Image source: CDC
The word “infection” is often associated with either bacteria or virus, but we all know there are some other bad guys that can infect us too. One must not forget about- the parasites. Even though they are more common in the rural areas where hygiene is still an issue, WHO counts that about 1.5 billion people worldwide still struggle with intestinal infection caused by helminth parasites. Interestingly, helminths have been found to regulate mammalian evolution, especially in the selection of genes responsible for autoimmunity. The importance of host microbiome in deciding host health is being increasingly discovered. Helminth infection widely alters host intestinal microbiome, and their interaction is known to modulate host immune responses. Today in our blog, we are discussing if host microbiota can impact those intestinal parasitic infections, and how?
Helminths, sometimes referred to as human worms, are infectious parasites that belong to phyla Nematoda (roundworms) and Platyhelminthes (flatworms). Their development starts with the eggs laid by adult parasites living in their definitive host.
Eggs are passed outside the body where they develop into infectious L3 larvae that will further develop into adult parasites (see image for larvae stages). Although the helminth life cycle follows a simple pattern, they are diverse in their means of infection, transmission, and target host sites to be occupied by the adults or larvae. Research by Moyat and collegues used a helminth parasite Heligmosomoide polygrus bakeri, which infects mouse intestine naturally. It closely resembles common Trichostrongylus infections that can affect humans.
So, how did the researchers set up their experiment? Moyat and collegues used specific pathogen free mice (SPF) as a positive control which contained microbiota; and germ free or antibiotic treated mice (atbM) for experimental treatments that will have no or depleted microbiota, respectively. They started with infecting mice orally with infectious L3 larvae. After 24 hours L3 larvae migrated to the upper small intestine. Within 3-4 days L4 larvae (adults in figure) developed in the intestine. After 8-9 days, adults would exit the tissue to reside in the intestinal lumen where they can stay for several months before leaving the host.
Next, the researchers asked three main questions:
Does the parasite quantity change in the absence of microbiota?
By comparing SPF and atbM, Moyat and group noticed that parasite numbers inside SPF peaked during week 2-4, but then the parasite quantity dropped rapidly. While in atbM numbers continued to be high even after week 4 and their egg production was elevated as well. Less microbiota meant more parasites, which also meant that the worms do not need to feed on microbiota but directly on host intestines! Ouch! These results also show that a diverse intestinal microbiota is needed to effectively get rid of the parasites for good.
Would microbiota affect anti-parasitic immune response?
Parasitic infection is known to produce a significant type 2 immune response that corresponds to production of IL-4 and IL-13 cytokines which can activate type 2 innate lymphoid cells. They subsequently activate T helper 2 cells which produce polyclonal IgE and parasite specific IgG1. All these processes remove worms from our body using a “weep and sweep” technique. Basically, this does 2 things: 1. Pushes worms out using intestinal contractions, and 2. Induces secretion of mucins from goblet cells and resistin-like molecule beta to resist further infection.
n this research they checked for both serum and peritoneal cytokines which were elevated equally between SPF and atbM, except for serum IL-12 that was higher in atbM. Same as antibodies (IgE and specific IgG1) that were higher in atbM. Concluding that mice lacking microbiota have the ability to induce a similar type 2 immune response to the ones with microbiota. However, they did see an early recruitment of myloid cells to the site of the larvae residence, but that had little effect on the larvae. Hence, it is not the change is microbiota-mediated anti-parasitic response that is causing the observed changes.
How does microbiota affect intestine motility and larvae distribution?
Next, to find the reason for increase in parasitic infection in microbiome depleted mice, they wanted to see how the microbiota affects small intestinal localization and migratory activity of larvae during parasitic infections. Firstly, they found that depletion or absence of microbiome makes the larvae concentrate to the proximal small intestine, whereas in SPF mice larvae were distributed throughout the intestine. Secondly, they found no difference in response to acetylcholine (neurotransmitter promoting muscle contractions and intestine motion) between SPF and atbM, indicating that microbiome does not change tissue responses to acetylcholine. However, they measured lower levels of natural acetylcholine in atbM. Maybe microbiome assists host cells produce acetylcholine which in turn induces the contractions to distribute the larvae throughout the intestine? This final mechanism of action was not further worked on but is definitely a strong speculation. Putting this together we can say that microbiota is important for intestinal motility (contractions) which will result in redistribution of larvae.
In conclusion, microbiota may not alter the parasite-induced type 2 immune response but help in reducing the parasite numbers in the intestine. The microbiota does so by increasing the intestinal motility which will help in redistributing the larvae from invading the tissue in their preferred site of infection. All of this will lead to reducing the chronicity of infection with parasitic worms. This interesting study made us very curious. Do people in rural areas have a different microbiome composition which makes them prone to helminth infection, or is it just the hygiene which is making them more vulnerable? Will adding beneficial bacteria, like drinking yogurt, prevent or cure helminth infections? Or will any particular nutrition pattern or prebiotic help? We hope to get more updates soon!
Moyat M, Lebon L, Perdijk O, Wickramasinghe LC, Zaiss MM, Mosconi I, Volpe B, Guenat N, Shah K, Coakley G, Bouchery T, Harris NL. Microbial regulation of intestinal motility provides resistance against helminth infection. Mucosal Immunol. 2022 Mar 14. doi: 10.1038/s41385-022-00498-8.
Article author: Ines Poljak. Ines is a MSc graduate from University of Copenhangen who worked on multiple myeloma bone disease. She worked in several clinical laboratories before committing herself completely to research.
Editor: Sutonuka Bhar. Sutonuka is a PhD candidate at the University of Florida. Her work focuses on host immune responses against viruses and bacterial membrane vesicles.
Check out Antibuddies’ blog post “Microbiota makes our intestines move and keeps the worms away”.Tweet