Gut microbiota, immunity, and bile acid metabolism: decoding metabolic disease interactions

  • Qixiang Zhao 1,2,3 ,
  • Jiayu Wu 1,2,3 ,
  • Yong Ding 1,2,3 ,
  • Yanli Pang , 1 ,
  • Changtao Jiang , 1,2,3
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  • 1. Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
  • 2. Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
  • 3. Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, Peking University, Beijing 100191, China
yanlipang@bjmu.edu.cn
jiangchangtao@bjmu.edu.cn

Received date: 07 May 2023

Revised date: 14 Jul 2023

Accepted date: 21 Jul 2023

Copyright

2023 The Author(s) 2023. Published by Oxford University Press on behalf of Higher Education Press.

Abstract

In recent decades, the global prevalence of metabolic syndrome has surged, posing a significant public health challenge. Metabolic disorders, encompassing diabetes, obesity, nonalcoholic fatty liver disease, and polycystic ovarian syndrome, have been linked to alterations in the gut microbiota. Nonetheless, the connection between gut microbiota and host metabolic diseases warrants further investigation. In this review, we delve into the associations between various metabolic disorders and the gut microbiota, focusing on immune responses and bile acid (BA) metabolism. Notably, T helper cells, innate lymphoid cells, macrophages, and dendritic cells have been shown to modulate host metabolism through interactions with intestinal microorganisms and the release of cytokines. Furthermore, secondary BA metabolites, derived from the microbiota, are involved in the pathogenesis of metabolic diseases via the farnesoid X receptor and Takeda G protein-coupled receptor 5. By covering both aspects of this immune system-microorganism axis, we present a comprehensive overview of the roles played by the gut microbiota, microbiota-derived BA metabolites, and immune responses in metabolic diseases, as well as the interplay between these systems.

Cite this article

Qixiang Zhao , Jiayu Wu , Yong Ding , Yanli Pang , Changtao Jiang . Gut microbiota, immunity, and bile acid metabolism: decoding metabolic disease interactions[J]. Life Metabolism, 2023 , 2(6) : 247 -265 . DOI: 10.1093/lifemeta/load032

1
Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet 2005;365:1415–28.

DOI

2
Lynch SV, Pedersen O. The human intestinal microbiome in health and disease. N Engl J Med 2016;375:2369–79.

DOI

3
Qin J, Li Y, Cai Z et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 2012;490:55–60.

DOI

4
Li F, Jiang C, Krausz KW et al. Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity. Nat Commun 2013;4:2384.

DOI

5
Demir M, Lang S, Hartmann P et al. The fecal mycobiome in non-alcoholic fatty liver disease. J Hepatol 2022;76:788–99.

DOI

6
Qi X, Yun C, Sun L et al. Gut microbiota-bile acid-interleukin-22 axis orchestrates polycystic ovary syndrome. Nat Med 2019;25:1225–33.

DOI

7
Collins SL, Stine JG, Bisanz JE et al. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol 2022;21:236–47.

DOI

8
Cai J, Sun L, Gonzalez FJ. Gut microbiota-derived bile acids in intestinal immunity, inflammation, and tumorigenesis. Cell Host Microbe 2022;30:289–300.

DOI

9
Zheng X, Chen T, Jiang R et al. Hyocholic acid species improve glucose homeostasis through a distinct TGR5 and FXR signaling mechanism. Cell Metab 2021;33:791–803.e7.

DOI

10
Jiang C, Xie C, Li F et al. Intestinal farnesoid X receptor signaling promotes nonalcoholic fatty liver disease. J Clin Invest 2015;125:386–402.

DOI

11
Gonzalez FJ, Jiang C, Patterson AD. An intestinal microbiota-farnesoid X receptor axis modulates metabolic disease. Gastroenterology 2016;151:845–59.

DOI

12
Jiang C, Xie C, Lv Y et al. Intestine-selective farnesoid X receptor inhibition improves obesity-related metabolic dysfunction. Nat Commun 2015;6:10166.

DOI

13
Kawano Y, Edwards M, Huang Y et al. Microbiota imbalance induced by dietary sugar disrupts immune-mediated protection from metabolic syndrome. Cell 2022;185:3501–19.e20.

DOI

14
Thingholm LB, Rühlemann MC, Koch M et al. Obese individuals with and without type 2 diabetes show different gut microbial functional capacity and composition. Cell Host Microbe 2019;26:252–64.e10.

DOI

15
Yang G, Wei J, Liu P et al. Role of the gut microbiota in type 2 diabetes and related diseases. Metabolism 2021;117:154712.

DOI

16
Karlsson FH, Tremaroli V, Nookaew I et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 2013;498:99–103.

DOI

17
Everard A, Lazarevic V, Derrien M et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice. Diabetes 2011;60:2775–86.

DOI

18
Santacruz A, Collado MC, García-Valdés L et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br J Nutr 2010;104:83–92.

DOI

19
Karlsson CL, Onnerfält J, Xu J et al. The microbiota of the gut in preschool children with normal and excessive body weight. Obesity (Silver Spring) 2012;20:2257–61.

DOI

20
Everard A, Belzer C, Geurts L et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A 2013;110:9066–71.

DOI

21
Depommier C, Everard A, Druart C et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med 2019;25:1096–103.

DOI

22
Plovier H, Everard A, Druart C et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med 2017;23:107–13.

DOI

23
Zhang J, Ni Y, Qian L et al. Decreased abundance of Akkermansia muciniphila leads to the impairment of insulin secretion and glucose homeostasis in lean type 2 diabetes. Adv Sci (Weinh) 2021;8:e2100536.

