The Association Of FGF19 With Gut Homeostasis And Glucose Metabolism And The Mechanism Of Crosstalk

The gut-derived hormone Fibroblast growth factor 19(FGF19)could regulate glucose metabolism and is induced by bile acids(BAs)through activating Farnesoid X Receptor(FXR).BAs are synthesized from enzymatic oxidation of cholesterol in the liver,and have long been known to facilitate dietary lipid absorption.Recent years,BAs are gaining increasing recognition as important metabolic signaling molecules.Primary BAs can be transformed to secondary BAs by enzymes in gut bacteria.Gut microbiota may affect metabolism through affecting the components of BAs.It has been found that intestinal flora participates in host glucose metabolism and is closely related to the development of diabetes.This study focuses on the associations and mechanism of FGF19,BAs and gut microbiota with glucose metabolism.The study is divided into three parts,the contents and main findings are as follows:1.The close relationship between FGF19 and insulin-independent glucose regulationOBJECTIVE:The ileum-derived FGF19 plays important roles in hepatic glucose homeostasis through insulin-independent pathways in animals.In this study,we analyzed the association of FGF19 with glucose effectiveness(GE,insulin-independent effects),as well as hepatic glucose production(HGP)in Chinese subjects.RESEARCH DESIGN AND METHODS:GE was measured by frequently sampled intravenous glucose tolerance test(FSIVGTT)in 31 normal glucose tolerance(NGT),34 isolated-impaired glucose tolerance and 31 isolated-impaired fasting glucose(I-IFG)subjects.The oral glucose tolerance test-derived surrogate of GE(oGE)was determined in 56 NGT,23 I-IFG,36 combined glucose intolerance(CGI)and 83 type 2 diabetes(T2DM)subjects.HGP was assessed by labelled([3-~3H]-glucose)hyperinsulinemic-euglycemic clamp in 14 NGT subjects.Insulin secretion and sensitivity were calculated by the hyperglycemic clamp and hyperinsulinemic-euglycemic clamp in 14NGT,10 I-IGT and 10 I-IFG subjects.RESULTS:FGF19 positively correlated with GE(r=0.29,P=0.004)as determined by FSIVGTT.The result was further confirmed by oGE(r=0.261,P<0.001).FGF19 was negatively associated with FPG(r=-0.228,P=0.025),but the association no longer existed after adjusting for GE(r=-0.177,P=0.086).FGF19 was negatively associated with basal HGP(r=-0.697,P=0.006).However,no significant association between FGF19 and insulin secretion and sensitivity were found.CONCLUSIONS:FGF19 levels are associated positively with GE and negatively with HGP.The increase of FPG in human is at least partially due to the decrease of FGF19 in an insulin-independent manner.2.The relationship between FGF19 levels and BAs in subjects with different glucose tolerance stateOBJECTIVE:FGF19 could regulate glucose metabolism and is induced by BAs through activating FXR.FGF19 was found to decrease in subjects with I-IFG and T2DM.However,the reason for the change of FGF19 in subjects with different glucometabolic status remained unclear.Here,we investigated the kinetics of serum BA composition after oral glucose challenge in different glucose tolerance state,and analyzed the correlation of FGF19 and BAs.RESEARCH DESIGN AND METHODS:Serum free BAs including chenodeoxycholic acid(CDCA),cholic acid,deoxycholic acid,and respective glycine conjugates were measured by liquid chromatography-mass spectrometry in 10 NGT,9 isolated-impaired glucose tolerance,10 I-IFG,12CGI and 24 T2DM subjects.Serum FGF19 levels were determined by ELISA.RESULTS:After OGTT,serum FGF19 peaked at 120min in all subjects.Glycine conjugated BAs peaked at 30min,while free BAs did not elevated significantly.Consistent with the decrease trend in FGF19 levels,fasting serum CDCA levels in subjects with I-IFG,CGI and T2DM were significantly lower than NGT subjects(P<0.05).Fasting serum CDCA was independently associated with FGF19.CDCA strongly upregulated FGF19 mRNA levels in LS174T cells in a dose-and time-dependent manner.CONCLUSIONS:Fasting serum CDCA levels were decreased in subjects with increased fasting plasma glucose and positively correlated with FGF19,suggesting that the decrease of FGF19 in subjects with I-IFG was at least partially due to their decrease of CDCA acting via FXR.3.The association of gut microbiota,BAs and FGF19 with glucose metabolism and the mechanism of regulationOBJECTIVE:In the second part of this study,it was found that the change of FGF19 levels were correlated with BAs.The metabolism of BAs is affected by the gut microbiota.Emerging evidence has linked the gut microbiome and BAs to T2DM.Here we study the relationship between gut microbiota,BAs,FGF19 and glucose metabolism in subjects with different state of metabolism,and investigated its mechanism of regulation.RESEARCH DESIGN AND METHODS:We performed a metagenome-wide association study and compared the gut microbiota composition in a cohort of 52 normal lean subjects(NL),52 normal obese subjects(NAO),22 T2DM lean subjects(TL)and 56 T2DM obese subjects(TAO).We measured serum BAs levels in a subgroup with 20 subjects per group by liquid chromatography-mass spectrometry.We identified clinically important“specific gut microbes”and investigate the possible“metabolites linking human metabolic phenotype and microbiota”.We then conducted experiments to study the influence of the“specific gut microbes”and“metabolites linking human metabolic phenotype and microbiota”on metabolism.RESULTS:The community-level microbiota diversity(?diversity)among the four groups showed that there was a significant shift between TL and TAO group(P=0.012),as well as between TL and NAO group(P=0.03),while NAO and TAO groups shared highly similar gut microbial community profiles.The association study between microbiota and clinical indices showed that Akkermansia muciniphila(A.muciniphila)abundance was positively correlated with insulin secretion and FGF19levels.We then investigated the“metabolites linking human metabolic phenotype and microbiota”and found that 20 bile acids(BAs)were significantly different among the four groups.Of all the 20 BAs,3?-chenodeoxycholic acid(?CDCA)was found to be negatively correlated with A.muciniphila abundance,insulin secretion and FGF19 levels.Consistently,supplementation with A.muciniphila reduced plasma?CDCA concentration,increased insulin secretion and FGF15 expression,and alleviated glucose intolerance in mice.Treatment of?CDCA to min6 cells and LS174T cells led to decreased insulin secretion and FGF19 mRNA expression.CONCLUSIONS:The decrease of A.muciniphila abundance in human gut correlated with the increase of?CDCA,and the decrease of insulin secretion and FGF19.A.muciniphila could stimulates insulin secretion and FGF19 expression by inhibition of?CDCA,which led to the improvement of glucose tolerance.