The potential of short-chain fatty acids-producing probiotics as a treatment for liver disease: a systematic review
Abstract
Recent insights reveal that liver diseases influence not only hepatic function but also disrupt gut microbial balance through the gut–liver axis. The gut–liver axis establishes a bidirectional relationship between the intestines and the liver, allowing microbial by-products such as short-chain fatty acids (SCFAs) to influence liver function and health. Short-chain fatty acids are known to maintain intestinal epithelial integrity, reduce inflammation, and support liver function. Probiotic bacteria including Lactobacillus, Bifidobacterium, and Clostridium, are natural SCFA producers and may offer therapeutic potential for liver disease by targeting the gut-liver axis. This systematic review was conducted using the PRISMA 2020 methodology to identify and evaluate preclinical studies examining the impact of SCFA-producing probiotics on liver disease. We searched PubMed, Scopus, and Google Scholar from August to October 2023, using predefined inclusion criteria based on the PICO framework. The SYRCLE risk of bias tool was employed to evaluate potential biases. A total of 14 animal studies fulfilled the inclusion criteria and were incorporated into the final analysis. The included studies demonstrated that SCFA-producing probiotics improved liver function by reducing serum liver enzymes (ALT, AST), increasing tight junction proteins (occluding, ZO-1), modulating pro-inflammatory cytokines (IL-1β, IL-6, TNF-α,), and improving lipid metabolism. These outcomes were mediated by increases in SCFA levels and improved gut barrier integrity in models of NAFLD, ALD, NASH, and autoimmune hepatitis. These findings support the promising potential of SCFA-producing probiotics as adjunctive therapies for liver disease through modulation of the microbiota-gut-liver axis. Yet, continued research is needed to determine strain-specific efficacy, optimal dosage, long-term safety, and clinical applicability. Future research should also explore personalized probiotic strategies and the integration of probiotic therapy into standard liver disease management.
References
Lynch S V, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med, 2016; 375(24):2369-79.
https://doi.org/10.1056/nejmra1600266
Li J, Jia H, Cai X, Zhong H, Feng Q, Sunagawa S, et al. An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol, 2014; 32(8):834-41.
https://doi.org/10.1038/nbt.2942
Akimbekov NS, Digel I, Sherelkhan DK, Lutfor AB, Razzaque MS. Vitamin d and the host-gut microbiome: a brief overview. Acta Histochem Cytochem, 2020; 53(3):33-42.
https://doi.org/10.1267/ahc.20011.
Yang T, Yang S, Zhao J, Wang P, Li S, Jin Y, et al. Comprehensive analysis of gut microbiota and fecal bile acid profiles in children with biliary atresia. Front Cell Infect Microbiol, 2022; 12:914247.
https://doi.org/10.3389/fcimb.2022.914247
Romijn JA, Corssmit EP, Havekes LM, Pijl H. Gut-brain axis. Curr Opin Clin Nutr Metab Care, 2008; 11(4):518-21.
Song W, Sun LY, Zhu ZJ, Wei L, Qu W, Zeng ZG, et al. Association of gut microbiota and metabolites with disease progression in children with biliary atresia. Front Immunol, 2021; 12:698900.
https://doi.org/10.3389/fimmu.2021.698900
Jain V, Alexander EC, Burford C, Verma A, Dhawan A. Gut microbiome: a potential modifiable risk factor in biliary atresia. J Pediatr Gastroenterol Nutr, 2021; 72(2):184-93.
https://doi.org/10.1097/MPG.0000000000002973
Degruttola AK, Low D, Mizoguchi A, Mizoguchi E. Current understanding of dysbiosis in disease in human and animal models. Inflamm Bowel Dis, 2016; 22(5):1137-50.
https://doi.org/10.1097/MIB.0000000000000750
Zhou S, Wang Z, He F, Qiu H, Wang Y, Wang H, et al. Association of serum bilirubin in newborns affected by jaundice with gut microbiota dysbiosis. J Nutr Biochem, 2019; 63:54-61.
https://doi.org/10.1016/j.jnutbio.2018.09.016
Rivière A, Selak M, Lantin D, Leroy F, De Vuyst L. Bifidobacteria and butyrate-producing colon bacteria: importance and strategies for their stimulation in the human gut. Front Microbiol, 2016; 7:979.
https://doi.org/10.3389/fmicb.2016.00979
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 2021; 372:n71.