DOI

24
Pedret A, Valls RM, Calderón-Pérez L et al. Effects of daily consumption of the probiotic Bifidobacterium animalis subsp. lactis CECT 8145 on anthropometric adiposity biomarkers in abdominally obese subjects: a randomized controlled trial. Int J Obes (Lond) 2019;43:1863–8.

DOI

25
Mcallister EJ, Dhurandhar NV, Keith SW et al. Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr 2009;49:868–913.

DOI

26
Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol 2015;11:182–90.

DOI

27
Wilkins AT, Reimer RA. Obesity, early life gut microbiota, and antibiotics. Microorganisms 2021;9:413.

DOI

28
Bailey LC, Forrest CB, Zhang P et al. Association of antibiotics in infancy with early childhood obesity. JAMA Pediatr 2014;168:1063–9.

DOI

29
Turnbaugh PJ, Ley RE, Mahowald MA et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027–31.

DOI

30
Fan Y, Pedersen O. Gut microbiota in human metabolic health and disease. Nat Rev Microbiol 2021;19:55–71.

DOI

31
Gophna U, Konikoff T, Nielsen HB. Oscillospira and related bacteria - from metagenomic species to metabolic features. Environ Microbiol 2017;19:835–41.

DOI

32
Miller TL, Wolin MJ, Conway de Macario E et al. Isolation of Methanobrevibacter smithii from human feces. Appl Environ Microbiol 1982;43:227–32.

DOI

33
Tims S, Derom C, Jonkers DM et al. Microbiota conservation and BMI signatures in adult monozygotic twins. ISME J 2013;7:707–17.

DOI

34
Canfora EE, Jocken JW, Blaak EE. Short-chain fatty acids in control of body weight and insulin sensitivity. Nat Rev Endocrinol 2015;11:577–91.

DOI

35
Abenavoli L, Scarpellini E, Colica C et al. Gut microbiota and obesity: a role for probiotics. Nutrients 2019;11:2690.

DOI

36
Ley RE, Bäckhed F, Turnbaugh P et al. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 2005;102:11070–5.

DOI

37
Zuo HJ, Xie ZM, Zhang WW et al. Gut bacteria alteration in obese people and its relationship with gene polymorphism. World J Gastroenterol 2011;17:1076–81.

DOI

38
Schwiertz A, Taras D, Schäfer K et al. Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 2010;18:190–5.

DOI

39
Brunt EM, Kleiner DE, Wilson LA et al. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011;53:810–20.

DOI

40
Younossi ZM, Koenig AB, Abdelatif D et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73–84.

DOI

41
Compare D, Coccoli P, Rocco A et al. Gut–liver axis: the impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 2012;22:471–6.

DOI

42
Jiang W, Wu N, Wang X et al. Dysbiosis gut microbiota associated with inflammation and impaired mucosal immune function in intestine of humans with non-alcoholic fatty liver disease. Sci Rep 2015;5:8096.

DOI

43
Zhu L, Baker SS, Gill C et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 2013;57:601–9.

DOI

44
Oh TG, Kim SM, Caussy C et al. A universal gut-microbiome-derived signature predicts cirrhosis. Cell Metab 2020;32:901.

DOI

45
Wang T, Guo XK, Xu H. Disentangling the progression of non-alcoholic fatty liver disease in the human gut microbiota. Front Microbiol 2021;12:728823.

DOI

46
Chen B, Sun L, Zeng G et al. Gut bacteria alleviate smoking-related NASH by degrading gut nicotine. Nature 2022;610:562–8.

DOI

47
Lee G, You HJ, Bajaj JS et al. Distinct signatures of gut microbiome and metabolites associated with significant fibrosis in nonobese NAFLD. Nat Commun 2020;11:4982.

DOI

48
Nair S, Cope K, Risby TH et al. Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis. Am J Gastroenterol 2001;96:1200–4.

DOI

49
Dawes EA, Foster SM. The formation of ethanol in Escherichia coli. Biochim Biophys Acta 1956;22:253–65.

DOI

50
Torres PJ, Siakowska M, Banaszewska B et al. Gut microbial diversity in women with polycystic ovary syndrome correlates with hyperandrogenism. J Clin Endocrinol Metab 2018;103:1502–11.

DOI

51
Insenser M, Murri M, Del Campo R et al. Gut microbiota and the polycystic ovary syndrome: influence of sex, sex hormones, and obesity. J Clin Endocrinol Metab 2018;103:2552–62.

DOI

52
Liu R, Zhang C, Shi Y et al. Dysbiosis of gut microbiota associated with clinical parameters in polycystic ovary syndrome. Front Microbiol 2017;8:324.

DOI

53
Zhou L, Ni Z, Cheng W et al. Characteristic gut microbiota and predicted metabolic functions in women with PCOS. Endocr Connect 2020;9:63–73.

DOI

54
Guo J, Shao J, Yang Y et al. Gut microbiota in patients with polycystic ovary syndrome: a systematic review. Reprod Sci 2022;29:69–83.

DOI

55
Ley RE. Gut microbiota in 2015: Prevotella in the gut: choose carefully. Nat Rev Gastroenterol Hepatol 2016;13:69–70.

DOI

56
Guo Y, Qi Y, Yang X et al. Association between polycystic ovary syndrome and gut microbiota. PLoS One 2016;11:e0153196.

DOI

57
Sherman SB, Sarsour N, Salehi M et al. Prenatal androgen exposure causes hypertension and gut microbiota dysbiosis. Gut Microbes 2018;9:400–21.

DOI

58
Hofer U. Microbiome: pro-inflammatory Prevotella? Nat Rev Microbiol 2014;12:5.

DOI

59
Jiang L, Shang M, Yu S et al. A high-fiber diet synergizes with Prevotella copri and exacerbates rheumatoid arthritis. Cell Mol Immunol 2022;19:1414–24.

