Sgamato, Costantino (2023) Gut Mucosa‑Associated Microbiota in Healthy Individuals and Patients at Different Stages of HCV‑Related Liver Disease. [Tesi di dottorato]

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Background: In the last decade, increasing evidence has highlighted the key role of gut microbiota (GM) in chronic liver disease and the development of complications, including hepatocellular carcinoma (HCC), the leading cause of death among patients with advanced liver disease. Little is known about the composition of gut mucosa-associated microbiota (MAM) in patients with hepatitis C virus (HCV) related liver disease. Aim: To characterise MAM of the terminal ileum and sigmoid colon in patients at different stages of HCV-related liver disease compared with healthy controls (HC). Methods: We performed shotgun metagenomic sequencing of MAM obtained through biopsy of the terminal ileum and sigma of HC and patients with HCV-related liver disease. Results: We enrolled 13 HC, 6 chronic HCV hepatitis (CHC), 9 liver cirrhosis (LC), and 14 HCC patients. α-diversity significantly decreased from HC to LC with a slight increase in HCC in sigmoid specimens according to the Shannon index (p= 0.047). β-diversity metric weighted UniFrac showed a significant clustering between the MAM of HC and those of the HCV groups (p≤ 0.05). In patients with CHC, the genus Catenibacterium (C. Mitzuokai) was enriched in both ileal and sigmoid mucosal specimens (p<0.0001). In patients with LC, genus Holdemania and genera Solobacterium (S.Moorei), Peptostreptococcus, and Eisenbergiella were increased in the ileal (p<0.00001) and sigmoid samples (p<0.0001), respectively. Genera of phylum Firmicutes, namely Granulicatella (G. para-adiacens) (p=0.0001), Streptococcus (S. sinensis) (p=0.008), Peptostreptococcus (P. stomatis), Solobacterium (S.Moorei) (p<0.0001) and Phorphyromonas of phila Bacteroidetes, were enriched in the ileal mucosal samples of HCC patients whereas genera Rothia (R. Mucilaginosa) of phyla Actinobacteria, Solobacterium (S.Moorei), and Cronobacter (C.sakazakii) of phyla Pseudomonadota were enriched in sigma specimens. Increasing trends from HC to HCC were found for five taxa, namely Granulicatella (G. para-adiacens) and Streptococci (S. thermophiles) in the ileal sample and Cloacibacterium, Streptococcus and Vulcaniibacterium in the sigmoid specimen, according to Jonckheere–Terpstra (JT) test. Conclusion: In patients with HCV-related liver disease, ileal and sigmoid MAM dysbiosis occurred. This is the first study to characterise MAM of patients at different stages of HCV-related liver disease compared to HC. Changes in MAM composition could be useful as biomarkers of CLD and its complications, mainly HCC. Thus, strategies to restore MAM eubiosis may slow liver disease progression in HCV infection.

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