Impact of High-Fat Diet on Obesity-Related Diseases: The Role of Gut Microbiota-Derived Short-Chain Fatty Acids

Yingsi Fang; Zhe Kan; Shuyi Dong; Lei Yan; Yuting Tang

doi:10.54254/2753-8818/2025.24207

Article Information

Received: 13 June 2025

Published: 20 June 2025

DOI: https://doi.org/10.54254/2753-8818/2025.24207

Article Type: Research Article

Cite this article

Fang,Y.;Kan,Z.;Dong,S.;Yan,L.;Tang,Y. (2025). Impact of High-Fat Diet on Obesity-Related Diseases: The Role of Gut Microbiota-Derived Short-Chain Fatty Acids. Theoretical and Natural Science,116,27-36.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

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Volume Title: TNS Vol.116

Part of Series: Theoretical and Natural Science

ISSN: 2753-8818 (Print) / 2753-8826 (Online)

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[1]Lu, Y., Yuan, X., Wang, M., He, Z., Li, H., Wang, J., Li, Q., Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies, Journal of hematology & oncology 15(1) (2022) 47.

[2]Lee, Y., Kamada, N., Moon, J.J., Oral nanomedicine for modulating immunity, intestinal barrier functions, and gut microbiome, Advanced drug delivery reviews 179 (2021) 114021.

[3]Honarpisheh, P., Bryan, R.M., McCullough, L.D., Aging Microbiota-Gut-Brain Axis in Stroke Risk and Outcome, Circulation research 130(8) (2022) 1112-1144.

[4]Gentile, C.L., Weir, T.L., The gut microbiota at the intersection of diet and human health, Science (New York, N.Y.) 362(6416) (2018) 776-780.

[5]Hill, C.J., Lynch, D.B., Murphy, K., Ulaszewska, M., Jeffery, I.B., O'Shea, C.A., Watkins, C., Dempsey, E., Mattivi, F., Tuohy, K., Ross, R.P., Ryan, C.A., PW, O.T., Stanton, C., Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort, Microbiome 5(1) (2017) 4.

[6]Hopkins, M.J., Sharp, R., Macfarlane, G.T., Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles, Gut 48(2) (2001) 198-205.

[7]Zmora, N., Suez, J., Elinav, E., You are what you eat: diet, health and the gut microbiota, Nature reviews. Gastroenterology & hepatology 16(1) (2019) 35-56.

[8]Krisanits, B., Randise, J.F., Burton, C.E., Findlay, V.J., Turner, D.P., Pubertal mammary development as a "susceptibility window" for breast cancer disparity, Advances in cancer research 146 (2020) 57-82.

[9]Popkin, B.M., Adair, L.S., Ng, S.W., Global nutrition transition and the pandemic of obesity in developing countries, Nutrition reviews 70(1) (2012) 3-21.

[10]da Cruz, L.L., Vesentini, G., Sinzato, Y.K., Villaverde, A., Volpato, G.T., Damasceno, D.C., Effects of high-fat diet-induced diabetes on autophagy in the murine liver: A systematic review and meta-analysis, Life sciences 309 (2022) 121012.

[11]Guinane, C.M., Cotter, P.D., Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ, Therapeutic advances in gastroenterology 6(4) (2013) 295-308.

[12]Bouter, K.E., van Raalte, D.H., Groen, A.K., Nieuwdorp, M., Role of the Gut Microbiome in the Pathogenesis of Obesity and Obesity-Related Metabolic Dysfunction, Gastroenterology 152(7) (2017) 1671-1678.

[13]Sergeev, I.N., Aljutaily, T., Walton, G., Huarte, E., Effects of Synbiotic Supplement on Human Gut Microbiota, Body Composition and Weight Loss in Obesity, Nutrients 12(1) (2020).

[14]Hong, Y., Sheng, L., Zhong, J., Tao, X., Zhu, W., Ma, J., Yan, J., Zhao, A., Zheng, X., Wu, G., Li, B., Han, B., Ding, K., Zheng, N., Jia, W., Li, H., Desulfovibrio vulgaris, a potent acetic acid-producing bacterium, attenuates nonalcoholic fatty liver disease in mice, Gut microbes 13(1) (2021) 1-20.