DOI

60
Zhao Q, Yu J, Zhou H et al. Intestinal dysbiosis exacerbates the pathogenesis of psoriasis-like phenotype through changes in fatty acid metabolism. Signal Transduct Target Ther 2023;8:40.

DOI

61
Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. Mol Cell Endocrinol 2013;368:17–29.

DOI

62
Cai J, Rimal B, Jiang C et al. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022;237:108238.

DOI

63
Forman BM, Goode E, Chen J et al. Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 1995;81:687–93.

DOI

64
Makishima M, Okamoto AY, Repa JJ et al. Identification of a nuclear receptor for bile acids. Science 1999;284:1362–5.

DOI

65
Parks DJ, Blanchard SG, Bledsoe RK et al. Bile acids: natural ligands for an orphan nuclear receptor. Science 1999;284:1365–8.

DOI

66
Sinal CJ, Tohkin M, Miyata M et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 2000;102:731–44.

DOI

67
Cariou B, van Harmelen K, Duran-Sandoval D et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 2006;281:11039–49.

DOI

68
Prawitt J, Abdelkarim M, Stroeve JHM et al. Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes 2011;60:1861–71.

DOI

69
Sun L, Cai J, Gonzalez FJ. The role of farnesoid X receptor in metabolic diseases, and gastrointestinal and liver cancer. Nat Rev Gastroenterol Hepatol 2021;18:335–47.

DOI

70
Jiang J, Ma Y, Liu Y et al. Glycine-β-muricholic acid antagonizes the intestinal farnesoid X receptor-ceramide axis and ameliorates NASH in mice. Hepatol Commun 2022;6:3363–78.

DOI

71
Fang S, Suh JM, Reilly SM et al. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance. Nat Med 2015;21:159–65.

DOI

72
Pathak P, Xie C, Nichols RG et al. Intestine farnesoid X receptor agonist and the gut microbiota activate G-protein bile acid receptor-1 signaling to improve metabolism. Hepatology 2018;68:1574–88.

DOI

73
Gillard J, Picalausa C, Ullmer C et al. Enterohepatic Takeda G-protein coupled receptor 5 agonism in metabolic dysfunction-associated fatty liver disease and related glucose dysmetabolism. Nutrients 2022;14:2707.

DOI

74
Zhang Y, Jackson JP, St. Claire RL et al. Obeticholic acid, a selective farnesoid X receptor agonist, regulates bile acid homeostasis in sandwich-cultured human hepatocytes. Pharmacol Res Perspect 2017;5:e00329.

DOI

75
Nevens F, Andreone P, Mazzella G et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016;375:631–43.

DOI

76
Chapman RW, Lynch KD. Obeticholic acid-a new therapy in PBC and NASH. Br Med Bull 2020;133:95–104.

DOI

77
Fickert P, Hirschfield GM, Denk G et al. norUrsodeoxycholic acid improves cholestasis in primary sclerosing cholangitis. J Hepatol 2017;67:549–58.

DOI

78
Zhu C, Boucheron N, Rica R et al. 24-Nor-ursodeoxycholic acid counteracts TH17/Treg imbalance and ameliorates intestinal inflammation by restricting glutaminolysis in differentiating TH17 cells. bioRxiv, 2022.

DOI

79
Nakajima A, Seki M, Taniguchi S et al. Safety and efficacy of elobixibat for chronic constipation: results from a randomised, double-blind, placebo-controlled, phase 3 trial and an open-label, single-arm, phase 3 trial. Lancet Gastroenterol Hepatol 2018;3:537–47.

DOI

80
Pathak P, Liu H, Boehme S et al. Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism. J Biol Chem 2017;292:11055–69.

DOI

81
Chiang JYL, Ferrell JM. Bile acid receptors FXR and TGR5 signaling in fatty liver diseases and therapy. Am J Physiol Gastrointest Liver Physiol 2020;318:G554–73.

DOI

82
Thomas C, Gioiello A, Noriega L et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 2009;10:167–77.

DOI

83
Makki K, Brolin H, Petersen N et al. 6α-hydroxylated bile acids mediate TGR5 signalling to improve glucose metabolism upon dietary fiber supplementation in mice. Gut 2023;72:314–24.

DOI

84
Wu Q, Liang X, Wang K et al. Intestinal hypoxia-inducible factor 2α regulates lactate levels to shape the gut microbiome and alter thermogenesis. Cell Metab 2021;33:1988–2003.e7.

DOI

85
Castellanos-Jankiewicz A, Guzmán-Quevedo O, Fénelon VS et al. Hypothalamic bile acid-TGR5 signaling protects from obesity. Cell Metab 2021;33:1483–92.e10.

DOI

86
Fang Y, Han SI, Mitchell C et al. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes. Hepatology 2004;40:961–71.

DOI

87
Ratziu V, de Ledinghen V, Oberti F et al. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J Hepatol 2011;54:1011–9.

DOI

88
Tsuchida T, Shiraishi M, Ohta T et al. Ursodeoxycholic acid improves insulin sensitivity and hepatic steatosis by inducing the excretion of hepatic lipids in high-fat diet-fed KK-Ay mice. Metabolism 2012;61:944–53.

DOI

89
Chen YS, Liu HM, Lee TY. Ursodeoxycholic acid regulates hepatic energy homeostasis and white adipose tissue macrophages polarization in leptin-deficiency obese mice. Cells 2019;8:253.

DOI

90
Liu J, Wei Y, Jia W et al. Chenodeoxycholic acid suppresses AML progression through promoting lipid peroxidation via ROS/p38 MAPK/DGAT1 pathway and inhibiting M2 macrophage polarization. Redox Biol 2022;56:102452.

DOI

91
Thaiss CA, Zmora N, Levy M et al. The microbiome and innate immunity. Nature 2016;535:65–74.

DOI

92
Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature 2016;535:75–84.

