The intestinal mucosa is a site of multiple stressors and forms the barrier between the internal and external environment. In the intestine, a complex interplay between the microbiota, epithelial barrier and the local immune system maintains homeostasis and promotes a healthy gut. One of the major cellular catabolic processes that regulate this homeostasis is autophagy. Autophagy is required to maintain anti-microbial defense, epithelial barrier integrity and mucosal immune response. Dysregulation of the autophagy process causes disruption of several aspects of the intestinal epithelium and the immune system that can lead to an inappropriate immune response and subsequent inflammation. Genome-wide association studies have found an association between several risk loci in autophagy genes and inflammatory bowel disease. The aim of the current review is to provide an update on the role of autophagy in intestinal mucosal physiology and in the control of inappropriate inflammation.

Elevated gut serotonin inhibits autophagy via mTOR promoting a disrupted microbiota and enhanced susceptibility to colitis.

Intestinal parasites, including helminths and protozoa, account for a significant portion of the global health burden. The gastrointestinal (GI) tract not only serves as the stage for these parasitic infections but also as the residence for millions of microbes. As the intricacies of the GI microbial milieu continue to unfold, it is becoming increasingly apparent that the interactions between host, parasite, and resident microbes help dictate parasite survival and, ultimately, disease outcomes. Across both clinical and experimental models, intestinal parasites have been shown to impact microbial composition and diversity. Reciprocally, microbes can directly influence parasitic survival, colonization and expulsion. The gut microbiota can also indirectly impact parasites through the influence and manipulation of the host. Studying this host–parasite–microbiota axis may help bring about novel therapeutic strategies for intestinal parasitic infection as well as conditions such as inflammatory bowel disease (IBD). In this review, we explore the relationship between intestinal parasites, with a particular focus on common protozoa and helminths, and the gut microbiota, and how these interactions can influence the host defence and intestinal immune response. We will also explore the impact of this tripartite relationship in a clinical setting and its broader implications for human health.

Macrophage adenosine monophosphate-activated protein kinase (AMPK) limits the development of experimental colitis. AMPK activation inhibits NADPH oxidase (NOX) 2 expression, reactive oxygen species (ROS) generation, and pro-inflammatory cytokine secretion in macrophages during inflammation, while increased NOX2 expression is reported in experimental models of colitis and inflammatory bowel disease (IBD) patients. Although there are reductions in AMPK activity in IBD, it remains unclear whether targeted inhibition of NOX2 in the presence of defective AMPK can reduce the severity of colitis. Here, we investigate whether the inhibition of NOX2 ameliorates colitis in mice independent of AMPK activation. Our study identified that VAS2870 (a pan-Nox inhibitor) alleviated dextran sodium sulfate (DSS)-induced colitis in macrophage-specific AMPKβ1-deficient (AMPKβ1^LysM) mice. Additionally, VAS2870 blocked LPS-induced TLR-4 and NOX2 expression, ROS production, nuclear translocation of NF-κB, and pro-inflammatory cytokine secretion in bone marrow-derived macrophages (BMDMs) from AMPKβ1^LysM mice, whereas sodium salicylate (SS; AMPK β1 activator) did not. Both VAS2870 and SS inhibited LPS-induced NOX2 expression, ROS production, and pro-inflammatory cytokine secretions in bone marrow-derived macrophages (BMDMs) from wildtype (AMPKβ1^fl/fl) mice but only VAS2870 inhibited these effects of LPSs in AMPKβ1^LysM BMDMs. Furthermore, in macrophage cells (RAW 264.7), both SS and VAS2870 inhibited ROS production and the secretion of pro-inflammatory cytokines and reversed the impaired autophagy induced by LPSs. These data suggest that inhibiting NOX2 can reduce inflammation independent of AMPK in colitis.