Krisztina Szabó

Proper organization of the enteric nervous system (ENS) is critical for normal gastrointestinal (GI) physiology. Inflammatory bowel disease (IBD) disrupts key GI functions, including bowel motility. However, in many IBD patients, motility disorders persist even during remission, suggesting an irreversible ENS defect secondary to IBD. Here, we show that postinflammatory GI motility dysfunction arises from structural remodeling of the ENS, driven by a combination of neuronal loss and neurogenesis. During mucosal inflammation, enteric neurons upregulate CCL2 expression, facilitating the recruitment of monocytes into the myenteric plexus within the intestinal muscle. Monocyte-derived macrophages infiltrate the myenteric ganglia, contributing to excessive ENS remodeling and postinflammatory motility dysfunction. This neuroimmune axis is counterbalanced by a hypoxia-induced stress response in enteric neurons mediated by HIF1α. Enhancing the neuron-intrinsic hypoxia pathway limits ENS remodeling and preserves motility. In summary, this study presents a mechanistic model of postinflammatory GI motility dysfunction and proposes a therapeutic strategy to maintain ENS integrity and function during inflammation.

The glucocorticoid betamethasone (BM) has potent anti-inflammatory and immunosuppressive effects; however, it increases the susceptibility of patients to superficial Candida infections. Previously we found that this disadvantageous side effect can be counteracted by menadione sodium bisulfite (MSB) induced oxidative stress treatment. The fungus specific protein phosphatase Z1 (CaPpz1) has a pivotal role in oxidative stress response of Candida albicans and was proposed as a potential antifungal drug target. The aim of this study was to investigate the combined effects of CaPPZ1 gene deletion and MSB treatment in BM pre-treated C. albicans cultures. We found that the combined treatment increased redox imbalance, enhanced the specific activities of antioxidant enzymes, and reduced the growth in cappz1 mutant (KO) strain. RNASeq data demonstrated that the presence of BM markedly elevated the number of differentially expressed genes in the MSB treated KO cultures. Accumulation of reactive oxygen species, increased iron content and fatty acid oxidation, as well as the inhibiting ergosterol biosynthesis and RNA metabolic processes explain, at least in part, the fungistatic effect caused by the combined stress exposure. We suggest that the synergism between MSB treatment and CaPpz1 inhibition could be considered in developing of a novel combinatorial antifungal strategy accompanying steroid therapy.