Advances in association and molecular mechanisms linking primary sarcopenia to gut microbiota_West China Medical Journal

Authors：

MA Wenxiang ¹ , ZHAO Shengbing ² , LIU Xusheng ¹ , XIE Jiajing ¹ , DU Nan ¹ , YANG Yang ¹ ,  YU Yongjiang ²

1. The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
2. Department of General Surgery, the First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;

Corresponding?author：

YU Yongjiang, Email: ylongy@163.com

Keywords：

Primary sarcopenia; gut microbiota; gut dysbiosis; gut-muscle axis

DOI：

10.7507/1002-0179.202504247

Video：

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Primary sarcopenia (PS) is an age-related degenerative disorder characterized by progressive loss of skeletal muscle mass and function. This review delineates three mechanisms whereby gut dysbiosis drives PS pathogenesis: decreased secondary bile acids inhibit farnesoid X receptor signaling, thereby attenuating muscle protein synthesis; disrupted short-chain fatty acid metabolism weakens free fatty acid receptor 2/adenosine monophosphate-activated protein kinase signaling, aggravating proteolysis and mitochondrial dysfunction; gut barrier impairment activates the endotoxin–Toll-like receptor 4-mediated inflammatory cascade, accelerating ubiquitin-proteasome system activation. Interventional evidence confirms that microbiota-targeted therapies (probiotics regulating bile acid metabolism and prebiotics enhancing short-chain fatty acid production) effectively improve muscle function. By synthesizing molecular evidence of the “gut-muscle axis”, this review offers theoretical references for developing PS prevention and treatment strategies.

Citation： MA Wenxiang, ZHAO Shengbing, LIU Xusheng, XIE Jiajing, DU Nan, YANG Yang, YU Yongjiang. Advances in association and molecular mechanisms linking primary sarcopenia to gut microbiota. West China Medical Journal, 2026, 41(1): 159-163. doi: 10.7507/1002-0179.202504247 Copy

