA, Salminen SJ, Scott K, Stanton C, Swanson KS, Cani PD, Verbeke K, Reid G. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of prebiotics. Nat Rev Gastroenterol Hepatol. 2017;14(8):491–502.

    Article  PubMed  Google Scholar 

  17. Hill C, Guarner F, Reid G, Gibson GR, Merenstein DJ, Pot B, Morelli L, Canani RB, Flint HJ, Salminen S, Calder PC, Sanders ME. Expert consensus document: the International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nat Rev Gastroenterol Hepatol. 2014;11:506–14.

    Article  PubMed  Google Scholar 

  18. Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. 2018;23(6):716–24.

    Article  CAS  PubMed  Google Scholar 

  19. Oliphant K, Allen-Vercoe E. Macronutrient metabolism by the human gut microbiome: major fermentation by-products and their impact on host health. Microbiome. 2019;7(1):91. A review describes in detail macronutrient metabolism by the gut microbiome and how the ensuing metabolites influence human health.

  20. Postler TS, Ghosh S. Understanding the holobiont: how microbial metabolites affect human health and shape the immune system. Cell Metab. 2017;26(1):110–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, et al. The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA. 2004;101(44):15718–23.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Lahiri S, Kim H, Garcia-Perez I, Reza MM, Martin KA, Kundu P, et al. The gut microbiota influences skeletal muscle mass and function in mice. Sci Transl Med. 2019;11(502). This research article is the first one to provide a detailed characterization of the muscle of germ-free mice, compared to conventional and conventionalized mice, and to establish the beneficial impact of short-chain fatty acids on muscle mass and function.

  23. Nay K, Jollet M, Goustard B, Baati N, Vernus B, Pontones M, et al. Gut bacteria are critical for optimal muscle function: a potential link with glucose homeostasis. Am J Physiol Endocrinol Metab. 2019. This research article contributes significantly to the evidence that gut microbiota modulates muscle function, as established through the administration of a broad spectrum antibiotics cocktail.

  24. Bindels LB, Segura Munoz RR, Gomes-Neto JC, Mutemberezi V, Martinez I, Salazar N, et al. Resistant starch can improve insulin sensitivity independently of the gut microbiota. Microbiome. 2017;5(1):12.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zarrinpar A, Chaix A, Xu ZZ, Chang MW, Marotz CA, Saghatelian A, Knight R, Panda S. Antibiotic-induced microbiome depletion alters metabolic homeostasis by affecting gut signaling and colonic metabolism. Nat Commun. 2018;9(1):2872.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Huang WC, Chen YH, Chuang HL, Chiu CC, Huang CC. Investigation of the effects of microbiota on exercise physiological adaption, performance, and energy utilization using a gnotobiotic animal model. Front Microbiol. 2019;10:1906.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Lee MC, Hsu YJ, Ho HH, Hsieh SH, Kuo YW, Sung HC, et al. Lactobacillus salivarius subspecies salicinius SA-03 is a new probiotic capable of enhancing exercise performance and decreasing fatigue. Microorganisms. 2020;8(4).

  28. Chen YM, Wei L, Chiu YS, Hsu YJ, Tsai TY, Wang MF, Huang CC. Lactobacillus plantarum TWK10 supplementation improves exercise performance and increases muscle mass in mice. Nutrients. 2016;8(4):205.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Huang WC, Hsu YJ, Huang CC, Liu HC, Lee MC. Exercise training combined with Bifidobacterium longum OLP-01 supplementation improves exercise physiological adaption and performance. Nutrients. 2020;12(4).

  30. Munukka E, Rintala A, Toivonen R, Nylund M, Yang B, Takanen A, Hänninen A, Vuopio J, Huovinen P, Jalkanen S, Pekkala S. Faecalibacterium prausnitzii treatment improves hepatic health and reduces adipose tissue inflammation in high-fat fed mice. ISME J. 2017;11(7):1667–79.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Li G, Jin B, Fan Z. Mechanisms involved in gut microbiota regulation of skeletal muscle. Oxid Med Cell Longev. 2022;2022:2151191–15.

