Abstract
The intestinal barrier is a dynamic structure composed of the mucus layer, epithelial layer and the microbiome. It has the complex task of allowing nutrient absorption while limiting the entry of harmful microbes and microbial antigens present in the intestinal lumen. The 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 responses which could affect each layer of the intestinal barrier. Helminths are proposed to prevent, or even treat, many of the diseases implicated in the epithelial barrier theory, highlighting enhancement of intestinal barrier function as a potential mechanism through which helminths deliver their health benefit. Despite this, the effect of a chronic helminth infection on intestinal barrier function remains elusive. Using mice chronically infected with Heligmosomoides polygyrus and humans experimentally challenged with human hookworm (Necator americanus), this thesis examines helminths’ impact on each layer of the intestinal barrier and explores whether an improvement in intestinal barrier function could explain the proposed health benefits delivered by helminths.
In the intestinal mucus layer, a site-specific and persistent mucus response is observed, including the upregulation of goblet-cell derived functional proteins and mucin sialylation, recognised to enhance barrier function. Consistent with these mucus changes, the colonic mucus-associated microbiome is altered which could have implications for host health. In the epithelial layer, dynamic changes in the expression of tight junction proteins are demonstrated, resulting in increased epithelial permeability in the acute infection phase and decreased permeability in the chronic infection phase. Finally, infection with helminths reduces microbial translocation suggesting an overall improvement in intestinal barrier function. Importantly, this thesis demonstrates similar changes in the intestinal barrier of humans experimentally challenged with N. americanus, highlighting a conserved barrier response to infection with small intestinal helminths between humans and mice.
The improvement in intestinal barrier function induced by helminths could be utilised to treat intestinal disorders caused by a defective intestinal barrier, such as irritable bowel syndrome or ulcerative colitis. This thesis investigates the effect of controlled doses of hookworm on functional gut symptoms. It finds that a chronic hookworm infection may improve symptoms of visceral hypersensitivity. Next, the feasibility of performing a randomised controlled trial using controlled doses of N. americanus as a maintenance therapy in patients with ulcerative colitis is assessed. It demonstrates that patients can be successfully recruited to a study of this design, a viable hookworm infection can be established in most participants from a single inoculation and can remain viable for years, and controlled hookworm infections appear well-tolerated. These findings indicate that a full-scale clinical trial is feasible.
Together, the demonstrated changes in intestinal barrier function provide a plausible mechanism through which helminths could deliver benefits to human health. These changes could be harnessed to treat diseases, such as ulcerative colitis or irritable bowel syndrome, using controlled hookworm therapy.