DOI

93
Odegaard JI, Chawla A. Alternative macrophage activation and metabolism. Annu Rev Pathol 2011;6:275–97.

DOI

94
Weisberg SP, McCann D, Desai M et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796–808.

DOI

95
Lumeng CN, DelProposto JB, Westcott DJ et al. Phenotypic switching of adipose tissue macrophages with obesity is generated by spatiotemporal differences in macrophage subtypes. Diabetes 2008;57:3239–46.

DOI

96
Lumeng CN, Bodzin JL, Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 2007;117:175–84.

DOI

97
Lumeng CN, Deyoung SM, Saltiel AR. Macrophages block insulin action in adipocytes by altering expression of signaling and glucose transport proteins. Am J Physiol Endocrinol Metab 2007;292:E166–74.

DOI

98
Odegaard JI, Ricardo-Gonzalez RR, Goforth MH et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 2007;447:1116–20.

DOI

99
Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol 2011;11:738–49.

DOI

100
Pan Y, Suga A, Kimura I et al. Cyclooxygenase-2 in adipose tissue macrophages limits adipose tissue dysfunction in obese mice. J Clin Invest 2022;132:e153589.

DOI

101
Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol 2017;17:306–21.

DOI

102
Huby T, Gautier EL. Immune cell-mediated features of non-alcoholic steatohepatitis. Nat Rev Immunol 2022;22:429–43.

DOI

103
Jaitin DA, Adlung L, Thaiss CA et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell 2019;178:686–98.e14.

DOI

104
Hou J, Zhang J, Cui P et al. TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis. J Clin Invest 2021;131:e135197.

DOI

105
Wang X, He Q, Zhou C et al. Prolonged hypernutrition impairs TREM2-dependent efferocytosis to license chronic liver inflammation and NASH development. Immunity 2022;56:58–77.e11.

DOI

106
Li X, Zhang X, Xia J et al. Macrophage HIF-2α suppresses NLRP3 inflammasome activation and alleviates insulin resistance. Cell Rep 2021;36:109607.

DOI

107
Lian G, Li X, Zhang L et al. Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway. EBioMedicine 2019;49:291–304.

DOI

108
Sell H, Habich C, Eckel J. Adaptive immunity in obesity and insulin resistance. Nat Rev Endocrinol 2012;8:709–16.

DOI

109
Winer S, Chan Y, Paltser G et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 2009;15:921–9.

DOI

110
Rocha VZ, Folco EJ, Sukhova G et al. Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ Res 2008;103:467–76.

DOI

111
Winer S, Paltser G, Chan Y et al. Obesity predisposes to Th17 bias. Eur J Immunol 2009;39:2629–35.

DOI

112
Zuniga LA, Shen WJ, Joyce-Shaikh B, et al. IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J Immunol 2010;185:6947–59.

DOI

113
Chen Y, Tian J, Tian X et al. Adipose tissue dendritic cells enhances inflammation by prompting the generation of Th17 cells. PLoS One 2014;9:e92450.

DOI

114
Cavallari JF, Denou E, Foley KP et al. Different Th17 immunity in gut, liver, and adipose tissues during obesity: the role of diet, genetics, and microbes. Gut Microbes 2016;7:82–9.

DOI

115
Garidou L, Pomié C, Klopp P et al. The gut microbiota regulates intestinal CD4 T cells expressing RORγt and controls metabolic disease. Cell Metab 2015;22:100–12.

DOI

116
Cox LM, Yamanishi S, Sohn J et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014;158:705–21.

DOI

117
Feuerer M, Herrero L, Cipolletta D et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009;15:930–9.

DOI

118
Deiuliis J, Shah Z, Shah N et al. Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One 2011;6:e16376.

DOI

119
Cipolletta D, Kolodin D, Benoist C et al. Tissular Tregs: a unique population of adipose-tissue-resident Foxp3+CD4+ T cells that impacts organismal metabolism. Semin Immunol 2011;23:431–7.

DOI

120
Yuan N, Zhang H-F, Wei Q et al. Expression of CD4+CD25+Foxp3+ regulatory T cells, interleukin 10 and transforming growth factor β in newly diagnosed type 2 diabetic patients. Exp Clin Endocrinol Diabetes 2018;126:96–101.

DOI

121
Wagner NM, Brandhorst G, Czepluch F et al. Circulating regulatory T cells are reduced in obesity and may identify subjects at increased metabolic and cardiovascular risk. Obesity (Silver Spring) 2013;21:461–8.

DOI

122
Gyllenhammer LE, Lam J, Alderete TL et al. Lower omental t-regulatory cell count is associated with higher fasting glucose and lower β-cell function in adults with obesity. Obesity (Silver Spring) 2016;24:1274–82.

DOI

123
Ramadori P, Kam S, Heikenwalder M. T cells: friends and foes in NASH pathogenesis and hepatocarcinogenesis. Hepatology 2022;75:1038–49.

DOI

124
Bhattacharjee J, Kirby M, Softic S et al. Hepatic natural killer T-cell and CD8+ T-cell signatures in mice with nonalcoholic steatohepatitis. Hepatol Commun 2017;1:299–310.

DOI

125
Breuer DA, Pacheco MC, Washington MK et al. CD8+ T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 2020;318:G211–24.

DOI

126
Inzaugarat ME, Ferreyra Solari NE, Billordo LA et al. Altered phenotype and functionality of circulating immune cells characterize adult patients with nonalcoholic steatohepatitis. J Clin Immunol 2011;31:1120–30.

DOI

127
Sun G, Jin H, Zhang C et al. OX40 regulates both innate and adaptive immunity and promotes nonalcoholic steatohepatitis. Cell Rep 2018;25:3786–99.e4.