https://doi.org/10.1136/bmj.n71
Schiavenato M, Chu F. PICO: What it is and what it is not. Nurse Educ Pract, 2021; 56:103194.
https://doi.org/10.1016/j.nepr.2021.103194
Hooijmans CR, Rovers MM, De Vries RBM, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol, 2014; 14:43.
https://doi.org/10.1186/1471-2288-14-43
Yoon SJ, Yu JS, Min BH, Gupta H, Won SM, Park HJ, et al. Bifidobacterium-derived short-chain fatty acids and indole compounds attenuate nonalcoholic fatty liver disease by modulating gut-liver axis. Front Microbiol, 2023; 14:1129904.
https://doi.org/10.3389/fmicb.2023.1129904
Jiang XW, Li YT, Ye JZ, Lv LX, Yang LY, Bian XY, et al. New strain of Pediococcus pentosaceus alleviates ethanol-induced liver injury by modulating the gut microbiota and short-chain fatty acid metabolism. World J Gastroenterol, 2020; 26(40):6224-40.
https://doi.org/10.3748/wjg.v26.i40.6224
Hong Y, Sheng L, Zhong J, Tao X, Zhu W, Ma J, et al. Desulfovibrio vulgaris, a potent acetic acid-producing bacterium, attenuates nonalcoholic fatty liver disease in mice. Gut Microbes, 2021; 13(1):1-20.
https://doi.org/10.1080/19490976.2021.1930874
Yan F, Li N, Shi J, Li H, Yue Y, Jiao W, et al. Lactobacillus acidophilus alleviates type 2 diabetes by regulating hepatic glucose, lipid metabolism and gut microbiota in mice. Food Funct, 2019; 10(9):5804-15.
https://doi.org/10.1039/c9fo01062a.
Liang Y, Liang S, Zhang Y, Deng Y, He Y, Chen Y, et al. Oral administration of compound probiotics ameliorates HFD-induced gut microbe dysbiosis and chronic metabolic inflammation via the G protein-coupled receptor 43 in non-alcoholic fatty liver disease Rats. Probiot Antimicrob Proteins, 2019;11(1):175–85. https://doi.org/10.1007/s12602-017-9378-3.
Zhang H, Liu M, Liu X, Zhong W, Li Y, Ran Y, et al. Bifidobacterium animalis ssp. lactis 420 mitigates autoimmune hepatitis through regulating intestinal barrier and liver immune cells. Front Immunol, 2020; 11:569104.
https://doi.org/10.3389/fimmu.2020.569104
Zheng F, Wang Z, Stanton C, Ross RP, Zhao J, Zhang H, et al. Lactobacillus rhamnosus FJSYC4-1 and Lactobacillus reuteri FGSZY33L6 alleviate metabolic syndrome via gut microbiota regulation. Food Funct, 2021; 12(9):3919-30.
https://doi.org/10.1039/d0fo02879g
Endo H, Niioka M, Kobayashi N, Tanaka M, Watanabe T. Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis. PLoS ONE, 2013; 8(5):63388.
https://doi.org/10.1371/journal.pone.0063388
Yang T, Yang H, Heng C, Wang H, Chen S, Hu Y, et al. Amelioration of non-alcoholic fatty liver disease by sodium butyrate is linked to the modulation of intestinal tight junctions in db/db mice. Food Funct, 2020; 11(12):10675-89.
https://doi.org/10.1039/d0fo01954b
Li X, Xiao Y, Huang Y, Song L, Li M, Ren Z. Lactobacillus gasseri RW2014 ameliorates hyperlipidemia by modulating bile acid metabolism and gut microbiota composition in rats. Nutrients, 2022; 14(23):4945.
https://doi.org/10.3390/nu14234945
Wang G, Jiao T, Xu Y, Li D, Si Q, Hao J, et al. Bifidobacterium adolescentis and Lactobacillus rhamnosus alleviate non-alcoholic fatty liver disease induced by a high-fat, high-cholesterol diet through modulation of different gut microbiota-dependent pathways. Food Funct, 2020; 11(7):6115-27.
https://doi.org/10.1039/c9fo02905b
Seif el-Din SH, Salem MB, El-Lakkany NM, Hammam OA, Nasr SM, Okasha H, et al. Early intervention with probiotics and metformin alleviates liver injury in NAFLD rats via targeting gut microbiota dysbiosis and p-AKT/mTOR/LC-3II pathways. Humd Expl Toxicol, 2021; 40(9):1496-509.