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2.	Petermann-Rocha F, Balntzi V, Gray SR, et al. Global prevalence of sarcopenia and severe sarcopenia: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle, 2022, 13(1): 86-99.
3.	Chen Z, Li WY, Ho M, et al. The prevalence of sarcopenia in Chinese older adults: meta-analysis and meta-regression. Nutrients, 2021, 13(5): 1441.
4.	Lan L, Shao S, Zheng X. Associations between sarcopenia and trajectories of activities of daily living disability: a nationwide longitudinal study of middle-aged and older adults in China from 2011 to 2018. Arch Public Health, 2024, 82(1): 97.
5.	Houston DK, Nicklas BJ, Ding J, et al. Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) Study. Am J Clin Nutr, 2008, 87(1): 150-155.
6.	Liu ZJ, Zhu CF. Causal relationship between insulin resistance and sarcopenia. Diabetol Metab Syndr, 2023, 15(1): 46.
7.	Mo Y, Zhou Y, Chan H, et al. The association between sedentary behaviour and sarcopenia in older adults: a systematic review and meta-analysis. BMC Geriatr, 2023, 23(1): 877.
8.	Xie S, Wu Q. Association between the systemic immune-inflammation index and sarcopenia: a systematic review and meta-analysis. J Orthop Surg Res, 2024, 19(1): 314.
9.	Lo JH, U KP, Yiu T, et al. Sarcopenia: current treatments and new regenerative therapeutic approaches. J Orthop Translat, 2020, 23: 38-52.
10.	Agus A, Clément K, Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut, 2021, 70(6): 1174-1182.
11.	Mancin L, Wu GD, Paoli A. Gut microbiota-bile acid-skeletal muscle axis. Trends Microbiol, 2023, 31(3): 254-269.
12.	Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med, 2016, 375(24): 2369-2379.
13.	DeJong EN, Surette MG, Bowdish DME. The gut microbiota and unhealthy aging: disentangling cause from consequence. Cell Host Microbe, 2020, 28(2): 180-189.
14.	Hawley JA. Microbiota and muscle highway - two way traffic. Nat Rev Endocrinol, 2020, 16(2): 71-72.
15.	Coman V, Vodnar DC. Gut microbiota and old age: modulating factors and interventions for healthy longevity. Exp Gerontol, 2020, 141: 111095.
16.	Cao Y, Oh J, Xue M, et al. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites. Science, 2022, 378(6618): eabm3233.
17.	Guo CJ. Immune activation kickstarts the gut microbiota. Cell Host Microbe, 2021, 29(3): 318-320.
18.	Kim KH, Chung Y, Huh JW, et al. Gut microbiota of the young ameliorates physical fitness of the aged in mice. Microbiome, 2022, 10(1): 238.
19.	Mo X, Shen L, Cheng R, et al. Faecal microbiota transplantation from young rats attenuates age-related sarcopenia revealed by multiomics analysis. J Cachexia Sarcopenia Muscle, 2023, 14(5): 2168-2183.
20.	Chen S, Zhang P, Duan H, et al. Gut microbiota in muscular atrophy development, progression, and treatment: new therapeutic targets and opportunities. Innovation (Camb), 2023, 4(5): 100479.
21.	Xu L, Mao T, Xia M, et al. New evidence for gut-muscle axis: lactic acid bacteria-induced gut microbiota regulates duck meat flavor. Food Chem, 2024, 450: 139354.
22.	Severinsen MCK, Pedersen BK. Muscle-organ crosstalk: the emerging roles of myokines. Endocr Rev, 2020, 41(4): 594-609.
23.	Sartori R, Romanello V, Sandri M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease. Nat Commun, 2021, 12(1): 330.
24.	Schiaffino S, Dyar KA, Ciciliot S, et al. Mechanisms regulating skeletal muscle growth and atrophy. FEBS J, 2013, 280(17): 4294-4314.
25.	Lahiri S, Kim H, Garcia-Perez I, et al. The gut microbiota influences skeletal muscle mass and function in mice. Sci Transl Med, 2019, 11(502): eaan5662.
26.	Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
27.	Zhao J, Liang R, Song Q, et al. Investigating association between gut microbiota and sarcopenia-related traits: a Mendelian randomization study. Precis Clin Med, 2023, 6(2): pbad010.
28.	Wahlstr?m A, Sayin SI, Marschall HU, et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab, 2016, 24(1): 41-50.
