Research Article
Modulation of the fecal bile acid profile by gut microbiota in cirrhosis

https://doi.org/10.1016/j.jhep.2013.01.003Get rights and content

Background & Aims

The 7α-dehydroxylation of primary bile acids (BAs), chenodeoxycholic (CDCA) and cholic acid (CA) into the secondary BAs, lithocholic (LCA) and deoxycholic acid (DCA), is a key function of the gut microbiota. We aimed at studying the linkage between fecal BAs and gut microbiota in cirrhosis since this could help understand cirrhosis progression.

Methods

Fecal microbiota were analyzed by culture-independent multitagged-pyrosequencing, fecal BAs using HPLC and serum BAs using LC–MS in controls, early (Child A) and advanced cirrhotics (Child B/C). A subgroup of early cirrhotics underwent BA and microbiota analysis before/after eight weeks of rifaximin.

Results

Cross-sectional: 47 cirrhotics (24 advanced) and 14 controls were included. In feces, advanced cirrhotics had the lowest total, secondary, secondary/primary BA ratios, and the highest primary BAs compared to early cirrhotics and controls. Secondary fecal BAs were detectable in all controls but in a significantly lower proportion of cirrhotics (p <0.002). Serum primary BAs were higher in advanced cirrhotics compared to the rest. Cirrhotics, compared to controls, had a higher Enterobacteriaceae (potentially pathogenic) but lower Lachonospiraceae, Ruminococcaceae and Blautia (7α-dehydroxylating bacteria) abundance. CDCA was positively correlated with Enterobacteriaceae (r = 0.57, p <0.008) while Ruminococcaceae were positively correlated with DCA (r = 0.4, p <0.05). A positive correlation between Ruminococcaceae and DCA/CA (r = 0.82, p <0.012) and Blautia with LCA/CDCA (r = 0.61, p <0.03) was also seen. Prospective study: post-rifaximin, six early cirrhotics had reduction in Veillonellaceae and in secondary/primary BA ratios.

Conclusions

Cirrhosis, especially advanced disease, is associated with a decreased conversion of primary to secondary fecal BAs, which is linked to abundance of key gut microbiome taxa.

Introduction

There is emerging evidence that the gut milieu plays an important role in the progression of complications of cirrhosis [1], [2], [3]. Studies have found dysbiosis in the gut microbiota in patients with cirrhosis that has the potential to influence complications such as hepatic encephalopathy [1], [2]. The gut milieu in cirrhosis involves the interaction between the microbiota and secreted factors, such as bile acids (BAs) that can also modulate the gut barrier [4]. The gut microbiota is known to convert 7α-dehydroxylate primary BAs and chenodeoxycholic acid (CDCA) and cholic acid (CA) into the secondary bile acids lithocholic acid (LCA) and deoxycholic acid (DCA), respectively [5]. Cirrhotic patients have been shown to have a lower proportion of secondary BAs in their bile but the mechanism for this is not clear [6]. Since BAs have important downstream pathophysiologic effects, a better understanding of the interaction between the intestinal microbiome and BAs is important to gain insight into the pathophysiology of cirrhosis [7], [8]. We hypothesized that gut dysbiosis in cirrhosis may be related to this altered bile acid profile and that modulating the gut microbiota using a non-absorbable antibiotic may further affect the conversion of primary to secondary bile acids.

We aimed at studying the linkage between fecal bile acid concentrations and the gut microbiota in cirrhotic patients with differing disease severity compared to healthy controls and to define the changes in this correlation after the administration of gut-selective, non-absorbable antibiotic rifaximin.

Section snippets

Patients and methods

This study was divided into cross-sectional (comparison between cirrhotic patients and age-matched controls) and longitudinal (a subgroup of patients with early cirrhosis were studied before and after rifaximin therapy) components.

Results

In this cross-sectional study, 47 cirrhotic patients (age 56 ± 4 years, 32 men) and 14 age-matched controls (age 54 ± 3 years, 10 men) were included. The mean MELD was 12.3 ± 6.5 and the majority had hepatitis C (66%) while 15% had alcoholic liver disease. Advanced cirrhosis was found in 24 patients; all had treated hepatic encephalopathy (100% on lactulose alone, 25% with additional rifaximin) while 88% had ascites on therapy with diuretics (Table 1). Dietary constituents were similar between controls

Discussion

We found a decrease in total fecal BA concentration and reduction in the ratio of secondary to primary BAs with worsening of liver disease severity. There was a significant reduction in the ratio of fecal secondary to primary BA concentrations in those on rifaximin, in the cross-sectional study and also after rifaximin therapy in the prospective portion of the study. The microbiome in cirrhosis showed dysbiosis with overgrowth of Enterobacteriaceae and decrease in autochthonous genera compared

Financial support

This work was supported by grant U01AT004428 from the National Center for Complementary and Alternative Medicine, grant RO1AA020203 from the National Institute on Alcohol Abuse and Alcoholism, grant RO1DK087913 from the National Institute of Diabetes and Digestive and Kidney Diseases, VA Merit Review grant BX0013280-01, the McGuire Research Institute and partly by an investigator-initiated grant from Salix Pharmaceuticals. The funders had no role in study design, data collection and analysis,

Conflict of interest

JSB is a consultant for Salix Pharmaceuticals.

The underlying research reported in the study was funded by the NIH Institutes of Health.

References (27)

  • H.M. Hamer et al.

    Functional analysis of colonic bacterial metabolism: relevant to health?

    Am J Physiol Gastrointest Liver Physiol

    (2011)
  • P. Gillevet et al.

    Quantitative assessment of the human gut microbiome using multitag pyrosequencing

    Chem Biodivers

    (2010)
  • S. Devkota et al.

    Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10−/− mice

    Nature

    (2012)
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    Portions of this manuscript were an oral presentation for the International Liver Congress by EASL held in 2012 in Barcelona.

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