https://doi.org/10.1177/0960327121999445
Cao F, Ding Q, Zhuge H, Lai S, Chang K, Le C, et al. Lactobacillus plantarum ZJUIDS14 alleviates non-alcoholic fatty liver disease in mice in association with modulation in the gut microbiota. Front Nutr, 2023; 9:1071284.
https://doi.org/10.3389/fnut.2022.1071284
Zhou D, Pan Q, Liu XL, Yang RX, Chen YW, Liu C, et al. Clostridium butyricum B1 alleviates high-fat diet-induced steatohepatitis in mice via enterohepatic immunoregulation. J Gastroenterol Hepatol, 2017; 32(9):1640-8.
https://doi.org/10.1111/jgh.13742
Rowell RJ, Anstee QM. Alcohol and health. Clin Med, 2015; 15(6): s77-82.
Wang L, Jiao T, Yu Q, Wang J, Wang L, Wang G, et al. Bifidobacterium bifidum shows more diversified ways of relieving non-alcoholic fatty liver compared with Bifidobacterium adolescentis. Biomedicines, 2022; 10(1):84.
https://doi.org/10.3390/biomedicines10010084
Khan RS, Houlihan DD, Newsome PN. Investigation of jaundice. Medicine, 2019; 47(11):713-7.
https://doi.org/10.1016/j.mpmed.2019.08.011
Khan A, Ding Z, Ishaq M, Bacha AS, Khan I, Hanif A, et al. Understanding the effects of gut microbiota dysbiosis on nonalcoholic fatty liver disease and the possible probiotics role: recent updates. Int J Biol Sci, 2021; 17(3): 818-33.
https://doi.org/10.7150/ijbs.56214
Bessone F, Razori MV, Roma MG. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci, 2019; 76(1):99-128.
https://doi.org/10.1007/s00018-018-2947-0.
Aron-Wisnewsky J, Gaborit B, Dutour A, Clement K. Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect, 2013; 19(4):338-48.
https://doi.org/10.1111/1469-0691.12140
Cheng Y, Liu J, Ling Z. Short-chain fatty acids-producing probiotics: a novel source of psychobiotics. Crit Rev Food Sci Nutr, 2022; 7929-59.
https://doi.org/10.1080/10408398.2021.1920884
Górska A, Przystupski D, Niemczura MJ, Kulbacka J. Probiotic bacteria: a promising tool in cancer prevention and therapy. Curr Microbiol, 2019; 76(8):939-49.
https://doi.org/10.1007/s00284-019-01679-8
Dargenio VN, Castellaneta S, Panico S, Papagni ME, Dargenio C, Schettini F, et al. Probiotics and gastrointestinal diseases. Minerva Pediatr (Torino), 2022; 74(6):703-23. https://doi.org/10.23736/S2724-5276.22.07031-8
Pohl K, Moodley P, Dhanda A. The effect of increasing intestinal short-chain fatty acid concentration on gut permeability and liver injury in the context of liver disease: a systematic review. J Gastroenterol Hepatol, 2022; 37(8):1498-506.
https://doi.org/10.1111/jgh.15899
Zhang D, Jian YP, Zhang YN, Li Y, Gu LT, Sun HH, et al. Short-chain fatty acids in diseases. Cell Commun Signal, 2023; 21(1):212.
https://doi.org/10.1186/s12964-023-01219-9
Portincasa P, Bonfrate L, Vacca M, De Angelis M, Farella I, Lanza E, et al. Gut microbiota and short chain fatty acids: implications in glucose homeostasis. Int J Mol Sci, 2022; 23(3):1105.
https://doi.org/10.3390/ijms23031105
Nogal A, Valdes AM, Menni C. The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health. Gut Microbes, 2021; 13(1):1-24.
https://doi.org/10.1080/19490976.2021.1897212
Wang J, Qian T, Jiang J, Yang Y, Shen Z, Huang Y, et al. Gut microbial profile in biliary atresia: a case-control study. J Gastroenterol Hepatol, 2020; 35(2):334-42.
https://doi.org/10.1111/jgh.14777
Van Wessel D, Nomden M, Bruggink J, De Kleine R, Kurilshikov A, Verkade H, et al. Gut microbiota composition of biliary atresia patients before kasai portoenterostomy associates with long-term outcome. J Pediatr Gastroenterol Nutr, 2021; 73(4):485-90.
