Changes in gut microbiota associated with inflammation during ageing and non-alcoholic steatohepatitis
Author
Rubio Caballero, CarmenEntity
UAM. Departamento de Biología Molecular; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM); Centro de Biología Molecular Severo Ochoa (CBM)Date
2018-12-14Subjects
Hígado - Enfermedades - Tesis doctorales; Envejecimiento - Aspectos fisiológicos - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 14-12-2018Esta tesis tiene embargado el acceso al texto completo hasta el 14-06-2020
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
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
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