Abstract
Cholestasis is a major hepatic disease in infants, with increasing morbidity in recent years. Accumulating evidence has revealed that the gut microbiota (GM) is associated with liver diseases, such as non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. However, GM alterations in cholestatic infants and the correlation between the GM and hepatic functions remain uninvestigated. In this study, 43 cholestatic infants (IC group) and 37 healthy infants (H group) were enrolled to detect GM discrepancies using 16S rDNA analysis. The diversity in the bacterial community was significantly lower in the IC group than that in the H group (P = 0.013). After determining the top 10 abundant genera of microbes in the IC and H groups, we found that 13 of them were differentially enriched, including Bifidobacterium, Bacteroides, Streptococcus, Enterococcus, and Staphylococcus. As compared with the H group, the IC group had a more complex GM co-occurrence network featured by three core nodes: Phyllobacterium, Ruminococcus, and Anaerostipes. In addition, the positive correlation between Faecalibacterium and Erysipelatoclostridium (r = 0.689, P = 0.000, FDR = 0.009) was not observed in the IC patients. Using the GM composition, the cholestatic patients can be distinguished from healthy infants with high accuracy [areas under receiver operating curve (AUC) > 0.97], wherein Rothia, Eggerthella, Phyllobacterium, and Blautia are identified as valuable biomarkers. Using KEGG annotation, we identified 32 functional categories with significant difference in enrichment of the GM of IC patients, including IC-enriched functional categories that were related to lipid metabolism, biodegradation and metabolism of xenobiotics, and various diseases. In contrast, the number of functions associated with amino acid metabolism, nucleotide metabolism, and vitamins metabolism was reduced in the IC patients. We also identified significant correlation between GM composition and indicators of hepatic function. Megasphaera positively correlated with total bilirubin (r = 0.455, P = 0.002) and direct bilirubin (r = 0.441, P = 0.003), whereas γ-glutamyl transpeptidase was positively associated with Parasutterella (r = 0.466, P = 0.002) and negatively related to Streptococcus (r = -0.450, P = 0.003). This study describes the GM characteristics in the cholestatic infants, illustrates the association between the GM components and the hepatic function, and provides a solid theoretical basis for GM intervention for the treatment of infantile cholestasis.
Highlights
Cholestasis is a major hepatic disease in infants, with increasing incidence, with nearly one in every 2,500 individuals being affected (Fischler and Lamireau, 2014)
Among the infantile cholestasis (IC) patients, 5 had cholestasis due to cytomegalovirus hepatitis, 9 had cholestasis due to biliary atresia, and the rest of the patients were diagnosed without any discernible cause (Supplementary Table S1). 16S rRNA sequencing of the samples and the connection of high-quality pair-end reads yielded 17,889 ± 5,012 tags, which ranged from 4,863 to 25,213
After RDP database alignment, 93 genera of 7 phyla were identified from the samples, and the feeding pattern of the infants had an impact on the difference in gut microbiota (GM) between the H and IC groups (P = 0.009, PERMANOVA analysis, Supplementary Table S2)
Summary
Cholestasis is a major hepatic disease in infants, with increasing incidence, with nearly one in every 2,500 individuals being affected (Fischler and Lamireau, 2014). Numerous studies have reported that infantile cholestasis (IC) can be caused by infection of the liver (e.g., hepatitis A, B, and C viral infection, Epstein-Barr virus infection, and cytomegalovirus infection) (Delemos and Friedman, 2013; Fawaz et al, 2017), abnormal structure of the biliary tract (e.g., biliary atresia and choledochal cyst) (Hoerning et al, 2014; Fawaz et al, 2017), hereditary diseases (e.g., Alagille syndrome, progressive familial intrahepatic cholestasis, and Aagenaes syndrome) (Hartley et al, 2013; Fawaz et al, 2017), and metabolic disorders [e.g., abnormal amino acid metabolism (Reichardt and Woo, 1991), abnormal carbohydrate metabolism (Phaneuf et al, 1991), and abnormal lipid metabolism (Vance, 2006)]. BAs affect GM composition by controlling the PH of the gut environment, repressing the growth of pathogens and maintaining the balance of the GM (Islam et al, 2011)
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