The microbiome of the helminth infected host: Implications for immunity and intestinal homeostasis

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

Worm parasites (helminthes) are capable of infecting the gastrointestinal tract of a broad range of animals including humans. Helminth infection is often associated with pronounced effects on the health of the infected individual host. An example of such a parasite is the human whipworm that infects 1 billion people worldwide. An analogous model system exists in the mouse that allows us to study the interaction between the whipworm and the host?s immune system and understand the mechanisms by which the host attempts to eradicate the worm. The site of whipworm infection in the large intestine is home to the host?s gut flora, these bacteria are important in the development and maintenance of the host?s immune response and in digesting complex dietary molecules. We have data showing that in a chronic whipworm infection in the mouse there are dramatic changes in the gut flora of the infected animal. In this research we aim to precisely define these changes in the gut flora following whipworm infection and then to understand the functional implications to the host as a result of these changes. Specifically, do the changes in gut flora provide a new ecosystem in the gut more beneficial to long term worm survival? Do they compromise the ability of the infected individual to digest complex carbohydrates thereby leading to long-term weight loss? Finally, do these changes in gut flora have implications on the way we mount immune responses e.g. to other infectious agents or in terms of immune disease such as autoimmunity or allergy.

Technical Summary

Worm parasites (helminthes) are capable of infecting the gastrointestinal tract a broad range of animals and are often associated with pronounced effects on the health of the host. Although interactions between helminthes and the host have been studied there is no research on the interaction between helminthes and the host?s gut microbiota and the impact on the host of worm-induced changes in its gut microbiota. Considering the importance of the gut microbiota to the health of the animal, this represents a new and exciting research area that we propose to address. Understanding this three-way interaction between the host, worm and microbiota that will have serious implications on our understanding of the pathology of parasitic infections The human whipworm (Trichuris trichiura) infects 1 billion people worldwide and resides in the large intestine, home to a complex diverse microbiota. Human whipworm infection has been successfully modeled using the mouse whip worm Trichuris muris and has generated many of the current paradigms of immunity to intestinal nematode infection. Critically, using this model the response phenotype to T. muris can easily be manipulated, thereby providing a setting whereby resistance or chronic infection can readily be investigated. Having demonstrated that chronic T. muris infection causes changes the mouse microbiota we now propose to use this model to study in detail the effect of a chronic infection on the host microbiota.
The research objectives are:
1. To use metagenomics to reveal the changes in the mouse caecal microbiome during the establishment of a chronic T. muris infection.
2. To determine if a functional consequence of changes in the caecal microbiome associated with chronicity is an alteration in the ability of the microbiome to process complex dietary molecules, having long-term nutritional implications for chronically infected individuals.
3. To determine if a functional consequence of changes in the caecal microbiome associated with chronicity is to establish an ecosystem that influences subsequent T. muris egg hatching either decreasing it to reduce inter parasite competition or enhancing it thus allowing greater worm numbers to establish.
4. To demonstrate that changes in the microbiome will influence host immune status, are of a consequence of both the worm and the host response to it and are not maintained in the absence of the worm.
Comprehension of the interactions between the host, worm and microbiota will increase our understanding of the pathology of parasitic infections, informing the way we might treat such infections.