Biology subjects

Modilevsky, S.

Publications and source records attributed to Modilevsky, S..

3 recordsLinked to original sources

bioRxiv2024

Antibiotics damage the colonic mucus barrier in a microbiota-independent manner

Antibiotic use is a risk factor for development of inflammatory bowel diseases (IBDs). IBDs are characterized by a damaged mucus layer, which does not properly separate the host intestinal epithelium from the microbiota. Here, we hypothesized that antibiotics might affect the integrity of the mucus barrier. By systematically determining the effects of different antibiotics on mucus layer penetrability we found that oral antibiotic treatment led to breakdown of the mucus barrier and penetration of bacteria into the mucus layer. Using fecal microbiota transplant, RNA sequencing followed by machine learning and ex vivo mucus secretion measurements, we determined that antibiotic treatment induces ER stress in the colonic tissue which inhibits colonic mucus secretion in a microbiota-independent manner. This mucus secretion flaw led to penetration of bacteria into the colonic mucus layer, translocation of microbial antigens into circulation and exacerbation of ulcerations in a mouse model of IBD. Thus, antibiotic use might predispose to development of intestinal inflammation by impeding mucus production.

immunology↗

bioRxiv2023

Salmonella manipulates the host to drive pathogenicity via induction of interleukin 1β

Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the inflammasome and the release of the proinflammatory cytokine interleukin 1{beta} (IL-1{beta}). However, the role of IL-1{beta} in intestinal defense against Salmonella remains unclear. Here, we show that IL-1{beta} production is detrimental during Salmonella infection. Mice lacking IL-1{beta} (IL-1{beta} -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid-producing commensals. Changes in epithelial cell metabolism that typically support pathogen expansion, such as switching energy production from fatty acid oxidation to fermentation, were absent in infected IL-1{beta}-/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1{beta} induces expression of complement anaphylatoxins and suppresses the complement-inactivator Carboxypeptidase N (CPN1). Disrupting this process via IL-1{beta} loss completely prevented mortality in Salmonella-infected IL-1{beta}-/- mice and led to chronic infection. Thus, Salmonella exploits IL-1{beta} signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1{beta} signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

immunology↗

bioRxiv2022

Autophagy controls mucus secretion from intestinal goblet cells by alleviating ER stress

Colonic goblet cells are specialized epithelial cells that secrete mucus to form a barrier between the host and its microbiota, thus preventing bacterial invasion and inflammation. How goblet cells control the amount of mucus they secrete is unclear. We found that constitutive activation of autophagy in mice via Beclin 1 led to production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, inhibiting Beclin 1-induced autophagy via Bcl-2 impaired mucus secretion. Furthermore, alleviating intestinal ER stress with a bile acid, or activating the unfolded protein response (UPR) pharmacologically via eIF2 phosphorylation, led to excessive mucus production. Over-production of mucus altered the gut microbiome, with expansion of mucus-utilizing bacteria, and protected from intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, while autophagy maintains proper mucus secretion and intestinal homeostasis by relieving ER stress.

immunology↗