Networking between helminths, microbes, and mammals

Abstract

Just as mammals have coevolved with the intestinal bacterial communities that are part of the microbiota, intestinal helminths represent an important selective force on their mammalian host. The complex interaction between helminths, microbes, and their mammalian host is likely an important determinant of mutual fitness. The host immune system in particular is a critical interface with both helminths and the microbiota, and this crosstalk often determines the balance between tolerance and resistance against these widespread parasites. Hence, there are many examples of how both helminths and the microbiota can influence tissue homeostasis and homeostatic immunity. Understanding these processes at a cellular and molecular level is an exciting area of research that we seek to highlight in this review and that will potentially guide future treatment approaches.

Keywords: helminth; inflammatory disease; intestine; microbiota; parasites.

Figure 1:. Predicted mechanisms of helminth-bacterial interactions.

The mechanisms by which helminth infection results in altered intestinal bacterial communities are many and include indirect and direct interactions. Indirect effects result from helminth-induced type two immune response in the mammalian host. This response has been shown to alter intestinal bacterial communities via a number of mechanisms including; i) increased production of SPRR2A and Relmβ proteins that exert antimicrobial activity against gram-positive and gram-negative bacterial spp, respectively and ii) increased and altered production of mucins. It is also likely that type 2 cytokine mediated “weep and sweep’ response, characterised by increased intestinal motility and secretions, impacts microbial communities along the entire intestinal tract. A direct impact of helminth on bacterial communities is likely to occur through multiple mechanisms including, but not restricted to, helminth-induced modulation of bacterial gene expression, the production of shared metabolites and/or toxic metabolic by-products, or competition for essential nutrients. Nutrients could be derived from the host diet, the helminth or bacteria and include; i) macronutrients such as carbohydrates (CHO), lipids and proteins, ii) micronutrients (minerals and vitamins). “Created with BioRender.com”.

Figure 2:. Technological advances in studying network interactions of helminths, microbes, and host.

Advances in high dimensional technologies and computational approaches are driving forces in studying the interactions of microbes and helminths with the host immune system. As intestinal helminths and the gut microbiota occupy the same ecological niche, the host intestines have been the major focus of this work. Sequencing technology is a primary driver of many analytical approaches, with newer strategies providing a comprehensive picture of the metagenome, virome and transcriptome of the intestinal microbiota. Other developments include the use of flow cytometry, which can provide absolute count data, as well as sort bacterial populations of interest. Metabolomic profiling provide insights into the biochemical language exchange between host, bacteria and helminths. New imaging and sequencing approaches could enable a better understanding of the biogeography of helminth-bacterial interactions in the intestine. Intestinal biopsies can be used to generate organoid cultures, providing in vitro assay systems to study interactions between helminth secreted molecules and epithelial cells. Bacteria can also be introduced into the organoids in this reductionist system. These high dimensional datasets will then have to undergo extensive data analysis with modern computational biology approaches, including neural network strategies to discern interaction networks. Finally, this information needs to be translated to the clinical setting where there is greater heterogeneity at the host level with many different genetic profiles but has the promise of developing better therapeutic strategies against helminth infections, as well as inflammatory diseases. “Created with BioRender.com”.