Sequential changes in the mesenteric lymph node microbiome and immune response during cirrhosis induction in rats. Human gut metagenome

Background: Cirrhosis severity in patients is associated with progressive changes inthe gut microbiome. Microbial translocation from the gastrointestinal tract to extraintestinalsites plays a major role in poor disease outcome and patient survival.However, whether the interaction between the gut microbiota and the immuneresponse influences the evolution of cirrhosis is poorly understood. We aimed toinvestigate the progression of cirrhosis, the immune response as well as themodification of the microbiome in a spatial and temporal setting.Results: The microbiome of mesenteric lymph node (MLN), blood and ascitic fluid (AF)showed distinctive composition and function compared to stool and ileo-cecal content(ICC), thus validating a compartimentalized microbiome in both control and CCl4-treated rat groups. Upon CCl4-induction, pathobionts attempted to displace symbiontsin ICC samples. This compensation failed when rats developed ascites. Microbial loadincreased and showed a positive correlation with the relative abundance of pathobiontsin the MLN of ascitic (decompensated) rats. Among several genera, Escherichia andCandidatus Arthromitus, were correlated with elevated levels of systemic proinflammatorycytokines, tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) inthe MLN. Candidatus Arthromitus, a well known segmented filamentous bacterium(SFB), was detected in ICC, MLN and AF samples, suggesting a possible translocationfrom the gut to the AF through the lymphatic system, whereas Escherichia wasdetected in ICC, MLN, AF also blood, suggesting a possible translocation from the gutto the AF through the blood stream.Conclusion: In the present study, we demonstrate that microbiome changes inintestinal sites are associated with microbial shifts in the MLNs as well as an increasein cytokine production, linking inflammation to decompensated cirrhosis in the gut-liverimmunityaxis.