Exclusive dependence of IL-10R[alpha] signalling on intestinal microbiota homeostasis and control of whipworm infection

The whipworm Trichuris trichiura is a soil-transmitted helminth that dwells in the epithelium of the caecum and proximal colon of their hosts causing the human disease, trichuriasis. Trichuriasis is characterized by colitis attributed to the inflammatory response elicited by the parasite while tunnelling through intestinal epithelial cells (IECs). The IL-10 family of receptors, comprising combinations of subunits IL-10R[alpha], IL-10R[beta], IL-22R[alpha] and IL-28R[alpha], modulates intestinal inflammatory responses. Here we carefully dissected the role of these subunits in the resistance of mice to infection with T. muris, a mouse model of the human whipworm T. trichiura. Our findings demonstrate that whilst IL-22R[alpha] and IL-28R[alpha] are dispensable in the host response to whipworms, IL-10 signalling through IL-10R[alpha] and IL-10R[beta] is essential to control caecal pathology, worm expulsion and survival during T. muris infections. We show that deficiency of IL-10, IL-10R[alpha] and IL-10R[beta] results in dysbiosis of the caecal microbiota characterised by expanded populations of opportunistic bacteria of the families Enterococcaceae and Enterobacteriaceae. Moreover, breakdown of the epithelial barrier after whipworm infection in IL-10, IL-10R[alpha] and IL-10R[beta]-deficient mice, allows the translocation of these opportunistic pathogens or their excretory products to the liver causing organ failure and lethal disease. Importantly, bone marrow chimera experiments indicate that signalling through IL-10R[alpha] and IL-10R[beta] in haematopoietic cells, but not IECs, is crucial to control worm expulsion and immunopathology. These findings are supported by worm expulsion upon infection of conditional mutant mice for the IL-10R[alpha] on IECs. Our findings emphasize the pivotal and complex role of systemic IL-10R[alpha] signalling on immune cells in promoting microbiota homeostasis and maintaining the intestinal epithelial barrier, thus preventing immunopathology during whipworm infections.