    PubMed  PubMed Central  Google Scholar 

  32. Giron M, Thomas M, Dardevet D, Chassard C, Savary-Auzeloux I. Gut microbes and muscle function: can probiotics make our muscles stronger? J Cachexia Sarcopenia Muscle. 2022. This review provides a summary of the impact of probiotics on muscle mass and function in mice and humans.

  33. Fielding RA, Reeves AR, Jasuja R, Liu C, Barrett BB, Lustgarten MS. Muscle strength is increased in mice that are colonized with microbiota from high-functioning older adults. Exp Gerontol. 2019;127:110722.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Buigues C, Fernandez-Garrido J, Pruimboom L, Hoogland AJ, Navarro-Martinez R, Martinez-Martinez M, et al. Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial. Int J Mol Sci. 2016;17(6).

  35. Fu SK, Tseng WC, Tseng KW, Lai CC, Tsai YC, Tai HL, et al. Effect of daily oral Lactobacillus plantarum PS128 on exercise capacity recovery after a half-marathon. Nutrients. 2021;13(11).

  36. Reijnders D, Goossens GH, Hermes GDA, Smidt H, Zoetendal EG, Blaak EE. Short-term microbiota manipulation and forearm substrate metabolism in obese men: a randomized, double-blind, placebo-controlled trial. Obes Facts. 2018;11(4):318–26.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Mitchell CM, Davy BM, Ponder MA, McMillan RP, Hughes MD, Hulver MW, et al. Prebiotic inulin supplementation and peripheral insulin sensitivity in adults at elevated risk for type 2 diabetes: a pilot randomized controlled trial. Nutrients. 2021;13(9).

  38. Backhed F, Manchester JK, Semenkovich CF, Gordon JI. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA. 2007;104(3):979–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Rodriguez J, Delzenne NM. Modulation of the gut microbiota-adipose tissue-muscle interactions by prebiotics. J Endocrinol. 2021;249(1):R1–R23.

    Article  CAS  PubMed  Google Scholar 

  40. Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol. 2015;11(10):577–91.

    Article  CAS  PubMed  Google Scholar 

  41. Canfora EE, Meex RCR, Venema K, Blaak EE. Gut microbial metabolites in obesity, NAFLD and T2DM. Nat Rev Endocrinol. 2019;15(5):261–73.

    Article  CAS  PubMed  Google Scholar 

  42. Dalile B, Van Oudenhove L, Vervliet B, Verbeke K. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol. 2019;16(8):461–78.

    Article  PubMed  Google Scholar 

  43. Frampton J, Murphy KG, Frost G, Chambers ES. Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function. Nat Metab. 2020;2(9):840-8. This review provides an extensive summary of the impact of short-chain fatty acids on muscle.

  44. Walsh ME, Bhattacharya A, Sataranatarajan K, Qaisar R, Sloane L, Rahman MM, Kinter M, van Remmen H. The histone deacetylase inhibitor butyrate improves metabolism and reduces muscle atrophy during aging. Aging Cell. 2015;14(6):957–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Scheiman J, Luber JM, Chavkin TA, MacDonald T, Tung A, Pham LD, et al. Meta-omics analysis of elite athletes identifies a performance-enhancing microbe that functions via lactate metabolism. Nat Med. 2019;25(7):1104-9. This research article provides a mechanistic demonstration of the crosstalk between one specific microbe, Veillonella atypica, and the muscle upon exercise.

  46. Chen F, Li Q, Chen Y, Wei Y, Liang J, Song Y, Shi L, Wang J, Mao L, Zhang B, Zhang Z. Association of the gut microbiota and fecal short-chain fatty acids with skeletal muscle mass and strength in children. FASEB J. 2022;36(1):e22109.

    Article  CAS  PubMed  Google Scholar 

  47. Lv WQ, Lin X, Shen H, Liu HM, Qiu X, Li BY, Shen WD, Ge CL, Lv FY, Shen J, Xiao HM, Deng HW. Human gut microbiome impacts skeletal muscle mass via gut microbial synthesis of the short-chain fatty acid butyrate among healthy menopausal women. J Cachexia Sarcopenia Muscle. 2021;12(6):1860–70.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Thibaut MM, Bindels LB. Crosstalk between bile acid-activated receptors and microbiome in entero-hepatic inflammation. Trends Mol Med. 2022;28(3):223-36. This review describes how gut microbes modulate bile acid metabolism and pathways.

