Abstract
The balanced interplay between epithelial barrier, immune system, and microbiota maintains gut homeostasis, while disruption of this interplay may lead to inflammation. Paracellular permeability is governed by intercellular tight-junctions (TJs). Zonulin is, to date, the only known physiological regulator of intestinal TJs. We used a zonulin transgenic mouse (Ztm) model characterized by increased small intestinal permeability to elucidate the role of a primary impaired gut barrier on microbiome composition and/or immune profile. Ztm exhibit an altered gene expression profile of TJs in the gut compared to wild-type mice (WT): Claudin-15, Claudin-5, Jam-3, and Myosin-1C are decreased in the male duodenum whereas Claudin-15, Claudin-7, and ZO-2 are reduced in the female colon. These results are compatible with loss of gut barrier function and are paralleled by an altered microbiota composition with reduced abundance of the genus Akkermansia, known to have positive effects on gut barrier integrity and strengthening, and an increased abundance of the Rikenella genus, associated to low-grade inflammatory conditions. Immune profile analysis shows a subtly skewed distribution of immune cell subsets toward a pro-inflammatory phenotype with more IL-17 producing adaptive and innate-like T cells in Ztm. Interestingly, microbiota “normalization” involving the transfer of WT microbiota into Ztm, did not rescue the altered immune profile. Our data suggest that a primary impaired gut barrier causing an uncontrolled trafficking of microbial products leads to a latent pro-inflammatory status, with a skewed microbiota composition and immune profile that, in the presence of an environmental trigger, as we have previously described (1), might promote the onset of overt inflammation and an increased risk of chronic disease.
Highlights
The interplay among host genetics, immune response, intestinal microbiota composition and function, and exposure to environmental factors is critical in the breakdown of the normally coordinated, homeostatic mucosal immune tolerance leading to the development of chronic inflammatory disorders
We have previously shown that zonulin transgenic mouse (Ztm) mice exhibit a significantly increased small intestinal permeability both in-vivo and invitro at baseline associated to a higher susceptibility to DSS colitis, in male mice, compared to wild-type mice (WT) [1]
Our results show an altered regulation of several TJs genes in Ztm compared to WT (Figure 1)
Summary
The interplay among host genetics, immune response, intestinal microbiota composition and function, and exposure to environmental factors is critical in the breakdown of the normally coordinated, homeostatic mucosal immune tolerance leading to the development of chronic inflammatory disorders. In this scenario, the role of increased gut permeability has been recently appreciated and seems to be a critical factor in the chain of events leading to break of tolerance and onset of inflammation, whose sequence is still largely unknown. Increased intestinal permeability has been proposed in the pathogenesis of several diseases affecting the gastrointestinal system and metabolic disorders such as obesity and diabetes and/or diseases of the brain and the nervous system such as Parkinson’s disease, multiple sclerosis, and the autism spectrum [11,12,13,14,15,16]
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