29.	Qiu Y, Yu J, Li Y, et al. Depletion of gut microbiota induces skeletal muscle atrophy by FXR-FGF15/19 signalling. Ann Med, 2021, 53(1): 508-522.
30.	Qiu Y, Yu J, Ji X, et al. Ileal FXR-FGF15/19 signaling activation improves skeletal muscle loss in aged mice. Mech Ageing Dev, 2022, 202: 111630.
31.	Benoit B, Meugnier E, Castelli M, et al. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat Med, 2017, 23(8): 990-996.
32.	Krautkramer KA, Fan J, B?ckhed F. Gut microbial metabolites as multi-kingdom intermediates. Nat Rev Microbiol, 2021, 19(2): 77-94.
33.	Tang G, Du Y, Guan H, et al. Butyrate ameliorates skeletal muscle atrophy in diabetic nephropathy by enhancing gut barrier function and FFA2-mediated PI3K/Akt/mTOR signals. Br J Pharmacol, 2022, 179(1): 159-178.
34.	Liu C, Wong PY, Wang Q, et al. Short-chain fatty acids enhance muscle mass and function through the activation of mTOR signalling pathways in sarcopenic mice. J Cachexia Sarcopenia Muscle, 2024, 15(6): 2387-2401.
35.	Frampton J, Murphy KG, Frost G, et al. Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function. Nat Metab, 2020, 2(9): 840-848.
36.	Tan J, McKenzie C, Potamitis M, et al. The role of short-chain fatty acids in health and disease. Adv Immunol, 2014, 121: 91-119.
37.	Huang W, Man Y, Gao C, et al. Short-chain fatty acids ameliorate diabetic nephropathy via GPR43-mediated inhibition of oxidative stress and NF-κB signaling. Oxid Med Cell Longev, 2020, 2020: 4074832.
38.	Vacca M, Celano G, Calabrese FM, et al. The controversial role of human gut lachnospiraceae. Microorganisms, 2020, 8(4): 573.
39.	Jollet M, Nay K, Chopard A, et al. Does physical inactivity induce significant changes in human gut microbiota? New answers using the dry immersion hypoactivity model. Nutrients, 2021, 13(11): 3865.
40.	Buigues C, Fernández-Garrido J, Pruimboom L, et al. Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial. Int J Mol Sci, 2016, 17(6): 932.
41.	Chen LH, Chang SS, Chang HY, et al. Probiotic supplementation attenuates age-related sarcopenia via the gut-muscle axis in SAMP8 mice. J Cachexia Sarcopenia Muscle, 2022, 13(1): 515-531.
42.	Zhou J, Liu J, Lin Q, et al. Characteristics of the gut microbiome and metabolic profile in elderly patients with sarcopenia. Front Pharmacol, 2023, 14: 1279448.
43.	Ni Y, Yang X, Zheng L, et al. Lactobacillus and bifidobacterium improves physiological function and cognitive ability in aged mice by the regulation of gut microbiota. Mol Nutr Food Res, 2019, 63(22): e1900603.
44.	Picca A, Ponziani FR, Calvani R, et al. Gut microbial, inflammatory and metabolic signatures in older people with physical frailty and sarcopenia: results from the BIOSPHERE study. Nutrients, 2019, 12(1): 65.
45.	Castro-Mejía JL, Khakimov B, Krych ?, et al. Physical fitness in community-dwelling older adults is linked to dietary intake, gut microbiota, and metabolomic signatures. Aging Cell, 2020, 19(3): e13105.
46.	Kim YS, Unno T, Kim BY, et al. Sex differences in gut microbiota. World J Mens Health, 2020, 38(1): 48-60.
47.	Rondanelli M, Gasparri C, Barrile GC, et al. Effectiveness of a novel food composed of leucine, omega-3 fatty acids and probiotic Lactobacillus paracasei PS23 for the treatment of sarcopenia in elderly subjects: a 2-month randomized double-blind placebo-controlled trial. Nutrients, 2022, 14(21): 4566.
48.	Chen YM, Wei L, Chiu YS, et al. Lactobacillus plantarum TWK10 supplementation improves exercise performance and increases muscle mass in mice. Nutrients, 2016, 8(4): 205.
49.	Huang WC, Lee MC, Lee CC, et al. Effect of Lactobacillus plantarum TWK10 on exercise physiological adaptation, performance, and body composition in healthy humans. Nutrients, 2019, 11(11): 2836.
50.	Huang WC, Hsu YJ, Huang CC, et al. Exercise training combined with Bifidobacterium longum OLP-01 supplementation improves exercise physiological adaption and performance. Nutrients, 2020, 12(4): 1145.