[15]Hong, Y., Sheng, L., Zhong, J., Tao, X., Zhu, W., Ma, J., Yan, J., Zhao, A., Zheng, X., Wu, G., Li, B., Han, B., Ding, K., Zheng, N., Jia, W., Li, H., Desulfovibrio vulgaris, a potent acetic acid-producing bacterium, attenuates nonalcoholic fatty liver disease in mice, Gut microbes 13(1) (2021) 1-20.

[16]Sarkar, A., Mitra, P., Lahiri, A., Das, T., Sarkar, J., Paul, S., Chakrabarti, P., Butyrate limits inflammatory macrophage niche in NASH, Cell death & disease 14(5) (2023) 332.

[17]Song, Q., Zhang, X., Liu, W., Wei, H., Liang, W., Zhou, Y., Ding, Y., Ji, F., Ho-Kwan Cheung, A., Wong, N., Yu, J., Bifidobacterium pseudolongum-generated acetate suppresses non-alcoholic fatty liver disease-associated hepatocellular carcinoma, Journal of hepatology 79(6) (2023) 1352-1365.

[18]Takayama, S., Katada, K., Takagi, T., Iida, T., Ueda, T., Mizushima, K., Higashimura, Y., Morita, M., Okayama, T., Kamada, K., Uchiyama, K., Handa, O., Ishikawa, T., Yasukawa, Z., Okubo, T., Itoh, Y., Naito, Y., Partially hydrolyzed guar gum attenuates non-alcoholic fatty liver disease in mice through the gut-liver axis, World journal of gastroenterology 27(18) (2021) 2160-2176.

[19]Takayama, S., Katada, K., Takagi, T., Iida, T., Ueda, T., Mizushima, K., Higashimura, Y., Morita, M., Okayama, T., Kamada, K., Uchiyama, K., Handa, O., Ishikawa, T., Yasukawa, Z., Okubo, T., Itoh, Y., Naito, Y., Partially hydrolyzed guar gum attenuates non-alcoholic fatty liver disease in mice through the gut-liver axis, World journal of gastroenterology 27(18) (2021) 2160-2176.

[20]Ecklu-Mensah, G., Choo-Kang, C., Maseng, M.G., Donato, S., Bovet, P., Viswanathan, B., Bedu-Addo, K., Plange-Rhule, J., Oti Boateng, P., Forrester, T.E., Williams, M., Lambert, E.V., Rae, D., Sinyanya, N., Luke, A., Layden, B.T., O'Keefe, S., Gilbert, J.A., Dugas, L.R., Gut microbiota and fecal short chain fatty acids differ with adiposity and country of origin: the METS-microbiome study, Nature communications 14(1) (2023) 5160.

[21]Panyod, S., Wu, W.K., Peng, S.Y., Tseng, Y.J., Hsieh, Y.C., Chen, R.A., Huang, H.S., Chen, Y.H., Chuang, H.L., Hsu, C.C., Shen, T.D., Yang, K.C., Ho, C.T., Wu, M.S., Sheen, L.Y., Ginger essential oil and citral ameliorates atherosclerosis in ApoE(-/-) mice by modulating trimethylamine-N-oxide and gut microbiota, NPJ science of food 7(1) (2023) 19.

[22]Luo, T., Guo, Z., Liu, D., Guo, Z., Wu, Q., Li, Q., Lin, R., Chen, P., Ou, C., Chen, M., Deficiency of PSRC1 accelerates atherosclerosis by increasing TMAO production via manipulating gut microbiota and flavin monooxygenase 3, Gut microbes 14(1) (2022) 2077602.

[23]Shi, X., Huang, H., Zhou, M., Liu, Y., Wu, H., Dai, M., Paeonol Attenuated Vascular Fibrosis Through Regulating Treg/Th17 Balance in a Gut Microbiota-Dependent Manner, Frontiers in pharmacology 12 (2021) 765482.

[24]Tian, Q., Leung, F.P., Chen, F.M., Tian, X.Y., Chen, Z., Tse, G., Ma, S., Wong, W.T., Butyrate protects endothelial function through PPARδ/miR-181b signaling, Pharmacological research 169 (2021) 105681.

