Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome

Abstract

Introduction: Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD).

Methods: Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing.

Results: In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response-related genes implicated in AD showed associations with BA profiles.

Discussion: We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.

Keywords: Alzheimer's disease; Atlas for Alzheimer; Genetic variants; Gut microbiome; Gut-liver-brain axis; Immunity; Inflammation; Lipidomics; Metabolome; Metabolomics.

Fig. 1. Bile acid synthesis and cholesterol clearance pathway.

Regulation of bile acid synthesis by feedback mechanism and bile acid transport through enterohepatic circulation. In the liver the bile acids (CDCA, DCA, LCA, CA) activate FXR that inhibits (via a repressor SHP, not shown here) the rate-limiting enzyme CYP7A1. The bile acids via FXR/SHP also inhibit the influx transporter NTCP; induce BSEP and canalicular bile acid secretion. In the intestine, bile acids, via FXR, inhibit the uptake transporter ASBT, decreasing absorption and increasing basolateral secretion into portal circulation by inducing OSTα & β. Bile acid activated FXR in the intestine also exerts inhibition on CYP7A1 in the liver via FGF19 pathway. At the basolateral membrane of hepatocytes, transporters OSTα & β, and also MRP3 and MRP4, secrete bile acids into the systemic circulation. Abbreviations: ASBT: Apical Sodium-dependent Bile acid Transporters; BSEP: Bile Salt Export Pump; FXR: Farnesoid X Receptor; NTCP: Sodium/Taurocholate Co-transporting Polypeptide; SHP: Small heterodimer partner.

Fig. 1. Bile acid synthesis and cholesterol clearance pathway.

Regulation of bile acid synthesis by feedback mechanism and bile acid transport through enterohepatic circulation. In the liver the bile acids (CDCA, DCA, LCA, CA) activate FXR that inhibits (via a repressor SHP, not shown here) the rate-limiting enzyme CYP7A1. The bile acids via FXR/SHP also inhibit the influx transporter NTCP; induce BSEP and canalicular bile acid secretion. In the intestine, bile acids, via FXR, inhibit the uptake transporter ASBT, decreasing absorption and increasing basolateral secretion into portal circulation by inducing OSTα & β. Bile acid activated FXR in the intestine also exerts inhibition on CYP7A1 in the liver via FGF19 pathway. At the basolateral membrane of hepatocytes, transporters OSTα & β, and also MRP3 and MRP4, secrete bile acids into the systemic circulation. Abbreviations: ASBT: Apical Sodium-dependent Bile acid Transporters; BSEP: Bile Salt Export Pump; FXR: Farnesoid X Receptor; NTCP: Sodium/Taurocholate Co-transporting Polypeptide; SHP: Small heterodimer partner.

Fig.2.

Schematic representation of study design.

Fig. 3.

Ratios of bile acids reflective of liver and gut microbiome enzymatic activities in CN, Early MCI, Late MCI and AD patients. Three types of ratios were calculated to inform about possible enzymatic activity changes in Alzheimer’s patients. These ratios reflect one of the following: (1) Shift in bile acid metabolism from primary to alternative pathway. (2) Changes in gut microbiome correlated with production of secondary bile acids. (3) Changes in glycine and taurine conjugation of secondary bile acids. Color code: Green: cognitively normal; Yellow: EMCI; Blue: LMCI; Red: AD. Composition of selected ratios stratified by clinical diagnosis. Error bars indicate standard error of the means; Asterisks indicate statistical significance (*P<10⁻⁰³, ** P< 10⁻⁰⁴, and ***P< 10⁻⁰⁵). P-values were estimated from logistic regression models and adjusted for age, sex, body mass index, and APOE ε4 status. The significance level was adjusted for multiple testing according to Bonferroni method to 0.05/138 = 3.62E-4; LCA was excluded in the quality control steps.

Fig. 4.

Comparison of bile levels in MCI subjects who convert and those who did not convert to AD dementia. A and B. Lower levels of CA and higher levels of two secondary to primary ratios were significantly associated with higher odds of converting from MCI to AD. EMCI and LMCI patients that converted to AD dementia in 4 years after baseline were labeled as MCI-Converter; 9 bile acids and ratios that were significantly dysregulated between CN to AD were assessed; P-values were estimated from logistic regression models and adjusted for age, sex, body mass index, and APOE ε4 status; the significance level was adjusted for multiple testing according to Bonferroni 0.05/9 = 5.56 × 10⁻³. C and D. Cox hazards model of the association of conversion from MCI to AD. Red line: 1st quantile, Red line: 3rd quantile. Analysis was conducted using quantitative values and stratification by quantiles was used only for graphical representation.