Bile acids and microbes in metabolic disease

Table 2 Drugs that target bile acids and gut microbes to alleviate metabolic diseases

No.	Drugs	Model	Findings	Ref.
1	A combination of GLP-1 and DMR	An insulin-dependent T2DM clinical study	Combined treatment allowed the discontinuation of insulin treatment in 69% of patients, increased postprandial unconjugated bile acid responses, induced an overall increase in the secondary bile acid response, induced an increase in the 12α-hydroxy: non-12α-hydroxy BA ratio, and improved the microbiome response	[158]
2	Colesevelam	Germ-free C57BL/6 mice with obesity, NAFLD, and NASH	Reduced body and liver weight gain were noted in microbiome-humanized mice, in addition to the amelioration of hepatic inflammation, steatosis, fibrosis, and IR. Colesevelam increased de novo bile acid synthesis and reduced the hepatic cholesterol content in microbiome-humanized mice, induced the expression of the antimicrobial genes Reg3g and Reg3b in the distal small intestine, and reduced plasma LPS levels	[159]
3	Vancomycin	iNOS−/− mice	Metabolic disturbances, dyslipidemia, and insulin resistance in iNOS−/− mice were improved by the vancomycin-mediated reduction of gram-positive bacteria	[160]
4	Sevelamer	Western diet-fed C57BL/6J mice with NASH	Interruption of intestinal reabsorption and reduction of circulating bile acid levels were noted. Microbiota complexity in the cecum was reversed by increasing the abundance of Lactobacillus and decreasing the abundance of Desulfovibrio. Hepatic injury was reversed, and the progression of NASH, including steatosis, inflammation, and fibrosis, was inhibited	[161]
5	Sevelamer	CDHF-fed C57BL/6J mice	Hepatic steatosis, macrophage infiltration, and pericellular fibrosis were prevented in CDHF-fed mice. The portal levels of total bile acid were reduced, and hepatic and intestinal FXR activation was inhibited. The α-diversity was decreased, and decreases in Lactobacillaceae and Clostridiaceae populations and increases in Desulfovibrionaceae and Enterobacteriaceae populations were prevented in CDHF-fed mice. Intestinal tight junction proteins were restored and portal LPS levels were reduced, resulting in the suppression of the hepatic toll-like receptor 4 signaling pathway	[162]
6	B. animalis 01	A T2DM rat model	Treatment with B. animalis 01 improved OGTT, HOMA-IR, and lipid profiles; reduced hepatic tissue injury; increased glycogen levels; improved antioxidant levels; and modulated the expression of genes involved in hepatic glucose metabolism and the IRS/PI3K/AKT pathway. Moreover, it positively regulated the hepatic Keap1/Nrf2 pathway	[141]
7	A. muciniphila	Overweight/obese insulin-resistant volunteers	A. muciniphila improved insulin sensitivity; reduced insulinemia and plasma total cholesterol levels; and slightly reduced body weight, fat mass, and hip circumference. Three months after supplementation with A. muciniphila, liver dysfunction and inflammatory blood marker levels decreased without affecting the gut microbiome structure	[132]
8	Bacteroides transplantation	A clinical study on children with diabetes/germ-free NOD mice	Compared with germ-free NOD mice, the onset of diabetes was markedly delayed in all bacteriome-humanized participants	[163]
9	A. muciniphila	C57BL/6 mice/HFD-fed mice	A. muciniphila treatment reversed HFD-induced fat mass gain, metabolic endotoxemia, adipose tissue inflammation, and IR. A. muciniphila supplementation increased the intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion	[32]
10	Acarbose	A clinical study	The ratio of primary: secondary BAs and plasma levels of unconjugated BAs were increased. The relative abundance of Lactobacillus and Bifidobacterium species in the gut microbiota was increased and Bacteroides species were depleted in participants with T2DM	[164]
11	Metformin	A clinical study	Metformin-altered microbiota improved glucose tolerance, and a significant negative correlation was noted between unconjugated BAs and HbA1c levels	[165]
12	Lactobacillus acidophilus, L. casei, and Bifidobacterium bifidum for 6 wk	GDM: A clinical study	Significant reductions were noted in fasting plasma glucose, serum insulin, serum triglyceride, and VLDL cholesterol levels and a significant increase was noted in the quantitative insulin sensitivity check index in women with GDM	[119]
13	Probiotics	Cherry Valley Pekin ducks	The LXRα and CYP7α1 enzymatic activity increased and TG and TC concentrations decreased	[123]
14	Probiotics (Lactobacillus salivarius UCC118)	GDM: A clinical study	The body weight, FBG, and IR index significantly decreased and insulin sensitivity index increased in women with GDM	[166]
15	Probiotics (Lactobacillus salivarius UCC118)	Obese pregnant women: A clinical study	Significant alteration was noted in the BMI	[167]
16	Probiotic Lactobacillus sporogenes	Third-trimester pregnancy: a Clinical study	A significant decrease was noted in serum insulin levels and HOMA-IR, and a significant difference was noted in HOMA-B	[168]
17	Probiotics (VSL#3)	C57J/B6 male mice/HFD-fed mice	Probiotic supplementation reduced the body weight IR; modulated the gut microbe composition; and increased GLP-1 release, glucose tolerance, SCFA levels, and butyrate levels	[121]
18	Probiotics	Pregnant women: A clinical study	A significant reduction was noted in serum total LDL, HDL cholesterol, serum TG, and serum TC levels	[122]
19	Fecal microbiota transplantation	Male Caucasian obese participants	Improvement in peripheral and hepatic insulin sensitivity was noted, along with an increase in butyrate-producing intestinal microbiota	[126]
20	Probiotics	Obese (ob/ob) mice	An increase in the abundance of Bifidobacterium species reduced metabolic endotoxemia and inflammation. Intestinal permeability was lowered by altering GLP-2 levels	[147]
21	Probiotics (Lactobacillus rhamnosus GG and Bifidobacterium lactis Bb12; diet/probiotics)	First-trimester pregnancy: A clinical study	Reduced blood glucose and insulin levels, improved glucose tolerance, and the highest quantitative insulin sensitivity check index were noted	[169]

A. muciniphila: Akkermansia muciniphila; BAs: Bile acids; B. animalis: Bifidobacterium animalis; BMI: Body mass index; CDHF: Choline-deficient high-fat diet; DMR: Duodenal mucosal resurfacing; FBG: Fasting blood glucose; FXR: Farnesoid X receptor; GDM: Gestational diabetes mellitus; GLP-1: Glucagon-like peptide-1; HFD: High-fat diet; HbA1c: Hemoglobin A1C; HDL: High-density lipoprotein; HOMA: Homeostatic model assessment; IR: Insulin resistance; L. casei: Lactobacillus casei; LDL: Low-density lipoprotein; LPS: Lipopolysaccharide; NASH: Nonalcoholic steatohepatitis; NAFLD: Nonalcoholic fatty liver disease; SCFAs: Short-chain fatty acids; T2DM: Type 2 diabetes mellitus; TC: Total cholesterol; TGs: Triglycerides; VLDL: Very-low-density lipoprotein.