DOI

128
Su L, Wu Z, Chi Y et al. Mesenteric lymph node CD4+ T lymphocytes migrate to liver and contribute to non-alcoholic fatty liver disease. Cell Immunol 2019;337:33–41.

DOI

129
Rau M, Schilling AK, Meertens J et al. Progression from nonalcoholic fatty liver to nonalcoholic steatohepatitis is marked by a higher frequency of Th17 cells in the liver and an increased Th17/resting regulatory T cell ratio in peripheral blood and in the liver. J Immunol 2016;196:97–105.

DOI

130
Meng F, Wang K, Aoyama T et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology 2012;143:765–776.e3.

DOI

131
Rappez L, Stadler M, Triana S et al. SpaceM reveals metabolic states of single cells. Nat Methods 2021;18:799–805.

DOI

132
Moreno-Fernandez ME, Giles DA, Oates JR et al. PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease. Cell Metab 2021;33:1187–204.e9.

DOI

133
Li F, Hao X, Chen Y et al. The microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner. Nat Commun 2017;7:13839.

DOI

134
Yang Y, Xia J, Yang Z et al. The abnormal level of HSP70 is related to Treg/Th17 imbalance in PCOS patients. J Ovarian Res 2021;14:155.

DOI

135
Viel S, Besson L, Charrier E et al. Alteration of natural killer cell phenotype and function in obese individuals. Clin Immunol 2017;177:12–7.

DOI

136
Tobin LM, Mavinkurve M, Carolan E et al. NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient. JCI Insight 2017;2:e94939.

DOI

137
Wensveen FM, Jelenčić V, Valentić S et al. NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol 2015;16:376–85.

DOI

138
Lee BC, Kim M-S, Pae M et al. Adipose natural killer cells regulate adipose tissue macrophages to promote insulin resistance in obesity. Cell Metab 2016;23:685–98.

DOI

139
Kanda H, Tateya S, Tamori Y et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006;116:1494–505.

DOI

140
Bahr I, Spielmann J, Quandt D et al. Obesity-associated alterations of natural killer cells and immunosurveillance of cancer. Front Immunol 2020;11:245.

DOI

141
O’rourke RW, Gaston GD, Meyer KA et al. Adipose tissue NK cells manifest an activated phenotype in human obesity. Metabolism 2013;62:1557–61.

DOI

142
Ferno J, Strand K, Mellgren G et al. Natural killer cells as sensors of adipose tissue stress. Trends Endocrinol Metab 2020;31:3–12.

DOI

143
Bonamichi B, Lee J. Unusual suspects in the development of obesity-induced inflammation and insulin resistance: NK cells, iNKT cells, and ILCs. Diabetes Metab J 2017;41:229–50.

DOI

144
Stiglund N, Strand K, Cornillet M et al. Retained NK cell phenotype and functionality in non-alcoholic fatty liver disease. Front Immunol 2019;10:1255.

DOI

145
Theurich S, Tsaousidou E, Hanssen R et al. IL-6/Stat3-dependent induction of a distinct, obesity-associated NK cell subpopulation deteriorates energy and glucose homeostasis. Cell Metab 2017;26:171–84.e6.

DOI

146
Zhou L, Lin Q, Sonnenberg GF. Metabolic control of innate lymphoid cells in health and disease. Nat Metab 2022;4:1650–9.

DOI

147
Kim HY, Lee HJ, Chang YJ et al. Interleukin-17-producing innate lymphoid cells and the NLRP3 inflammasome facilitate obesity-associated airway hyperreactivity. Nat Med 2014;20:54–61.

DOI

148
Wang X, Ota N, Manzanillo P et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 2014;514:237–41.

DOI

149
Wang Y, Kuang Z, Yu X et al. The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 2017;357:912–6.

DOI

150
Sasaki T, Moro K, Kubota T et al. Innate lymphoid cells in the induction of obesity. Cell Rep 2019;28:202–17.e7.

DOI

151
Hamaguchi M, Okamura T, Fukuda T et al. Group 3 innate lymphoid cells protect steatohepatitis from high-fat diet induced toxicity. Front Immunol 2021;12:648754.

DOI

152
Ganguly D, Haak S, Sisirak V et al. The role of dendritic cells in autoimmunity. Nat Rev Immunol 2013;13:566–77.

DOI

153
Merad M, Sathe P, Helft J et al. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu Rev Immunol 2013;31:563–604.

DOI

154
Bertola A, Ciucci T, Rousseau D et al. Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 2012;61:2238–47.

DOI

155
Patsouris D, Li PP, Thapar D et al. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 2008;8:301–9.

DOI

156
Stefanovic-Racic M, Yang X, Turner MS et al. Dendritic cells promote macrophage infiltration and comprise a substantial proportion of obesity-associated increases in CD11c+ cells in adipose tissue and liver. Diabetes 2012;61:2330–9.

DOI

157
Macdougall CE, Wood EG, Loschko J et al. Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets. Cell Metab 2018;27:588–601.e4.

DOI

158
Hernandez-Garcia E, Cueto FJ, Cook ECL et al. Conventional type 1 dendritic cells protect against age-related adipose tissue dysfunction and obesity. Cell Mol Immunol 2022;19:260–75.

DOI

159
Haas JT, Vonghia L, Mogilenko DA et al. Transcriptional network analysis implicates altered hepatic immune function in NASH development and resolution. Nat Metab 2019;1:604–14.

DOI

160
Deczkowska A, David E, Ramadori P et al. XCR1+ type 1 conventional dendritic cells drive liver pathology in non-alcoholic steatohepatitis. Nat Med 2021;27:1043–54.

DOI

161
Galle-Treger L, Helou DG, Quach C et al. Autophagy impairment in liver CD11c+ cells promotes non-alcoholic fatty liver disease through production of IL-23. Nat Commun 2022;13:1440.