  49. Perino A, Demagny H, Velazquez-Villegas L, Schoonjans K. Molecular physiology of bile acid signaling in health, disease, and aging. Physiol Rev. 2021;101(2):683-731. Comprehensive review on bile acids, their metabolism, and their role in health, disease, and aging.

  50. Watanabe M, Houten SM, Mataki C, Christoffolete MA, Kim BW, Sato H, Messaddeq N, Harney JW, Ezaki O, Kodama T, Schoonjans K, Bianco AC, Auwerx J. Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation. Nature. 2006;439(7075):484–9.

    Article  CAS  PubMed  Google Scholar 

  51. Sasaki T, Kuboyama A, Mita M, Murata S, Shimizu M, Inoue J, Mori K, Sato R. The exercise-inducible bile acid receptor Tgr5 improves skeletal muscle function in mice. J Biol Chem. 2018;293(26):10322–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Abrigo J, Gonzalez F, Aguirre F, Tacchi F, Gonzalez A, Meza MP, et al. Cholic acid and deoxycholic acid induce skeletal muscle atrophy through a mechanism dependent on TGR5 receptor. J Cell Physiol. 2020.

  53. Sasaki T, Watanabe Y, Kuboyama A, Oikawa A, Shimizu M, Yamauchi Y, Sato R. Muscle-specific TGR5 overexpression improves glucose clearance in glucose-intolerant mice. J Biol Chem. 2021;296:100131.

    Article  CAS  PubMed  Google Scholar 

  54. Benoit B, Meugnier E, Castelli M, Chanon S, Vieille-Marchiset A, Durand C, Bendridi N, Pesenti S, Monternier PA, Durieux AC, Freyssenet D, Rieusset J, Lefai E, Vidal H, Ruzzin J. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat Med. 2017;23(8):990–6.

    Article  CAS  PubMed  Google Scholar 

  55. Qiu Y, Yu J, Ji X, Yu H, Xue M, Zhang F, Li Y, Bao Z. Ileal FXR-FGF15/19 signaling activation improves skeletal muscle loss in aged mice. Mech Ageing Dev. 2022;202:111630.

    Article  CAS  PubMed  Google Scholar 

  56. Guo A, Li K, Xiao Q. Fibroblast growth factor 19 alleviates palmitic acid-induced mitochondrial dysfunction and oxidative stress via the AMPK/PGC-1alpha pathway in skeletal muscle. Biochem Biophys Res Commun. 2020;526(4):1069–76.

    Article  CAS  PubMed  Google Scholar 

  57. Koppe L, Pillon NJ, Vella RE, Croze ML, Pelletier CC, Chambert S, Massy Z, Glorieux G, Vanholder R, Dugenet Y, Soula HA, Fouque D, Soulage CO. p-Cresyl sulfate promotes insulin resistance associated with CKD. J Am Soc Nephrol. 2013;24(1):88–99.

    Article  CAS  PubMed  Google Scholar 

  58. Savira F, Cao L, Wang I, Yang W, Huang K, Hua Y, Jucker BM, Willette RN, Huang L, Krum H, Li Z, Fu Q, Wang BH. Apoptosis signal-regulating kinase 1 inhibition attenuates cardiac hypertrophy and cardiorenal fibrosis induced by uremic toxins: implications for cardiorenal syndrome. PLoS ONE. 2017;12(11):e0187459.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Han H, Zhu J, Zhu Z, Ni J, Du R, Dai Y, et al. p-Cresyl sulfate aggravates cardiac dysfunction associated with chronic kidney disease by enhancing apoptosis of cardiomyocytes. J Am Heart Assoc. 2015;4(6):e001852.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Huang TH, Yip HK, Sun CK, Chen YL, Yang CC, Lee FY. P-cresyl sulfate causes mitochondrial hyperfusion in H9C2 cardiomyoblasts. J Cell Mol Med. 2020;24(15):8379–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Koh A, Molinaro A, Stahlman M, Khan MT, Schmidt C, Manneras-Holm L, et al. Microbially produced imidazole propionate impairs insulin signaling through mTORC1. Cell. 2018;175(4):947–61 e17.

