Changes in gut microbiota associated with inflammation during ageing and non-alcoholic steatohepatitis

Resumen

In this Thesis we have explored the changes in gut microbiota and several gut barrier features in two pathophysiological conditions that commonly concur with systemic inflammation, ageing and non-alcoholic steatohepatitis (NASH). In order to facilitate the description of our studies, the results of each model are presented separately. Ageing is characterized by alterations in the homeostatic mechanisms that regulate energy balance leading to an increased body weight. Although the presence of a low-grade chronic inflammation has been proposed as the responsible of the homeostatic misbalance, the primary alteration has not been yet fully elucidated. Since gut microbiota has emerged as a key player in a wide range of physiological and pathological stages, the concept gut-brain axis is getting high interest. Using metagenomics we demonstrate that ageing in Wistar rats associates with alterations in the fecal microbial community leading to a higher presence of LPS-producing bacteria, a decrease of anti-inflammatory microorganisms and an increase in mucin-degrading bacteria. The histological analysis of the colon shows alterations in crypt width and mucin content, revealing a weaker gut barrier in aged animals. Gut-brain axis is also altered regarding impairment in cholecystokinin satiating effect that could contribute to the increased adiposity in old rats. Some of the observed changes in gut microbiota are also shared by obese animals, suggesting that ageing and obesity microbiota are likely two different ways to induce fat accretion. NASH is characterized by a robust pro-inflammatory component at both hepatic and systemic levels. Protein tyrosine phosphatase 1B (PTP1B) plays distinct roles in non-immune and immune cells, in the latter inhibiting pro-inflammatory responses. In this Thesis we have explored the role of PTP1B in the composition of gut microbiota, as well as in gut barrier dynamics in methionine and choline-deficient (MCD) diet-induced NASH in mice. Our results revealed that a shift in the gut microbiota shape, disruption in gut barrier function, decrease in mucins abundance and higher levels of serum bile acids are gut features during NASH. Surprisingly, despite of the pro-inflammatory phenotype of global PTP1B deficiency in mice manifested by increased GLP-1 release by the gut, it protects against the alterations in gut microbiota composition and improves gut barrier function during NASH, an effect that concurred with preservation of mucin abundance and decreased serum bile acids compared to their wild-type mice counterparts. Altogether our results have unravelled a potential role of PTP1B in the gut-liver axis during NASH