Gut microbiota transplantation drives the adoptive transfer of colonic genotype-phenotype characteristics between mice lacking catestatin and their wild type counterparts

Abstract

The gut microbiota is in continuous interaction with the intestinal mucosa via metabolic, neuro-immunological, and neuroendocrine pathways. Disruption in levels of antimicrobial peptides produced by the enteroendocrine cells, such as catestatin, has been associated with changes in the gut microbiota and imbalance in intestinal homeostasis. However, whether the changes in the gut microbiota have a causational role in intestinal dyshomeostasis has remained elusive. To this end, we performed reciprocal fecal microbial transplantation in wild-type mice and mice with a knockout in the catestatin coding region of the chromogranin-A gene (CST-KO mice). Combined microbiota phylogenetic profiling, RNA sequencing, and transmission electron microscopy were employed. Fecal microbiota transplantation from mice deficient in catestatin (CST-KO) to microbiota-depleted wild-type mice induced transcriptional and physiological features characteristic of a distorted colon in the recipient animals, including impairment in tight junctions, as well as an increased collagen area fraction indicating colonic fibrosis. In contrast, fecal microbiota transplantation from wild-type mice to microbiota-depleted CST-KO mice reduced collagen fibrotic area, restored disrupted tight junction morphology, and altered fatty acid metabolism in recipient CST-KO mice. This study provides a comprehensive overview of the murine metabolic- and immune-related cellular pathways and processes that are co-mediated by the fecal microbiota transplantation and supports a prominent role for the gut microbiota in the colonic distortion associated with the lack of catestatin in mice. Overall, the data show that the gut microbiota may play a causal role in the development of features of intestinal inflammation and metabolic disorders, known to be associated with altered levels of catestatin and may, thus, provide a tractable target in the treatment and prevention of these disorders.

A multi-omic analysis reveals the esophageal dysbiosis as the predominant trait of eosinophilic esophagitis

“…For this purpose, we recently released the IBD TaMMA framework [ 9 ], which is currently exploited worldwide as a support for research and has already led to new scientific outputs further dissecting the complexity and heterogeneity of IBD pathogenesis [ 9 , 41 , 44 ]. Hence, we sought to create a similar computational framework for EoE by surveying the already published transcriptomics studies.…”

Catestatin: Antimicrobial Functions and Potential Therapeutics

“…Of note, CST-KO mice are insulin-resistant on normal chow diet [44]. In contrast, CST-KO that received FMT from the WT mice (CST-KO FMT-WT ) showed an increase in richness, a notable reduction of Staphylococcus, and an increase in the butyrate-producing Intestinimonas [178] (Fig. 7).…”

“…As discussed above, CST-KO mice are associated with an altered gut microbiota composition and richness. WT mice that received FMT from the CST-KO mice were shown to encompass a reduction of Clostridia and Akkermansia [178], which are linked to metabolic disorders and insulin resistance [179; 180]. Furthermore, WT FMT-CST-KO mice exhibit a marked increase in the Proteobacteria population, which are associated with active inflammatory bowel disease (IBD) states [181; 182].…”

Catestatin: Antimicrobial Functions and Potential Therapeutics

“…Therefore, attempts were made recently to assess whether gut microbial population in mice can be reversed by reciprocal FMT. WT mice that received FMT from the CST-KO mice (WT FMT-CST-KO ) encompassed a reduction of Clostridia and Akkermansia [ 109 ], which are linked to metabolic disorders and insulin resistance [ 110 , 111 ] and a marked increase in the Proteobacteria population, which are associated with active inflammatory bowel disease (IBD) states [ 112 , 113 ]. Of note, CST-KO mice are insulin-resistant on a normal chow diet [ 97 ].…”

“…Of note, CST-KO mice are insulin-resistant on a normal chow diet [ 97 ]. In contrast, insulin-resistant CST-KO mice that received FMT from the WT mice (CST-KO FMT-WT ) showed an increase in richness, a notable reduction of Staphylococcus , and an increase in the butyrate-producing Intestinimonas [ 109 ] ( Figure 6 ). Butyrate, taken up directly by colonocytes, serves not only as a direct source of energy that contributes directly to a healthy gut, but also acts as a signaling molecule that affects many factors such as satiety, secretion of hormones, and glucose metabolism [ 114 , 115 , 116 ].…”