1. Cruz-Jentoft AJ, Sayer AA. Sarcopenia. Lancet, 2019, 393(10191): 2636-2646.
2. Petermann-Rocha F, Balntzi V, Gray SR, et al. Global prevalence of sarcopenia and severe sarcopenia: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle, 2022, 13(1): 86-99.
3. Chen Z, Li WY, Ho M, et al. The prevalence of sarcopenia in Chinese older adults: meta-analysis and meta-regression. Nutrients, 2021, 13(5): 1441.
4. Lan L, Shao S, Zheng X. Associations between sarcopenia and trajectories of activities of daily living disability: a nationwide longitudinal study of middle-aged and older adults in China from 2011 to 2018. Arch Public Health, 2024, 82(1): 97.
5. Houston DK, Nicklas BJ, Ding J, et al. Dietary protein intake is associated with lean mass change in older, community-dwelling adults: the Health, Aging, and Body Composition (Health ABC) Study. Am J Clin Nutr, 2008, 87(1): 150-155.
6. Liu ZJ, Zhu CF. Causal relationship between insulin resistance and sarcopenia. Diabetol Metab Syndr, 2023, 15(1): 46.
7. Mo Y, Zhou Y, Chan H, et al. The association between sedentary behaviour and sarcopenia in older adults: a systematic review and meta-analysis. BMC Geriatr, 2023, 23(1): 877.
8. Xie S, Wu Q. Association between the systemic immune-inflammation index and sarcopenia: a systematic review and meta-analysis. J Orthop Surg Res, 2024, 19(1): 314.
9. Lo JH, U KP, Yiu T, et al. Sarcopenia: current treatments and new regenerative therapeutic approaches. J Orthop Translat, 2020, 23: 38-52.
10. Agus A, Clément K, Sokol H. Gut microbiota-derived metabolites as central regulators in metabolic disorders. Gut, 2021, 70(6): 1174-1182.
11. Mancin L, Wu GD, Paoli A. Gut microbiota-bile acid-skeletal muscle axis. Trends Microbiol, 2023, 31(3): 254-269.
12. Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med, 2016, 375(24): 2369-2379.
13. DeJong EN, Surette MG, Bowdish DME. The gut microbiota and unhealthy aging: disentangling cause from consequence. Cell Host Microbe, 2020, 28(2): 180-189.
14. Hawley JA. Microbiota and muscle highway - two way traffic. Nat Rev Endocrinol, 2020, 16(2): 71-72.
15. Coman V, Vodnar DC. Gut microbiota and old age: modulating factors and interventions for healthy longevity. Exp Gerontol, 2020, 141: 111095.
16. Cao Y, Oh J, Xue M, et al. Commensal microbiota from patients with inflammatory bowel disease produce genotoxic metabolites. Science, 2022, 378(6618): eabm3233.
17. Guo CJ. Immune activation kickstarts the gut microbiota. Cell Host Microbe, 2021, 29(3): 318-320.
18. Kim KH, Chung Y, Huh JW, et al. Gut microbiota of the young ameliorates physical fitness of the aged in mice. Microbiome, 2022, 10(1): 238.
19. Mo X, Shen L, Cheng R, et al. Faecal microbiota transplantation from young rats attenuates age-related sarcopenia revealed by multiomics analysis. J Cachexia Sarcopenia Muscle, 2023, 14(5): 2168-2183.
20. Chen S, Zhang P, Duan H, et al. Gut microbiota in muscular atrophy development, progression, and treatment: new therapeutic targets and opportunities. Innovation (Camb), 2023, 4(5): 100479.
21. Xu L, Mao T, Xia M, et al. New evidence for gut-muscle axis: lactic acid bacteria-induced gut microbiota regulates duck meat flavor. Food Chem, 2024, 450: 139354.
22. Severinsen MCK, Pedersen BK. Muscle-organ crosstalk: the emerging roles of myokines. Endocr Rev, 2020, 41(4): 594-609.
23. Sartori R, Romanello V, Sandri M. Mechanisms of muscle atrophy and hypertrophy: implications in health and disease. Nat Commun, 2021, 12(1): 330.
24. Schiaffino S, Dyar KA, Ciciliot S, et al. Mechanisms regulating skeletal muscle growth and atrophy. FEBS J, 2013, 280(17): 4294-4314.
25. Lahiri S, Kim H, Garcia-Perez I, et al. The gut microbiota influences skeletal muscle mass and function in mice. Sci Transl Med, 2019, 11(502): eaan5662.
26. Emdin CA, Khera AV, Kathiresan S. Mendelian randomization. JAMA, 2017, 318(19): 1925-1926.
27. Zhao J, Liang R, Song Q, et al. Investigating association between gut microbiota and sarcopenia-related traits: a Mendelian randomization study. Precis Clin Med, 2023, 6(2): pbad010.