DOI

162
Winer DA, Luck H, Tsai S et al. The intestinal immune system in obesity and insulin resistance. Cell Metab 2016;23:413–26.

DOI

163
Bunker JJ, Bendelac A. IgA responses to microbiota. Immunity 2018;49:211–24.

DOI

164
Luck H, Khan S, Kim JH et al. Gut-associated IgA+ immune cells regulate obesity-related insulin resistance. Nat Commun 2019;10:3650.

DOI

165
Amar J, Chabo C, Waget A et al. Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol Med 2011;3:559–72.

DOI

166
Cani PD, Bibiloni R, Knauf C et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–81.

DOI

167
Cani PD, Amar J, Iglesias MA et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761–72.

DOI

168
Petersen C, Bell R, Klag KA et al. T cell-mediated regulation of the microbiota protects against obesity. Science 2019;365:eaat9351.

DOI

169
Hong CP, Park A, Yang BG et al. Gut-specific delivery of T-helper 17 cells reduces obesity and insulin resistance in mice. Gastroenterology 2017;152:1998–2010.

DOI

170
Shin NR, Lee JC, Lee HY et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 2014;63:727–35.

DOI

171
Zhao Q, Yu J, Hao Y et al. Akkermansia muciniphila plays critical roles in host health. Crit Rev Microbiol 2022;49:82–100.

DOI

172
Barcena C, Valdés-Mas R, Mayoral P et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat Med 2019;25:1234–42.

DOI

173
Li J, Lin S, Vanhoutte PM et al. Akkermansia muciniphila protects against atherosclerosis by preventing metabolic endotoxemia- induced inflammation in Apoe-/- mice. Circulation 2016;133:2434–46.

DOI

174
Wang J, Xu W, Wang R et al. The outer membrane protein Amuc_1100 of Akkermansia muciniphila promotes intestinal 5-HT biosynthesis and extracellular availability through TLR2 signalling. Food Funct 2021;12:3597–610.

DOI

175
Si J, Zhang H, Zhu L et al. The relationship between overweight/obesity and executive control in college students: the mediating effect of BDNF and 5-HT. Life (Basel) 2021;11:313.

DOI

176
Goto Y, Panea C, Nakato G et al. Segmented filamentous bacteria antigens presented by intestinal dendritic cells drive mucosal Th17 cell differentiation. Immunity 2014;40:594–607.

DOI

177
Ivanov I, Atarashi K, Manel N et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 2009;139:485–98.

DOI

178
Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014;146:1513–24.

DOI

179
Rahman K, Desai C, Iyer SS et al. Loss of junctional adhesion molecule a promotes severe steatohepatitis in mice on a diet high in saturated fat, fructose, and cholesterol. Gastroenterology 2016;151:733–46.e12.

DOI

180
Gabele E, Dostert K, Hofmann C et al. DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J Hepatol 2011;55:1391–9.

DOI

181
Craven L, Rahman A, Nair Parvathy S et al. Allogenic fecal microbiota transplantation in patients with nonalcoholic fatty liver disease improves abnormal small intestinal permeability: a randomized control trial. Am J Gastroenterol 2020;115:1055–65.

DOI

182
Juárez-Fernández M, Goikoetxea-Usandizaga N, Porras D et al. Enhanced mitochondrial activity reshapes a gut microbiota profile that delays NASH progression. Hepatology 2023;77:1654–69.

DOI

183
Mouries J, Brescia P, Silvestri A et al. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J Hepatol 2019;71:1216–28.

DOI

184
Morrison MC, Gart E, Duyvenvoorde WV et al. Heat-inactivated Akkermansia muciniphila improves gut permeability but does not prevent development of non-alcoholic steatohepatitis in diet-induced obese Ldlr-/-Leiden mice. Int J Mol Sci 2022;23:2325.

DOI

185
Shi Z, Lei H, Chen G et al. Impaired intestinal Akkermansia muciniphila and aryl hydrocarbon receptor ligands contribute to nonalcoholic fatty liver disease in mice. mSystems 2021;6:e00985-20.

DOI

186
Li T, Lin X, Shen B et al. Akkermansia muciniphila suppressing nonalcoholic steatohepatitis associated tumorigenesis through CXCR6+ natural killer T cells. Front Immunol 2022;13:1047570.

DOI

187
He S, Cui S, Song W et al. Interleukin-17 weakens the NAFLD/ NASH process by facilitating intestinal barrier restoration depending on the gut microbiota. mBio 2022;13:e0368821.

DOI

188
Leonardi I, Gao IH, Lin WY et al. Mucosal fungi promote gut barrier function and social behavior via type 17 immunity. Cell 2022;185:831–846.e14.

DOI

189
Lee JS, Tato CM, Joyce-Shaikh B et al. Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 2015;43:727–38.

DOI

190
Zeng S, Rosati E, Saggau C et al. Candida albicans-specific Th17 cell-mediated response contributes to alcohol-associated liver disease. Cell Host Microbe 2023;31:389–404.e7.

DOI

191
Schneider KM, Bieghs V, Heymann F et al. CX3CR1 is a gatekeeper for intestinal barrier integrity in mice: limiting steatohepatitis by maintaining intestinal homeostasis. Hepatology 2015;62:1405–16.

DOI

192
Lingaiah S, Arffman RK, Morin-Papunen L et al. Markers of gastrointestinal permeability and dysbiosis in premenopausal women with PCOS: a case-control study. BMJ Open 2021;11:e045324.

DOI

193
Lindheim L, Bashir M, Münzker J et al. Alterations in gut microbiome composition and barrier function are associated with reproductive and metabolic defects in women with polycystic ovary syndrome (PCOS): a pilot study. PLoS One 2017;12:e0168390.

