Sequential changes in the mesenteric lymph node microbiome and immune response during cirrhosis induction in rats

Background: Severity of cirrhosis in patients is associated with progressive changes in the gut microbiome; and microbial translocation from the gastrointestinal tract to extra-intestinal sites plays a major role in poor disease outcome and patient survival. However, whether the interaction between the gut microbiota and the immune response influences the evolution of cirrhosis is poorly understood. We aimed to investigate the progression of cirrhosis, the immune response as well as the modification 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, rats showed in their ICC samples an attempt of displacement of symbionts by pathobionts. This compensation failed when rats developed ascites. Microbial load increased and showed positive correlation with the relative abundance of pathobionts in the MLN of ascitic (decompensated) rats. Among several genera, Escherichia and Candidatus Arthromitus, were correlated with elevated levels of systemic pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-a) and interleukin 6 (IL-6) in the MLN. Candidatus Arthromitus, a well known segmented filamentous bacterium (SFB), was detected in ICC, MLN and AF samples, suggesting a possible translocation from the gut to the AF through the lymphatic system, whereas Escherichia was detected in ICC, MLN, blood and AF, suggesting a possible translocation from the gut to the AF through the blood stream.Conclusion: In the present study, we demonstrate that microbiome changes in intestinal sites are associated with microbial shifts in the MLNs as well as an increase in cytokine production, linking inflammation to decompensated cirrhosis in the gut-liver-immunity axis.