Altered gut microbiome, bile acid composition and metabolome in sarcopenia in liver cirrhosis

Abstract

Background: Sarcopenia in liver cirrhosis is associated with low quality of life and high mortality risk. The pathogenesis has yet to be fully understood. We hypothesized that gut microbiome, bile acid (BA) composition and metabolites differ between cirrhotic patients with and without sarcopenia and contribute to pathogenesis.

Methods: Cirrhotic patients with (n = 78) and without (n = 38) sarcopenia and non-cirrhotic controls with (n = 39) and without (n = 20) sarcopenia were included in this study. Faecal microbiome composition was studied by 16S rDNA sequencing, serum and faecal BA composition by ultra-high-performance liquid chromatography-tandem mass spectrometry, and metabolite composition in serum, faeces and urine by nuclear magnetic resonance.

Results: Bacteroides fragilis, Blautia marseille, Sutterella spp. and Veillonella parvula were associated with cirrhotic patients with sarcopenia, whereas Bacteroides ovatus was more abundant in cirrhotic patients without sarcopenia. We observed significantly elevated secondary BAs, deoxycholic acid (DCA; P = 0.01) and lithocholic acid (LCA; P = 0.02), and the ratios of deoxycholic acid to cholic acid (DCA:CA; P = 0.04), lithocholic acid to chenodeoxycholic acid (LCA:CDCA; P = 0.03) and 12 alpha-hydroxylated to non-12 alpha-hydroxylated BAs (12-α-OH:non-12-α-OH BAs; P = 0.04) in serum of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia, indicating an enhanced transformation of primary to secondary BAs by the gut microbiome. CA (P = 0.02) and the ratios of CA:CDCA (P = 0.03) and total ursodeoxycholic acid to total secondary BAs (T-UDCA:total-sec-BAs, P = 0.03) were significantly reduced in the stool of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia. Also, valine and acetate were significantly reduced in the serum of cirrhotic patients with sarcopenia compared with cirrhotic patients without sarcopenia (P = 0.01 and P = 0.03, respectively). Multivariate logistic regression further confirmed the association of B. ovatus (P = 0.01, odds ratio [OR]: 12.8, 95% confidence interval [CI]: 168.1; 2.2), the ratios of 12-α-OH:non-12-α-OH BAs (P = 0.03, OR: 2.54, 95% CI: 0.99; 6.55) and T-UDCA:total-sec-BAs (P = 0.04, OR: 0.25, 95% CI: 0.06; 0.98) in serum and stool CA:CDCA (P = 0.04, OR: 0.79, 95% CI: 0.62; 0.99), and serum valine (P = 0.04, OR: 1.00, 95% CI: 1.02; 1.00) with sarcopenia in cirrhosis after correcting for the severity of liver disease and sex.

Conclusions: Our study suggests a potential functional gut microbiome-host interaction linking sarcopenia with the altered gut microbiomes, BA profiles and amino acids pointing towards a potential mechanistic interplay in understanding sarcopenia pathogenesis.

Keywords: bile acids; cirrhosis; gut microbiome; metabolome; sarcopenia.

Figure 1

Chao1 index as a measure of alpha diversity between cirrhotic patients with and without sarcopenia (A). Bray–Curtis as a measure of beta diversity between cirrhotic patients with and without sarcopenia (B). Bacteria identified by regularized logistic least absolute shrinkage and selection operator (linear discriminant analysis [LDA] effect size) to be associated with cirrhotic patients with and without sarcopenia (C). Altered Bacteroides ovatus abundance between cirrhotic patients with and without sarcopenia (D). PCoA, principal coordinates analysis.

Figure 2

Tax4Fun‐predicted functional profiles between cirrhotic patients with and without sarcopenia (A) and controls with and without sarcopenia (B). LPS, lipopolysaccharide.

Figure 3

Altered secondary and primary bile acids (BAs) between cirrhotic patients with and without sarcopenia (A–C). Shift from the classical to the alternative pathways between cirrhotic patients with and without sarcopenia (D). Altered BA transformation from primary to secondary BAs between cirrhotic patients with and without sarcopenia (E–H). Altered BA pool hydrophilicity status between the cirrhotic patients with and without sarcopenia (I). Altered BA 12α‐hydroxylation between cirrhotic patients with and without sarcopenia (J). Altered gut microbiome‐derived metabolites, BCAA and short‐chain fatty acid between cirrhotic patients with and without sarcopenia (K, L).

Figure 4

(A) Altered serum metabolite sets and associated pathways, and (B) urine metabolite sets and associated pathways between cirrhotic patients with and without sarcopenia.