DOI

194
Paik D, Yao L, Zhang Y et al. Human gut bacteria produce TH17-modulating bile acid metabolites. Nature 2022;603:907–12.

DOI

195
Hang S, Paik D, Yao L et al. Bile acid metabolites control TH17 and Treg cell differentiation. Nature 2019;576:143–8.

DOI

196
Kleinridders A, Schenten D, Könner AC et al. MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 2009;10:249–59.

DOI

197
Everard A, Geurts L, Caesar R et al. Intestinal epithelial MyD88 is a sensor switching host metabolism towards obesity according to nutritional status. Nat Commun 2014;5:5648.

DOI

198
Wen L, Ley RE, Volchkov PY et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 2008;455:1109–13.

DOI

199
Duparc T, Plovier H, Marrachelli VG et al. Hepatocyte MyD88 affects bile acids, gut microbiota and metabolome contributing to regulate glucose and lipid metabolism. Gut 2017;66:620–32.

DOI

200
Sun L, Xie C, Wang G et al. Gut microbiota and intestinal FXR mediate the clinical benefits of metformin. Nat Med 2018;24:1919–29.

DOI

201
Rao Y, Kuang Z, Li C et al. Gut Akkermansia muciniphila ameliorates metabolic dysfunction-associated fatty liver disease by regulating the metabolism of L-aspartate via gut-liver axis. Gut Microbes 2021;13:1–19.

DOI

202
Hu W, Gao W, Liu Z et al. Specific strains of Faecalibacterium prausnitzii ameliorate nonalcoholic fatty liver disease in mice in association with gut microbiota regulation. Nutrients 2022;14:2945.

DOI

203
Juarez-Fernandez M, Porras D, Petrov P et al. The synbiotic combination of Akkermansia muciniphila and quercetin ameliorates early obesity and NAFLD through gut microbiota reshaping and bile acid metabolism modulation. Antioxidants (Basel) 2021;10:2001.

DOI

204
Younossi ZM, Ratziu V, Loomba R et al. Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2019;394:2184–96.

DOI

205
Clifford BL, Sedgeman LR, Williams KJ et al. FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption. Cell Metab 2021;33:1671–1684.e4.

DOI

206
Wang W, Zhao J, Gui W et al. Tauroursodeoxycholic acid inhibits intestinal inflammation and barrier disruption in mice with non-alcoholic fatty liver disease. Br J Pharmacol 2018;175:469–84.

DOI

207
Sun L, Pang Y, Wang X et al. Ablation of gut microbiota alleviates obesity-induced hepatic steatosis and glucose intolerance by modulating bile acid metabolism in hamsters. Acta Pharm Sin B 2019;9:702–10.

DOI

208
Ou H, Fu Y, Liao W et al. Association between smoking and liver fibrosis among patients with nonalcoholic fatty liver disease. Can J Gastroenterol Hepatol 2019;2019:6028952.

DOI

209
Jung HS, Chang Y, Kwon MJ et al. Smoking and the risk of non-alcoholic fatty liver disease: a cohort study. Am J Gastroenterol 2019;114:453–63.

DOI

210
Wang L, Zhou J, Gober HJ et al. Alterations in the intestinal microbiome associated with PCOS affect the clinical phenotype. Biomed Pharmacother 2021;133:110958.

DOI

211
Zhang J, Sun Z, Jiang S et al. Probiotic Bifidobacterium lactis V9 regulates the secretion of sex hormones in polycystic ovary syndrome patients through the gut-brain axis. mSystems 2019;4:00017-19.

DOI

212
Maldonado-Gomez MX, Martínez I, Bottacini F et al. Stable engraftment of Bifidobacterium longum AH1206 in the human gut depends on individualized features of the resident microbiome. Cell Host Microbe 2016;20:515–26.

DOI

213
De La Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V et al. Metformin is associated with higher relative abundance of mucin-degrading Akkermansia muciniphila and several shortchain fatty acid-producing microbiota in the gut. Diabetes Care 2017;40:54–62.

DOI

214
Han Q, Wang J, Li W et al. Androgen-induced gut dysbiosis disrupts glucolipid metabolism and endocrinal functions in polycystic ovary syndrome. Microbiome 2021;9:101.

DOI

215
Li T, Zhang T, Gao H et al. Tempol ameliorates polycystic ovary syndrome through attenuating intestinal oxidative stress and modulating of gut microbiota composition-serum metabolites interaction. Redox Biol 2021;41:101886.

DOI

216
Duan Y, Llorente C, Lang S et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature 2019;575:505–11.

DOI

217
Kim HJ, Vazquez Roque MI, Camilleri M et al. A randomized controlled trial of a probiotic combination VSL# 3 and placebo in irritable bowel syndrome with bloating. Neurogastroenterol Motil 2005;17:687–96.

DOI

218
Mencarelli A, Cipriani S, Renga B et al. VSL#3 resets insulin signaling and protects against NASH and atherosclerosis in a model of genetic dyslipidemia and intestinal inflammation. PLoS One 2012;7:e45425.

DOI

219
Jena PK, Sheng L, Li Y et al. Probiotics VSL#3 are effective in reversing non-alcoholic steatohepatitis in a mouse model. Hepatobiliary Surg Nutr 2020;9:170–82.

DOI

220
Alisi A, Bedogni G, Baviera G et al. Randomised clinical trial: the beneficial effects of VSL#3 in obese children with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2014;39:1276–85.

DOI

221
Wang Y, Wang Z, Wan Y et al. Assessing the in vivo ameliorative effects of Lactobacillus acidophilus KLDS1.0901 for induced non-alcoholic fatty liver disease treatment. Front Nutr 2023;10:1147423.

