Gut Microbial Dysbiosis Is Associated with Altered Hepatic Functions and Serum Metabolites in Chronic Hepatitis B Patients

Abstract

Chronic hepatitis B (CHB) is a global epidemic disease that results from hepatitis B virus (HBV) infection and may progress to severe liver failure, including liver fibrosis, cirrhosis and hepatocellular carcinoma. Previous evidence has indicated that the dysbiosis of gut microbiota occurs after liver virus infection and is associated with severe liver disease. The aim of this study is to elucidate the compositional and functional characteristics of the gut microbiota in early-stage CHB and to understand their influence on disease progression. We investigated the gut microbial composition of stool samples from 85 CHB patients with low Child-Pugh scores and 22 healthy controls using the Illumina MiSeq sequencing platform. Furthermore, the serum metabolome of 40 subjects was measured by gas chromatography mass spectrometry. Compared with the controls, significant alteration in the gut microbiota was observed in the CHB patients; 5 operational taxonomic units (OTUs) belonging to Actinomyces, Clostridium sensu stricto, unclassified Lachnospiraceae and Megamonas were increased, and 27 belonging to Alistipes, Asaccharobacter, Bacteroides, Butyricimonas, Clostridium IV, Escherichia/Shigella, Parabacteroides, Ruminococcus, unclassified Bacteria, unclassified Clostridiales, Unclassified Coriobacteriaceae, unclassified Enterobacteriaceae, unclassified Lachnospiraceae and unclassified Ruminococcaceae were decreased. The inferred metagenomic information of gut microbiota in CHB showed 21 enriched and 17 depleted KEGG level-2 pathways. Four OTUs, OTU38 (Streptococcus), OTU124 (Veillonella), OTU224 (Streptococcus), and OTU55 (Haemophilus), had high correlations with hosts' hepatic function indices and 10 serum metabolites, including phenylalanine and tyrosine, which are aromatic amino acids that play pathogenic roles in liver disease. In particular, these 4 OTUs were significantly higher in patients with higher Child-Pugh scores, who also showed diminished phenylalanine and tryptophan metabolisms in the inferred gut metagenomic functions. These compositional and functional changes in the gut microbiota in early-stage CHB patients suggest the potential contributions of gut microbiota to the progression of CHB, and thus provide new insight into gut microbiota-targeted interventions to improve the prognosis of this disease.

Modulation of bile acid profile by gut microbiota in chronic hepatitis B

“…Developing researches have demonstrated the roles of gut microbiota in liver diseases . The correlations between gut microbiome and HBV‐induced chronic liver diseases have been recently studied . Lu et al showed that the B/E ratio (Bifidobacteriaceae/Enterobacteriaceae) was significantly decreased in CHB patients, especially in patients with cirrhosis .…”

On the potential role of intestinal microbial community in hepatocarcinogenesis in chronic hepatitis B

“…Recent study in the diversity and composition of the intestinal microbiota in HBV‐induced chronic liver disease revealed alterations in the colonization of opportunistic intestinal bacteria. The intestinal microbiota of CHB patients has significant difference compared to healthy controls with increased bacterial charge in taxonomy: Actinomyces , Clostridium sensu stricto , unclassified Lachnospiraceae and Megamonas that influence on disease progression . Complicated patients with liver cirrhosis and liver cancer demonstrate intestinal dysbiosis that is also approved in animal studies .…”

“…The advantage of intestinal bacteria under normal physiological condition in the synthesis of essential products such as short‐chain fatty acids (SCFA) and secondary bile acids in metabolic homeostasis is well known. The produced SCFAs by commensal and probiotic bacteria carry out the transcriptional pathways through epigenomic modifications . The blood circulation of intestine with microbiota‐derived nutrients and metabolites is directed to the liver via the hepatic portal vein and the liver, in turn, has a reactive impact on intestinal functions beyond the biliary secretion in the intestinal lumen .…”

“…Furthermore, butyrate has the capacity to improve the growth of lactobacilli and bifidobacteria in the colon . Patients with chronic hepatitis have shown a decrease in polyunsaturated lipids by disrupting the integrity of the intestinal barrier in the alteration of the gut microbiota composition; however, the total lipid has been increased . In addition, CHB patients have significantly lower levels of fecal bile acids with positive association with F. prausnitzii , bifidobacteria and lactic acid‐producing bacteria .…”

“…The produced SCFAs by commensal and probiotic bacteria carry out the transcriptional pathways through epigenomic modifications. 14,22 The blood circulation of intestine with microbiota-derived nutrients and metabolites is directed to the liver via the hepatic portal vein and the liver, in turn, has a reactive impact on intestinal functions beyond the biliary secretion in the intestinal lumen. 22 Bacteria are mainly active in the proximal colon, where the availability of the substrate is in the maximum capacity.…”