[25]Haghikia, A., Zimmermann, F., Schumann, P., Jasina, A., Roessler, J., Schmidt, D., Heinze, P., Kaisler, J., Nageswaran, V., Aigner, A., Ceglarek, U., Cineus, R., Hegazy, A.N., van der Vorst, E.P.C., Döring, Y., Strauch, C.M., Nemet, I., Tremaroli, V., Dwibedi, C., Kränkel, N., Leistner, D.M., Heimesaat, M.M., Bereswill, S., Rauch, G., Seeland, U., Soehnlein, O., Müller, D.N., Gold, R., Bäckhed, F., Hazen, S.L., Haghikia, A., Landmesser, U., Propionate attenuates atherosclerosis by immune-dependent regulation of intestinal cholesterol metabolism, European heart journal 43(6) (2022) 518-533.

[26]Liu, S., Qin, P., Wang, J., High-Fat Diet Alters the Intestinal Microbiota in Streptozotocin-Induced Type 2 Diabetic Mice, Microorganisms 7(6) (2019).

[27]Cani, P.D., Bibiloni, R., Knauf, C., Waget, A., Neyrinck, A.M., Delzenne, N.M., Burcelin, R., Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice, Diabetes 57(6) (2008) 1470-81.

[28]Fang, W., Xue, H., Chen, X., Chen, K., Ling, W., Supplementation with Sodium Butyrate Modulates the Composition of the Gut Microbiota and Ameliorates High-Fat Diet-Induced Obesity in Mice, The Journal of nutrition 149(5) (2019) 747-754.

[29]Lu, Y., Fan, C., Liang, A., Fan, X., Wang, R., Li, P., Qi, K., Effects of SCFA on the DNA methylation pattern of adiponectin and resistin in high-fat-diet-induced obese male mice, The British journal of nutrition 120(4) (2018) 385-392.

[30]Vendrell, J., Broch, M., Vilarrasa, N., Molina, A., Gómez, J.M., Gutiérrez, C., Simón, I., Soler, J., Richart, C., Resistin, adiponectin, ghrelin, leptin, and proinflammatory cytokines: relationships in obesity, Obesity research 12(6) (2004) 962-71.

[31]Du, J., Zhang, P., Luo, J., Shen, L., Zhang, S., Gu, H., He, J., Wang, L., Zhao, X., Gan, M., Yang, L., Niu, L., Zhao, Y., Tang, Q., Tang, G., Jiang, D., Jiang, Y., Li, M., Jiang, A., Jin, L., Ma, J., Shuai, S., Bai, L., Wang, J., Zeng, B., Wu, D., Li, X., Zhu, L., Dietary betaine prevents obesity through gut microbiota-drived microRNA-378a family, Gut microbes 13(1) (2021) 1-19.

[32]Ottman, N., Geerlings, S.Y., Aalvink, S., de Vos, W.M., Belzer, C., Action and function of Akkermansia muciniphila in microbiome ecology, health and disease, Best practice & research. Clinical gastroenterology 31(6) (2017) 637-642.

[33]Watanabe, A., Tochio, T., Kadota, Y., Takahashi, M., Kitaura, Y., Ishikawa, H., Yasutake, T., Nakano, M., Shinohara, H., Kudo, T., Nishimoto, Y., Mizuguchi, Y., Endo, A., Shimomura, Y., Supplementation of 1-Kestose Modulates the Gut Microbiota Composition to Ameliorate Glucose Metabolism in Obesity-Prone Hosts, Nutrients 13(9) (2021).

[34]Loomba, R., Seguritan, V., Li, W., Long, T., Klitgord, N., Bhatt, A., Dulai, P.S., Caussy, C., Bettencourt, R., Highlander, S.K., Jones, M.B., Sirlin, C.B., Schnabl, B., Brinkac, L., Schork, N., Chen, C.H., Brenner, D.A., Biggs, W., Yooseph, S., Venter, J.C., Nelson, K.E., Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease, Cell metabolism 25(5) (2017) 1054-1062.e5.

[35]Zhu, L., Baker, S.S., Gill, C., Liu, W., Alkhouri, R., Baker, R.D., Gill, S.R., Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH, Hepatology (Baltimore, Md.) 57(2) (2013) 601-9.