    Article  CAS  PubMed  Google Scholar 

  62. Roager HM, Licht TR. Microbial tryptophan catabolites in health and disease. Nat Commun. 2018;9(1):3294.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Sato E, Mori T, Mishima E, Suzuki A, Sugawara S, Kurasawa N, Saigusa D, Miura D, Morikawa-Ichinose T, Saito R, Oba-Yabana I, Oe Y, Kisu K, Naganuma E, Koizumi K, Mokudai T, Niwano Y, Kudo T, Suzuki C, et al. Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease. Sci Rep. 2016;6:36618.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Enoki Y, Watanabe H, Arake R, Sugimoto R, Imafuku T, Tominaga Y, Ishima Y, Kotani S, Nakajima M, Tanaka M, Matsushita K, Fukagawa M, Otagiri M, Maruyama T. Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1. Sci Rep. 2016;6:32084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Thome T, Salyers ZR, Kumar RA, Hahn D, Berru FN, Ferreira LF, Scali ST, Ryan TE. Uremic metabolites impair skeletal muscle mitochondrial energetics through disruption of the electron transport system and matrix dehydrogenase activity. Am J Physiol Cell Physiol. 2019;317(4):C701–C13.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Lin YL, Liu CH, Lai YH, Wang CH, Kuo CH, Liou HH, Hsu BG. Association of serum indoxyl sulfate levels with skeletal muscle mass and strength in chronic hemodialysis patients: a 2-year longitudinal analysis. Calcif Tissue Int. 2020;107(3):257–65.

    Article  CAS  PubMed  Google Scholar 

  67. Enoki Y, Watanabe H, Arake R, Fujimura R, Ishiodori K, Imafuku T, Nishida K, Sugimoto R, Nagao S, Miyamura S, Ishima Y, Tanaka M, Matsushita K, Komaba H, Fukagawa M, Otagiri M, Maruyama T. Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction. J Cachexia Sarcopenia Muscle. 2017;8(5):735–47.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Du L, Qi R, Wang J, Liu Z, Wu Z. Indole-3-propionic acid, a functional metabolite of Clostridium sporogenes, promotes muscle tissue development and reduces muscle cell inflammation. Int J Mol Sci. 2021;22(22).

  69. Agus A, Clement K, Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut. 2021;70(6):1174–1182. https://pubmed.ncbi.nlm.nih.gov/33272977/

  70. Agudelo LZ, Ferreira DMS, Dadvar S, Cervenka I, Ketscher L, Izadi M, et al. Skeletal muscle PGC-1alpha1 reroutes kynurenine metabolism to increase energy efficiency and fatigue-resistance. Nat Commun. 2019;10(1):2767. This research article demonstrates that upon exercise, PGC-1α1 is activated and coordinates a program that leads to the production of glutamate and an improvement in muscle bioenergetics.

  71. Haikonen R, Karkkainen O, Koistinen V, Hanhineva K. Diet- and microbiota-related metabolite, 5-aminovaleric acid betaine (5-AVAB), in health and disease. Trends Endocrinol Metab. 2022;33:463–80.

    Article  CAS  PubMed  Google Scholar 

  72. Zhao M, Wei H, Li C, Zhan R, Liu C, Gao J, et al. Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy. Nat Commun. 2022;13(1):1757. Demonstration of the impact of the 5-AVAB on cardiac muscle cells and investigation of the underlying mechanisms.

  73. Karkkainen O, Tuomainen T, Koistinen V, Tuomainen M, Leppanen J, Laitinen T, et al. Whole grain intake associated molecule 5-aminovaleric acid betaine decreases beta-oxidation of fatty acids in mouse cardiomyocytes. Sci Rep. 2018;8(1):13036.