28. Wahlstr?m A, Sayin SI, Marschall HU, et al. Intestinal crosstalk between bile acids and microbiota and its impact on host metabolism. Cell Metab, 2016, 24(1): 41-50.
29. Qiu Y, Yu J, Li Y, et al. Depletion of gut microbiota induces skeletal muscle atrophy by FXR-FGF15/19 signalling. Ann Med, 2021, 53(1): 508-522.
30. Qiu Y, Yu J, Ji X, et al. Ileal FXR-FGF15/19 signaling activation improves skeletal muscle loss in aged mice. Mech Ageing Dev, 2022, 202: 111630.
31. Benoit B, Meugnier E, Castelli M, et al. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat Med, 2017, 23(8): 990-996.
32. Krautkramer KA, Fan J, B?ckhed F. Gut microbial metabolites as multi-kingdom intermediates. Nat Rev Microbiol, 2021, 19(2): 77-94.
33. Tang G, Du Y, Guan H, et al. Butyrate ameliorates skeletal muscle atrophy in diabetic nephropathy by enhancing gut barrier function and FFA2-mediated PI3K/Akt/mTOR signals. Br J Pharmacol, 2022, 179(1): 159-178.
34. Liu C, Wong PY, Wang Q, et al. Short-chain fatty acids enhance muscle mass and function through the activation of mTOR signalling pathways in sarcopenic mice. J Cachexia Sarcopenia Muscle, 2024, 15(6): 2387-2401.
35. Frampton J, Murphy KG, Frost G, et al. Short-chain fatty acids as potential regulators of skeletal muscle metabolism and function. Nat Metab, 2020, 2(9): 840-848.
36. Tan J, McKenzie C, Potamitis M, et al. The role of short-chain fatty acids in health and disease. Adv Immunol, 2014, 121: 91-119.
37. Huang W, Man Y, Gao C, et al. Short-chain fatty acids ameliorate diabetic nephropathy via GPR43-mediated inhibition of oxidative stress and NF-κB signaling. Oxid Med Cell Longev, 2020, 2020: 4074832.
38. Vacca M, Celano G, Calabrese FM, et al. The controversial role of human gut lachnospiraceae. Microorganisms, 2020, 8(4): 573.
39. Jollet M, Nay K, Chopard A, et al. Does physical inactivity induce significant changes in human gut microbiota? New answers using the dry immersion hypoactivity model. Nutrients, 2021, 13(11): 3865.
40. Buigues C, Fernández-Garrido J, Pruimboom L, et al. Effect of a prebiotic formulation on frailty syndrome: a randomized, double-blind clinical trial. Int J Mol Sci, 2016, 17(6): 932.
41. Chen LH, Chang SS, Chang HY, et al. Probiotic supplementation attenuates age-related sarcopenia via the gut-muscle axis in SAMP8 mice. J Cachexia Sarcopenia Muscle, 2022, 13(1): 515-531.
42. Zhou J, Liu J, Lin Q, et al. Characteristics of the gut microbiome and metabolic profile in elderly patients with sarcopenia. Front Pharmacol, 2023, 14: 1279448.
43. Ni Y, Yang X, Zheng L, et al. Lactobacillus and bifidobacterium improves physiological function and cognitive ability in aged mice by the regulation of gut microbiota. Mol Nutr Food Res, 2019, 63(22): e1900603.
44. Picca A, Ponziani FR, Calvani R, et al. Gut microbial, inflammatory and metabolic signatures in older people with physical frailty and sarcopenia: results from the BIOSPHERE study. Nutrients, 2019, 12(1): 65.
45. Castro-Mejía JL, Khakimov B, Krych ?, et al. Physical fitness in community-dwelling older adults is linked to dietary intake, gut microbiota, and metabolomic signatures. Aging Cell, 2020, 19(3): e13105.
46. Kim YS, Unno T, Kim BY, et al. Sex differences in gut microbiota. World J Mens Health, 2020, 38(1): 48-60.
47. Rondanelli M, Gasparri C, Barrile GC, et al. Effectiveness of a novel food composed of leucine, omega-3 fatty acids and probiotic Lactobacillus paracasei PS23 for the treatment of sarcopenia in elderly subjects: a 2-month randomized double-blind placebo-controlled trial. Nutrients, 2022, 14(21): 4566.
48. Chen YM, Wei L, Chiu YS, et al. Lactobacillus plantarum TWK10 supplementation improves exercise performance and increases muscle mass in mice. Nutrients, 2016, 8(4): 205.
49. Huang WC, Lee MC, Lee CC, et al. Effect of Lactobacillus plantarum TWK10 on exercise physiological adaptation, performance, and body composition in healthy humans. Nutrients, 2019, 11(11): 2836.
50. Huang WC, Hsu YJ, Huang CC, et al. Exercise training combined with Bifidobacterium longum OLP-01 supplementation improves exercise physiological adaption and performance. Nutrients, 2020, 12(4): 1145.

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