Biology subjects

Cavelti-Weder, C.

Publications and source records attributed to Cavelti-Weder, C..

4 recordsLinked to original sources

bioRxiv2025

The gut insulin receptor acts as gatekeeper of intestinal barrier integrity

An impaired gut barrier has emerged as a potential driver of the low-grade inflammation that accompanies obesity and its complications. Among these, hyperglycemia per se has been proposed to sustain such increased intestinal permeability and subsequent translocation of bacterial endotoxins in the systemic circulation. Because reduced insulin signaling in the gut epithelium has also been reported upon obese conditions, we hypothesized that, beyond hyperglycemia, defective intestinal insulin signaling could directly compromise epithelial integrity. To mimic this diabesity feature, we induced deletion of the insulin receptor (IR) in the adult gut epithelium of IR{Delta}GUT mice. Remarkably, gut IR loss persistently maintained normal body weight and glucose homeostasis, thereby allowing the specific role of insulin action to be investigated. While IR{Delta}GUT mice exhibited increased intestinal paracellular permeability, mechanistic characterization of this gut leakiness revealed that IR{Delta}GUT mice displayed a rapid and drastic decline in Paneth cells anti-microbial defenses. This paralleled the onset of a cecal dysbiosis, as characterized by increased abundance of Pseudomonadota, and enhanced microbiota encroachment. Of note, IR{Delta}GUT mice exhibited intestinal stem cell (ISC) defects, as evidenced by reduced expression of ISC markers and ISC-mediated growth of intestinal organoids. Although expression of niche factors such as Wnt3a was diminished in Paneth cells isolated from IR{Delta}GUT mice, pharmacological activation of the canonical Wnt pathway failed to rescue the growth defects of IR-deleted gut organoids. The direct contribution of IR-downstream signaling to ISCs homeostasis was confirmed by the transcriptional reprogramming of FACS-sorted ISCs from IR{Delta}ISC mice. Finally, while gut IR loss did not worsen endotoxemia or impaired glycemic control upon HFD-feeding, IR{Delta}GUT displayed a higher susceptibility to chemically induced colitis and enteric infections (S. typhimurium, C. rodentium), underscoring intestinal insulin signaling as a key determinant of barrier integrity and epithelial homeostasis.

physiology↗

bioRxiv2021

Epithelial GPR35 protects from Citrobacter rodentium infection by preserving goblet cells and mucosal barrier integrity

Goblet cells secrete mucin to create a protective mucus layer against invasive bacterial infection and are therefore essential for maintaining intestinal health. However, the molecular pathways that regulate goblet cell function remain largely unknown. Although GPR35 is highly expressed in colonic epithelial cells, its importance in promoting the epithelial barrier is unclear. In this study, we show that epithelial Gpr35 plays a critical role in goblet cell function. In mice, cell type-specific deletion of Gpr35 in epithelial cells but not in macrophages results in goblet cell depletion and dysbiosis, rendering these animals more susceptible to Citrobacter rodentium infection. Mechanistically, scRNA-seq analysis indicates that signaling of epithelial Gpr35 is essential to maintain normal pyroptosis levels in goblet cells. Our work shows that the epithelial presence of Gpr35 is a critical element for the function of goblet cell-mediated symbiosis between host and microbiota.

immunology↗

bioRxiv2019

Air pollution mediates diabetes by disrupting gut innate mucosal immunity

Air pollution has emerged as an unexpected risk factor for diabetes1-6. The mechanisms linking air pollution and diabetes remain, however, unknown. It has been postulated that lung exposure mediates diabetes via systemic inflammation and insulin resistance7-9. By contrast, gut exposure to pollutants has received little attention, even though a large proportion of air pollution particles are swallowed after mucociliary clearance from the upper airways10. Here, we identified intestinal macrophages as key mediators linking air pollutants with impaired beta-cell function. Upon oral exposure to air pollution, intestinal macrophages up-regulated inflammatory- and interferon-response pathways, which disrupted their normal differentiation towards an anti-inflammatory/resident phenotype. The resulting pro-inflammatory milieu in the gut impaired beta-cell identity and function via local cytokine secretion from macrophages as genetic and pharmacological macrophage or IL-1{beta} ablation protected mice from developing air pollution-induced diabetes. These data establish intestinal macrophage-derived cytokines as key mediators of air pollution associated beta-cell dysfunction, thus pointing towards novel therapeutic strategies.

immunology↗

bioRxiv2017

Pharmacological Macrophage Attenuation by Imatinib Reverts Hepatic Steatosis and Inflammation in Obese Mice

AimsNon-alcoholic fatty liver disease (NAFLD) has become one of the most common liver diseases worldwide. As macrophages play a key role in NAFLD, therapies targeting macrophages have been postulated. Indeed, strategies depleting macrophages or blocking monocyte recruitment into the liver improve NAFLD, however, are not feasible in clinical practice. Our goal was to assess whether attenuation of macrophages can be achieved by imatinib, an anti-leukemia drug with known anti-inflammatory and anti-diabetic properties, and how this impacts NAFLD.\n\nMaterials and MethodsMurine macrophages were polarized in vitro to different activation states in the presence or absence of imatinib; mice on high fat diet orally treated with imatinib or vehicle; and human monocytes of diabetic patients and healthy controls treated with or without imatinib for translational application.\n\nResultsImatinib specifically attenuated pro-inflammatory murine macrophages in vitro and in vivo. In livers of obese mice, imatinib caused Kupffer cells to adopt an attenuated phenotype via modulation of the TNF-pathway. This immune-modulation resulted in markedly improved hepatic steatosis along with beneficial effects on liver function, lipids and systemic inflammation. The immune-dampening effect of imatinib also prevailed in human monocytes, indicating translational applicability.\n\nConclusionsImmune-modulation of myeloid cells as exemplified by imatinib may be a novel therapeutic strategy in patients with NAFLD.

immunology↗