    Article  PubMed  PubMed Central  Google Scholar 

  74. González-Sarrías A, Espín JC, Tomás-Barberán FA. Non-extractable polyphenols produce gut microbiota metabolites that persist in circulation and show anti-inflammatory and free radical-scavenging effects. Trends Food Sci Technol. 2017;69:281–8.

    Article  Google Scholar 

  75. Houghton MJ, Kerimi A, Mouly V, Tumova S, Williamson G. Gut microbiome catabolites as novel modulators of muscle cell glucose metabolism. FASEB J. 2019;33(2):1887-98. In this research article, the authors demonstrated the ability of microbiota-derived phenolic metabolites to modulate glucose uptake and metabolism in human muscle cells.

  76. Rodriguez J, Pierre N, Naslain D, Bontemps F, Ferreira D, Priem F, Deldicque L, Francaux M. Urolithin B, a newly identified regulator of skeletal muscle mass. J Cachexia Sarcopenia Muscle. 2017;8(4):583–97.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab. 2019;1(6):595-603. This phase I study demonstrates the successful translation of the benefits of the natural food metabolite urolithin A to humans, with an improvement in mitochondrial health of elderly subjects.

  78. Rodriguez J, Caille O, Ferreira D, Francaux M. Pomegranate extract prevents skeletal muscle of mice against wasting induced by acute TNF-alpha injection. Mol Nutr Food Res. 2017;61(4).

  79. Pallister T, Jackson MA, Martin TC, Zierer J, Jennings A, Mohney RP, MacGregor A, Steves CJ, Cassidy A, Spector TD, Menni C. Hippurate as a metabolomic marker of gut microbiome diversity: modulation by diet and relationship to metabolic syndrome. Sci Rep. 2017;7(1):13670.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Huang M, Wei R, Wang Y, Su T, Li P, Chen X. The uremic toxin hippurate promotes endothelial dysfunction via the activation of Drp1-mediated mitochondrial fission. Redox Biol. 2018;16:303–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bitner BF, Ray JD, Kener KB, Herring JA, Tueller JA, Johnson DK, Tellez Freitas CM, Fausnacht DW, Allen ME, Thomson AH, Weber KS, McMillan RP, Hulver MW, Brown DA, Tessem JS, Neilson AP. Common gut microbial metabolites of dietary flavonoids exert potent protective activities in beta-cells and skeletal muscle cells. J Nutr Biochem. 2018;62:95–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Bindels LB, Beck R, Schakman O, Martin JC, De Backer FC, Sohet FM, et al. Restoring specific lactobacilli levels decreases inflammation and muscle atrophy markers in an acute leukemia mouse model. PLoS ONE. 2012;7(6):e37971.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Varian BJ, Goureshetti S, Poutahidis T, Lakritz JR, Levkovich T, Kwok C, Teliousis K, Ibrahim YM, Mirabal S, Erdman SE. Beneficial bacteria inhibit cachexia. Oncotarget. 2016;7(11):11803–16.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Song J, Wang C, Long D, Li Z, You L, Brand-Saberi B, Wang G, Yang X. Dysbacteriosis-induced LPS elevation disturbs the development of muscle progenitor cells by interfering with retinoic acid signaling. FASEB J. 2020;34(5):6837–53.

    Article  CAS  PubMed  Google Scholar 

  85. Doyle A, Zhang G, bdel Fattah EA, Eissa NT, Li YP. Toll-like receptor 4 mediates lipopolysaccharide-induced muscle catabolism via coordinate activation of ubiquitin-proteasome and autophagy-lysosome pathways. FASEB J. 2011;25(1):99-110.

  86. Bindels LB, Neyrinck AM, Claus SP, Le Roy CI, Grangette C, Pot B, et al. Synbiotic approach restores intestinal homeostasis and prolongs survival in leukaemic mice with cachexia. ISME J. 2016;10(6):1456–70.

    Article  CAS  PubMed  Google Scholar 

  87. Bindels LB, Neyrinck AM, Loumaye A, Catry E, Walgrave H, Cherbuy C, Leclercq S, van Hul M, Plovier H, Pachikian B, Bermúdez-Humarán LG, Langella P, Cani PD, Thissen JP, Delzenne NM. Increased gut permeability in cancer cachexia: mechanisms and clinical relevance. Oncotarget. 2018;9(26):18224–38.