DOI

222
Hendrikx T, Duan Y, Wang Y et al. Bacteria engineered to produce IL-22 in intestine induce expression of REG3G to reduce ethanol-induced liver disease in mice. Gut 2019;68:1504–15.

DOI

223
Traussnigg S, Schattenberg JM, Demir M et al. Norursodeoxycholic acid versus placebo in the treatment of non-alcoholic fatty liver disease: a double-blind, randomised, placebo-controlled, phase 2 dose-finding trial. Lancet Gastroenterol Hepatol 2019;4:781–93.

DOI

224
Yu H, Zhao T, Liu S et al. MRGPRX4 is a bile acid receptor for human cholestatic itch. Elife 2019;8:e48431.

DOI

225
Troisi G, Crisciotti F, Gianturco V et al. The treatment with ursodeoxycholic acid in elderly patients affected by NAFLD and metabolic syndrome: a case-control study. Clin Ter 2013;164:203–7.

226
Lindor KD, Kowdley KV, Heathcote EJ et al. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology 2004;39:770–8.

DOI

227
Marchiano S, Biagioli M, Roselli R et al. Beneficial effects of UDCA and norUDCA in a rodent model of steatosis are linked to modulation of GPBAR1/FXR signaling. Biochim Biophys Acta Mol Cell Biol Lipids 2022;1867:159218.

DOI

228
Traussnigg S, Schattenberg JM, Demir M et al. norUrsodeoxycholic acid (norUDCA) improves non-alcoholic fatty liver disease (NAFLD): results from a randomized placebo-controlled, double-blind phase IIa study. Hepatology 2017;66:106A–8.

229
Roth JD, Feigh M, Veidal SS et al. INT-767 improves histopathological features in a diet-induced ob/ob mouse model of biopsy- confirmed non-alcoholic steatohepatitis. World J Gastroenterol 2018;24:195–210.

DOI

230
Hernandez ED, Zheng L, Kim Y et al. Tropifexor-mediated abrogation of steatohepatitis and fibrosis is associated with the antioxidative gene expression profile in rodents. Hepatol Commun 2019;3:1085–97.

DOI

231
Tully DC, Rucker PV, Chianelli D et al. Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). J Med Chem 2017;60:9960–73.

DOI

232
Sanyal AJ, Lopez P, Lawitz EJ et al. Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial. Nat Med 2023;29:392–400.

DOI

233
Anfuso B, Tiribelli C, Adorini L et al. Obeticholic acid and INT-767 modulate collagen deposition in a NASH in vitro model. Sci Rep 2020;10:1699.

DOI

234
Van Wagner LB, Koppe SWP, Brunt EM et al. Pentoxifylline for the treatment of non-alcoholic steatohepatitis: a randomized controlled trial. Ann Hepatol 2011;10:277–86.

DOI

235
Zein CO, Yerian LM, Gogate P et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology 2011;54:1610–9.

DOI

236
Russell BJ, Brown SD, Siguenza N et al. Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes. Cell 2022;185:3263–77.e15.

DOI

237
Jin M, Chen J, Zhao X et al. An engineered lambda phage enables enhanced and strain-specific killing of enterohemorrhagic Escherichia coli. Microbiol Spectr 2022;10:e0127122.

DOI

238
Isabella VM, Ha BN, Castillo MJ et al. Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nat Biotechnol 2018;36:857–64.

DOI

239
Puurunen MK, Vockley J, Searle SL et al. Safety and pharmacodynamics of an engineered E. coli Nissle for the treatment of phenylketonuria: a first-in-human phase 1/2a study. Nat Metab 2021;3:1125–32.

DOI

240
Lynch JP, Goers L, Lesser CF. Emerging strategies for engineering Escherichia coli Nissle 1917-based therapeutics. Trends Pharmacol Sci 2022;43:772–86.

DOI

241
Kastl AJ Jr, Terry NA, Wu GD et al. The structure and function of the human small intestinal microbiota: current understanding and future directions. Cell Mol Gastroenterol Hepatol 2020;9:33–45.

DOI

242
James KR, Gomes T, Elmentaite R et al. Distinct microbial and immune niches of the human colon. Nat Immunol 2020;21:343–53.

DOI

243
Shalon D, Culver RN, Grembi JA et al. Profiling the human intestinal environment under physiological conditions. Nature 2023;617:581–91.

DOI

244
Le Chatelier E, Nielsen T, Qin J et al. Richness of human gut microbiome correlates with metabolic markers. Nature 2013;500:541–6.

DOI

245
Uusitupa HM, Rasinkangas P, Lehtinen MJ et al. Bifidobacterium animalis subsp. lactis 420 for metabolic health: review of the research. Nutrients 2020;12:892.

DOI

246
Wang J, Tang H, Zhang C et al. Modulation of gut microbiota during probiotic-mediated attenuation of metabolic syndrome in high fat diet-fed mice. ISME J 2015;9:1–15.

DOI

247
Verdam FJ, Fuentes S, de Jonge C et al. Human intestinal microbiota composition is associated with local and systemic inflammation in obesity. Obesity (Silver Spring) 2013;21:E607–15.

DOI

248
Wang K, Liao M, Zhou N et al. Parabacteroides distasonis alleviates obesity and metabolic dysfunctions via production of succinate and secondary bile acids. Cell Rep 2019;26:222–35.e5.

DOI

249
Yang J, Li Y, Wen Z et al. Oscillospira - a candidate for the next-generation probiotics. Gut Microbes 2021;13:1987783.

DOI

250
Konikoff T, Gophna UO. A central, enigmatic component of the human gut microbiota. Trends Microbiol 2016;24:523–4.

DOI

251
Barrow F, Khan S, Fredrickson G et al. Microbiota-driven activation of intrahepatic B cells aggravates NASH through innate and adaptive signaling. Hepatology 2021;74:704–22.

DOI

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