Berberine alters gut microbial function through modulation of bile acids

Patricia G Wolf,Lindsey K Ly,Tyler Moore,Hiroshi Nittono,Jason M Ridlon,Saravanan Devendran,H Rex Gaskins,Heidi L Doden,George E Chlipala,Tsuyoshi Murai,Genta Kakiyama,Patrick M Gillevet,Takao Kurosawa,Vance J Mccracken,Stefan J Green,Purna Kashyap,Hajime Takei

doi:10.1186/s12866-020-02020-1

Abstract

BackgroundBerberine (BBR) is a plant-based nutraceutical that has been used for millennia to treat diarrheal infections and in contemporary medicine to improve patient lipid profiles. Reduction in lipids, particularly cholesterol, is achieved partly through up-regulation of bile acid synthesis and excretion into the gastrointestinal tract (GI). The efficacy of BBR is also thought to be dependent on structural and functional alterations of the gut microbiome. However, knowledge of the effects of BBR on gut microbiome communities is currently lacking. Distinguishing indirect effects of BBR on bacteria through altered bile acid profiles is particularly important in understanding how dietary nutraceuticals alter the microbiome.ResultsGermfree mice were colonized with a defined minimal gut bacterial consortium capable of functional bile acid metabolism (Bacteroides vulgatus, Bacteroides uniformis, Parabacteroides distasonis, Bilophila wadsworthia, Clostridium hylemonae, Clostridium hiranonis, Blautia producta; B4PC2). Multi-omics (bile acid metabolomics, 16S rDNA sequencing, cecal metatranscriptomics) were performed in order to provide a simple in vivo model from which to identify network-based correlations between bile acids and bacterial transcripts in the presence and absence of dietary BBR. Significant alterations in network topology and connectivity in function were observed, despite similarity in gut microbial alpha diversity (P = 0.30) and beta-diversity (P = 0.123) between control and BBR treatment. BBR increased cecal bile acid concentrations, (P < 0.05), most notably deoxycholic acid (DCA) (P < 0.001). Overall, analysis of transcriptomes and correlation networks indicates both bacterial species-specific responses to BBR, as well as functional commonalities among species, such as up-regulation of Na+/H+ antiporter, cell wall synthesis/repair, carbohydrate metabolism and amino acid metabolism. Bile acid concentrations in the GI tract increased significantly during BBR treatment and developed extensive correlation networks with expressed genes in the B4PC2 community.ConclusionsThis work has important implications for interpreting the effects of BBR on structure and function of the complex gut microbiome, which may lead to targeted pharmaceutical interventions aimed to achieve the positive physiological effects previously observed with BBR supplementation.

Highlights

Berberine (BBR) is a plant-based nutraceutical that has been used for millennia to treat diarrheal infections and in contemporary medicine to improve patient lipid profiles
Effect of berberine on global bile acid metabolome Since previous reports have indicated that BBR affects hepatic lipids and cholesterol by increasing bile acid excretion into the large intestine [4, 6, 14], the global bile acid metabolome was examined in control and BBR treated gnotobiotic mice
We determined that total bile acids (P = 0.17;0.85) and deoxycholic acid (DCA) (P = 0.098; 0.23) in the liver and cecum did not differ between males and females, respectively

Summary

Introduction

Berberine (BBR) is a plant-based nutraceutical that has been used for millennia to treat diarrheal infections and in contemporary medicine to improve patient lipid profiles. There is considerable interest in the utilization of dietary components to modulate the gut microbiome in a manner that improves human and animal health This is especially true of plant-based nutraceutical compounds that have been used for millennia in traditional human societies. Since bile acids are themselves antimicrobial [10], and because bile acid concentrations are increased in response to BBR treatment, determining bile acid-dependent correlations with microbial gene expression is important Investigations into these responses are predicted to provide testable hypotheses that will enable future examinations of how BBR alters bacterial structure and function, and how bacteria adapt in the short-term to antimicrobial dietary compounds such as BBR, in response to increased influx of intestinal bile acids

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