    Article  PubMed  PubMed Central  Google Scholar 

  88. De Spiegeleer A, Elewaut D, Van Den Noortgate N, Janssens Y, Debunne N, Van Langenhove S, et al. Quorum sensing molecules as a novel microbial factor impacting muscle cells. Biochim Biophys Acta Mol Basis Dis. 2020;1866(3):165646. This research article reported for the first time that some quorum sensing molecules can affect muscle cell viability and inflammation in vitro.

  89. Schwarzer M, Makki K, Storelli G, Machuca-Gayet I, Srutkova D, Hermanova P, Martino ME, Balmand S, Hudcovic T, Heddi A, Rieusset J, Kozakova H, Vidal H, Leulier F. Lactobacillus plantarum strain maintains growth of infant mice during chronic undernutrition. Science. 2016;351(6275):854–7.

    Article  CAS  PubMed  Google Scholar 

  90. Martin A, Ecklu-Mensah G, Ha CWY, Hendrick G, Layman DK, Gilbert J, Devkota S. Gut microbiota mediate the FGF21 adaptive stress response to chronic dietary protein-restriction in mice. Nat Commun. 2021;12(1):3838.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Oost LJ, Kustermann M, Armani A, Blaauw B, Romanello V. Fibroblast growth factor 21 controls mitophagy and muscle mass. J Cachexia Sarcopenia Muscle. 2019;10(3):630–42.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Mardinoglu A, Shoaie S, Bergentall M, Ghaffari P, Zhang C, Larsson E, Bäckhed F, Nielsen J. The gut microbiota modulates host amino acid and glutathione metabolism in mice. Mol Syst Biol. 2015;11(10):834.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Neis EP, Dejong CH, Rensen SS. The role of microbial amino acid metabolism in host metabolism. Nutrients. 2015;7(4):2930–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Newsome SD, Feeser KL, Bradley CJ, Wolf C, Takacs-Vesbach C, Fogel ML. Isotopic and genetic methods reveal the role of the gut microbiome in mammalian host essential amino acid metabolism. Proc Biol Sci. 2020;287(1922):20192995.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Ren G, Zhang J, Li M, Tang Z, Yang Z, Cheng G, Wang J. Gut microbiota composition influences outcomes of skeletal muscle nutritional intervention via blended protein supplementation in posttransplant patients with hematological malignancies. Clin Nutr. 2021;40(1):94–102.

    Article  CAS  PubMed  Google Scholar 

  96. Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KCH. Cancer-associated cachexia. Nat Rev Dis Primers. 2018;4:17105.

    Article  PubMed  Google Scholar 

  97. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489–95.

    Article  PubMed  Google Scholar 

  98. Argiles JM, Stemmler B, Lopez-Soriano FJ, Busquets S. Inter-tissue communication in cancer cachexia. Nat Rev Endocrinol. 2018;15(1):9–20.

    Article  PubMed  Google Scholar 

  99. Schmidt SF, Rohm M, Herzig S, Berriel DM. Cancer cachexia: more than skeletal muscle wasting. Trends Cancer. 2018;4(12):849–60.

    Article  CAS  PubMed  Google Scholar 

  100. Bindels LB, Neyrinck AM, Salazar N, Taminiau B, Druart C, Muccioli GG, François E, Blecker C, Richel A, Daube G, Mahillon J, de los Reyes-Gavilán CG, Cani PD, Delzenne NM. Non digestible oligosaccharides modulate the gut microbiota to control the development of leukemia and associated cachexia in mice. PLoS ONE. 2015;10(6):e0131009.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Potgens SA, Brossel H, Sboarina M, Catry E, Cani PD, Neyrinck AM, et al. Klebsiella oxytoca expands in cancer cachexia and acts as a gut pathobiont contributing to intestinal dysfunction. Sci Rep. 2018;8(1):12321.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Pekkala S, Keskitalo A, Kettunen E, Lensu S, Nykanen N, Kuopio T, et al. Blocking activin receptor ligands is not sufficient to rescue cancer-associated gut microbiota-a role for gut microbial flagellin in colorectal cancer and cachexia? Cancers (Basel). 2019;11(11).