https://doi.org/10.1097/MPG.0000000000003234
Shen F, Zheng RD, Sun XQ, Ding WJ, Wang XY, Fan JG. Gut microbiota dysbiosis in patients with non-alcoholic fatty liver disease. Hepatobiliary Pancreat Dis Int, 2017; 16(4):375-81.
https://doi.org/10.1016/S1499-3872(17)60019-5
Bajaj JS, Heuman DM, Hylemon PB, Sanyal AJ, White MB, Monteith P, et al. Altered profile of human gut microbiome is associated with cirrhosis and its complications. J Hepatol, 2014; 60(5):940-47.
https://doi.org/10.1016/j.jhep.2013.12.019
Culp EJ, Goodman AL. Cross-feeding in the gut microbiome: Ecology and mechanisms. Cell Host Microbe, 2023; 31(4):485-99.
https://doi.org/10.1016/j.chom.2023.03.016
Lee JG, Lee J, Lee AR, Jo SV, Park CH, Han DS, et al. Impact of short-chain fatty acid supplementation on gut inflammation and microbiota composition in a murine colitis model. J Nutr Biochem, 2022; 101:108926.
https://doi.org/10.1016/j.jnutbio.2021.108926
Hodgkinson K, El Abbar F, Dobranowski P, Manoogian J, Butcher J, Figeys D, et al. Butyrate’s role in human health and the current progress towards its clinical application to treat gastrointestinal disease. Clin Nutr, 2023; 42(2):61-75.
https://doi.org/10.1016/j.clnu.2022.10.024
Du Y, He C, An Y, Huang Y, Zhang H, Fu W, et al. The role of short chain fatty acids in inflammation and body health. Int J Mol Sci, 2024; 25(13):7379.
https://doi.org/10.3390/ijms25137379
Du B, Mu K, Sun M, Yu Z, Li L, Hou L, et al. Biliary atresia and cholestasis plasma non-targeted metabolomics unravels perturbed metabolic pathways and unveils a diagnostic model for biliary atresia. Sci Rep, 2024; 14(1):15796.
https://doi.org/10.1038/s41598-024-66893-2
Bernini LJ, Simão ANC, Alfieri DF, Lozovoy MAB, Mari NL, de Souza CHB, et al. Beneficial effects of Bifidobacterium lactis on lipid profile and cytokines in patients with metabolic syndrome: a randomized trial. Effects of probiotics on metabolic syndrome. Nutrition, 2016; 32(6):716-9.
https://doi.org/10.1016/j.nut.2015.11.001
He M, Shi B. Gut microbiota as a potential target of metabolic syndrome: the role of probiotics and prebiotics. Cell Biosci, 2017; 7:54.
https://doi.org/10.1186/s13578-017-0183-1
Haghikia A, Zimmermann F, Schumann P, Jasina A, Roessler J, Schmidt D, et al. Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism. Eur Heart J, 2022; 43(6):518-33.
https://doi.org/10.1093/eurheartj/ehab644
Jia X, Lu S, Zeng Z, Liu Q, Dong Z, Chen Y, et al. Characterization of gut microbiota, bile acid metabolism, and cytokines in intrahepatic cholangiocarcinoma. Hepatology, 2020; 71(3):893-906.
https://doi.org/10.1002/hep.30852/suppinfo.
Liu Y, Chen K, Li F, Gu Z, Liu Q, He L, et al. Probiotic Lactobacillus rhamnosus GG prevents liver fibrosis through inhibiting hepatic bile acid synthesis and enhancing bile acid excretion in mice. Hepatology, 2020; 71(6):2050-66.
https://doi.org/10.1002/hep.30975
Cheng L, Shi J, Peng H, Tong R, Hu Y, Yu D. Probiotics and liver fibrosis: an evidence-based review of the latest research. J Funct Foods, 2023; 109(3):105773.
https://doi.org/10.1016/j.jff.2023.105773
Ayob N, Nawawi KNM, Mohamad Nor MH, Raja Ali RA, Ahmad HF, Oon SF, et al. The effects of probiotics on small intestinal microbiota composition, inflammatory cytokines and intestinal permeability in patients with non-alcoholic fatty liver disease. Biomedicines, 2023; 11(2):640.