[36]Liu, S., Kang, W., Mao, X., Ge, L., Du, H., Li, J., Hou, L., Liu, D., Yin, Y., Liu, Y., Huang, K., Melatonin mitigates aflatoxin B1-induced liver injury via modulation of gut microbiota/intestinal FXR/liver TLR4 signaling axis in mice, Journal of pineal research 73(2) (2022) e12812.

[37]Shashni, B., Tajika, Y., Ikeda, Y., Nishikawa, Y., Nagasaki, Y., Self-assembling polymer-based short chain fatty acid prodrugs ameliorate non-alcoholic steatohepatitis and liver fibrosis, Biomaterials 295 (2023) 122047.

[38]Wang, Y., Dilidaxi, D., Wu, Y., Sailike, J., Sun, X., Nabi, X.H., Composite probiotics alleviate type 2 diabetes by regulating intestinal microbiota and inducing GLP-1 secretion in db/db mice, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 125 (2020) 109914.

[39]Pedersen, S.S., Ingerslev, L.R., Olsen, M., Prause, M., Billestrup, N., Butyrate functions as a histone deacetylase inhibitor to protect pancreatic beta cells from IL-1β-induced dysfunction, The FEBS journal 291(3) (2024) 566-583.

[40]Fawad, J.A., Luzader, D.H., Hanson, G.F., Moutinho, T.J., Jr., McKinney, C.A., Mitchell, P.G., Brown-Steinke, K., Kumar, A., Park, M., Lee, S., Bolick, D.T., Medlock, G.L., Zhao, J.Y., Rosselot, A.E., Chou, C.J., Eshleman, E.M., Alenghat, T., Hong, C.I., Papin, J.A., Moore, S.R., Histone Deacetylase Inhibition by Gut Microbe-Generated Short-Chain Fatty Acids Entrains Intestinal Epithelial Circadian Rhythms, Gastroenterology 163(5) (2022) 1377-1390.e11.

[41]Lu, H., Xu, X., Fu, D., Gu, Y., Fan, R., Yi, H., He, X., Wang, C., Ouyang, B., Zhao, P., Wang, L., Xu, P., Cheng, S., Wang, Z., Zou, D., Han, L., Zhao, W., Butyrate-producing Eubacterium rectale suppresses lymphomagenesis by alleviating the TNF-induced TLR4/MyD88/NF-κB axis, Cell host & microbe 30(8) (2022) 1139-1150.e7.

[42]Tolhurst, G., Heffron, H., Lam, Y.S., Parker, H.E., Habib, A.M., Diakogiannaki, E., Cameron, J., Grosse, J., Reimann, F., Gribble, F.M., Short-chain fatty acids stimulate glucagon-like peptide-1 secretion via the G-protein-coupled receptor FFAR2, Diabetes 61(2) (2012) 364-71.

[43]Rittiphairoj, T., Pongpirul, K., Janchot, K., Mueller, N.T., Li, T., Probiotics Contribute to Glycemic Control in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis, Advances in nutrition (Bethesda, Md.) 12(3) (2021) 722-734.

[44]Wang, S., Ren, H., Zhong, H., Zhao, X., Li, C., Ma, J., Gu, X., Xue, Y., Huang, S., Yang, J., Chen, L., Chen, G., Qu, S., Liang, J., Qin, L., Huang, Q., Peng, Y., Li, Q., Wang, X., Zou, Y., Shi, Z., Li, X., Li, T., Yang, H., Lai, S., Xu, G., Li, J., Zhang, Y., Gu, Y., Wang, W., Combined berberine and probiotic treatment as an effective regimen for improving postprandial hyperlipidemia in type 2 diabetes patients: a double blinded placebo controlled randomized study, Gut microbes 14(1) (2022) 2003176.

[45]Luo, J., Jiang, L., Gao, B., Chai, Y., Bao, Y., Comprehensive in silico analysis of the probiotics, and preparation of compound probiotics-Polygonatum sibiricum saponin with hypoglycemic properties, Food chemistry 404(Pt A) (2023) 134569.

[46]Quinn-Bohmann, N., Wilmanski, T., Sarmiento, K.R., Levy, L., Lampe, J.W., Gurry, T., Rappaport, N., Ostrem, E.M., Venturelli, O.S., Diener, C., Gibbons, S.M., Microbial community-scale metabolic modelling predicts personalized short-chain fatty acid production profiles in the human gut, Nature microbiology 9(7) (2024) 1700-1712.