Helminths' therapeutic potential to treat intestinal barrier dysfunction

Abstract

The intestinal barrier is a dynamic multi‐layered structure which can adapt to environmental changes within the intestinal lumen. It has the complex task of allowing nutrient absorption while limiting entry of harmful microbes and microbial antigens present in the intestinal lumen. Excessive entry of microbial antigens via microbial translocation due to ‘intestinal barrier dysfunction’ is hypothesised to contribute to the increasing incidence of allergic, autoimmune and metabolic diseases, a concept referred to as the ‘epithelial barrier theory’. Helminths reside in the intestinal tract are in intimate contact with the mucosal surfaces and induce a range of local immunological changes which affect the layers of the intestinal barrier. Helminths are proposed to prevent, or even treat, many of the diseases implicated in the epithelial barrier theory. This review will focus on the effect of helminths on intestinal barrier function and explore whether this could explain the proposed health benefits delivered by helminths.

Modulation of intestinal epithelial permeability by chronic small intestinal helminth infections

“…Intestinal epithelial permeability increases in the acute phase of a helminth infection but the effect of helminths' chronic infection phase on epithelial permeability remains elusive 3–6 . Furthermore, whether changes in epithelial permeability observed in preclinical models translate to humans has not been examined 3 . This study demonstrates that mice acutely infected with the helminth H. polygyrus exhibit increased expression of jejunal claudin‐2 mRNA and downregulation of jejunal tricellulin mRNA, and an increase in intestinal epithelial permeability.…”

“…Intestinal epithelial permeability increases in the acute phase of a helminth infection but the effect of helminths' chronic infection phase on epithelial permeability remains elusive 3–6 . Furthermore, whether changes in epithelial permeability observed in preclinical models translate to humans has not been examined 3 .…”

“…Excessive intestinal epithelial permeability can allow the entry of microbes, microbial products and other toxins into the body. This process is proposed to cause or contribute to the pathogenesis of a range of human diseases 3,21 . Data from epidemiological, preclinical and, to a lesser extent, human clinical studies, suggest that helminths may protect their host from developing many of the same diseases that are associated with excessive intestinal epithelial permeability, including inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis and metabolic disease 22 .…”

“…Acute infection with intestinal helminths, multicellular organisms that have co‐evolved with their hosts over millennia, increases epithelial permeability in preclinical models 3–6 . The adaptive immune response to a helminth infection, characterized by the release of type 2 cytokines, interleukin‐4 and interleukin‐13, from type 2 innate lymphoid cells and CD4 + T helper type 2 (T h 2) cells, opens tight junctions to generate a surge of fluid into the intestinal lumen to wash the helminth away from its intestinal niche 4,7–9 .…”

“…For example, elevated intestinal permeability could contribute to the negative health effects experienced by individuals with a high infection burden 11 . Conversely, evidence from epidemiological and preclinical studies, and to a lesser degree from human clinical trials using controlled doses of helminths, suggests that helminths may protect their host against diseases linked to heightened epithelial permeability 3 . This implies that helminths might decrease permeability under specific conditions.…”