RESUMEN

Antibiotic use is a risk factor for development of inflammatory bowel diseases (IBDs). IBDs are characterized by a damaged mucus layer, which does not separate the intestinal epithelium from the microbiota. Here, we hypothesized that antibiotics affect the integrity of the mucus barrier, which allows bacterial penetrance and predisposes to intestinal inflammation. We found that antibiotic treatment led to breakdown of the colonic mucus barrier and penetration of bacteria into the mucus layer. Using fecal microbiota transplant, RNA sequencing followed by machine learning, ex vivo mucus secretion measurements, and antibiotic treatment of germ-free mice, we determined that antibiotics induce endoplasmic reticulum stress in the colon that inhibits colonic mucus secretion in a microbiota-independent manner. This antibiotic-induced 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 intestinal inflammation by impeding mucus production.

Asunto(s)

Antibacterianos , Colon , Microbioma Gastrointestinal , Mucosa Intestinal , Moco , Animales , Antibacterianos/farmacología , Antibacterianos/efectos adversos , Ratones , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Microbioma Gastrointestinal/efectos de los fármacos , Colon/metabolismo , Colon/efectos de los fármacos , Colon/patología , Colon/microbiología , Moco/metabolismo , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/microbiología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Modelos Animales de Enfermedad , Trasplante de Microbiota Fecal , Ratones Endogámicos C57BL , Humanos

RESUMEN

Acute gastrointestinal infection with intracellular pathogens like Salmonella Typhimurium triggers the release of the proinflammatory cytokine interleukin 1ß (IL-1ß). However, the role of IL-1ß in intestinal defense against Salmonella remains unclear. Here, we show that IL-1ß production is detrimental during Salmonella infection. Mice lacking IL-1ß (IL-1ß -/-) failed to recruit neutrophils to the gut during infection, which reduced tissue damage and prevented depletion of short-chain fatty acid (SCFA)-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-1ß -/- mice which inhibited Salmonella expansion. Additionally, we found that IL-1ß induces expression of complement anaphylatoxins and suppresses the complement-inactivator carboxypeptidase N (CPN1). Disrupting this process via IL-1ß loss prevented mortality in Salmonella-infected IL-1ß -/- mice. Finally, we found that IL-1ß expression correlates with expression of the complement receptor in patients suffering from sepsis, but not uninfected patients and healthy individuals. Thus, Salmonella exploits IL-1ß signaling to outcompete commensal microbes and establish gut colonization. Moreover, our findings identify the intersection of IL-1ß signaling and the complement system as key host factors involved in controlling mortality during invasive Salmonellosis.

Asunto(s)

Interleucina-1beta , Infecciones por Salmonella , Animales , Humanos , Ratones , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Neutrófilos/metabolismo , Infecciones por Salmonella/metabolismo , Salmonella typhimurium/metabolismo , Virulencia

RESUMEN

Colonic goblet cells are specialized epithelial cells that secrete mucus to physically separate 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 enables the production of a thicker and less penetrable mucus layer by reducing endoplasmic reticulum (ER) stress. Accordingly, genetically inhibiting Beclin 1-induced autophagy impairs mucus secretion, while pharmacologically alleviating ER stress results in excessive mucus production. This ER-stress-mediated regulation of mucus secretion is microbiota dependent and requires the Crohn's-disease-risk gene Nod2. Overproduction of mucus alters the gut microbiome, specifically expanding mucus-utilizing bacteria, such as Akkermansia muciniphila, and protects against chemical and microbial-driven intestinal inflammation. Thus, ER stress is a cell-intrinsic switch that limits mucus secretion, whereas autophagy maintains intestinal homeostasis by relieving ER stress.

Asunto(s)

Células Caliciformes , Inflamación , Animales , Ratones , Beclina-1 , Moco , Autofagia , Mucosa Intestinal/microbiología

RESUMEN

Lysozyme-secreting Paneth cells are abnormally present in the distal colons of patients with inflammatory bowel disease (IBD), along with high amounts of lysozyme in feces. In a recent article in Immunity, Yu et al. show that lysozyme-mediated processing of luminal bacteria in the colon triggers a proinflammatory response and predisposes mice to experimental IBD.

Asunto(s)

Enfermedades Inflamatorias del Intestino , Microbiota , Animales , Colon , Expectorantes , Humanos , Ratones , Muramidasa , Células de Paneth

RESUMEN

Stressful life events are considered a risk factor for autoimmune disorders, though the mechanisms are unclear. Here we demonstrate that chronic social stress induces virulence-associated transcriptional patterns in the murine gut microbiota. The stress-influenced microbiota increased the presence of effector T helper cells in the mesenteric lymph nodes, including myelin-autoreactive cells. Inhibition of the bacterial quorum sensor QseC, which is also responsive to norepinephrine, diminished the presence of effector T helper cells and bacteria such as Acinetobacter in the mesenteric lymph nodes, without remarkably affecting the gut microbial composition. Together, our results delineate a model in which the immune reaction to stress-responsive microbiota may compromise tolerance to self and therefore may increase the risk for autoimmune diseases in susceptible individuals. IMPORTANCE How do stressful life events increase the risk for autoimmune disorders? Here we show that chronic social stress in mice promotes the expression of virulent genes in the gut microbiota and alters the microbial translocation into the mesenteric lymph nodes. Our results also suggest that the consequent immune response to the stress-affected microbiota may endanger the tolerance for self. The presence of specific translocated bacteria and the immune response in the mesenteric lymph nodes can be diminished using an inhibitor of the bacterial communication system without drastically affecting the gut microbial composition as antibiotics do.