  103. Castellani C, Singer G, Kaiser M, Kaiser T, Huang J, Sperl D, Kashofer K, Fauler G, Guertl-Lackner B, Höfler G, Till H. Neuroblastoma causes alterations of the intestinal microbiome, gut hormones, inflammatory cytokines, and bile acid composition. Pediatr Blood Cancer. 2017;64:e26425.

    Article  Google Scholar 

  104. Jabes DL, de Maria Y, Aciole Barbosa D, Santos K, Carvalho LM, Humberto AC, et al. Fungal dysbiosis correlates with the development of tumor-induced cachexia in mice. J Fungi (Basel). 2020;6(4).

  105. Potgens SA, Thibaut MM, Joudiou N, Sboarina M, Neyrinck AM, Cani PD, et al. Multi-compartment metabolomics and metagenomics reveal major hepatic and intestinal disturbances in cancer cachectic mice. J Cachexia Sarcopenia Muscle. 2021;12(2):456–475. https://pubmed.ncbi.nlm.nih.gov/33599103/

  106. Thibaut MM, Sboarina M, Roumain M, Potgens SA, Neyrinck AM, Destree F, et al. Inflammation-induced cholestasis in cancer cachexia. J Cachexia Sarcopenia Muscle. 2021;12(1):70–90. https://pubmed.ncbi.nlm.nih.gov/33350058. First paper demonstrating an alteration in bile acid pathways in mice and humans with cancer cachexia, and how this altered bile acid profile contributes to hepatic inflammation.

  107. Thibaut MM, Gillard J, Dolly A, Roumain M, Leclercq IA, Delzenne NM, et al. Bile acid dysregulation is intrinsically related to cachexia in tumor-bearing mice. Cancers (Basel). 2021;13(24).

  108. Ni Y, Lohinai Z, Heshiki Y, Dome B, Moldvay J, Dulka E, et al. Distinct composition and metabolic functions of human gut microbiota are associated with cachexia in lung cancer patients. ISME J. 2021. First paper reporting an alteration in the gut microbiota between lung cancer patients classified as well-nourished and patients classified as malnourished (19/12 patients).

  109. Ubachs J, Ziemons J, Soons Z, Aarnoutse R, van Dijk DPJ, Penders J, et al. Gut microbiota and short-chain fatty acid alterations in cachectic cancer patients. J Cachexia Sarcopenia Muscle. 2021. First paper showing a reduction in fecal acetate levels, alongside alterations in the gut microbiota, in patients demonstrating a weight loss of 5% or more within the last 6 months versus weigh stable patients (33/74 patients, diverse cancer types).

  110. Bindels LB, Porporato P, Dewulf EM, Verrax J, Neyrinck AM, Martin JC, Scott KP, Buc Calderon P, Feron O, Muccioli GG, Sonveaux P, Cani PD, Delzenne NM. Gut microbiota-derived propionate reduces cancer cell proliferation in the liver. Br J Cancer. 2012;107(8):1337–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

LBB is the recipient of subsidies from the FSR (Action de Recherche Concertée LIPOCAN, 19-24.096), the Télévie (7.4511.21), from the Walloon Region in the context of the funding of the strategic axis FRFS-WELBIO (40009849), as well as the Fonds Wetenschappelijk Onderzoek – Vlaanderen (FWO) and the Fonds de la Recherche Scientifique – FNRS under EOS Project No. 40007505. CL is a postdoctoral fellow from the Télévie (7.4511.21).

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  1. Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Avenue Mounier 73, B1.73.11, 1200, Brussels, Belgium

    Camille Lefevre & Laure B. Bindels

  2. Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Avenue Pasteur 6, 1300, Wavre, Belgium

    Laure B. Bindels

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Lefevre, C., Bindels, L.B. Role of the Gut Microbiome in Skeletal Muscle Physiology and Pathophysiology. Curr Osteoporos Rep 20, 422–432 (2022). https://doi.org/10.1007/s11914-022-00752-9

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