Intestinal helminths modulate the gut microbiome

Intestinal parasitic worms (commonly named intestinal helminths) affect close to one quarter of the world population and cause major losses for the livestock industry. These parasites establish chronic infections by modulation the immunity of their host. The immune system of mammals has been challenged by this immuno-modulation all along the course of evolution. Although intestinal parasites constitute a threat to human health, their recent eradication from industrialized regions may not be without consequence. In fact, the loss of intestinal helminth-driven immuno-regulation has been proposed to underlie the increased frequency of immune disorders observed in developed areas. Here, we first showed that one immune-modulatory strategy of intestinal helminths involves alterations of the intestinal bacterial communities. Although a lot remained to be understood about these alterations, they were characterized by higher intestinal levels of short-chain fatty acids (SCFAs), bacterial metabolites with immuno-suppressive activity. A better understanding of how intestinal helminths modulate host immunity via the intestinal microbiome may open the door to novel strategies to fight both intestinal parasites and immune disorders. In this context, I further characterized the impact of intestinal helminths on fecal bacterial communities in children living in a rural region of Ecuador and naturally infected with Ascaris lumbricoides, a parasite affecting 1.2 billion people worldwide. I then used a mouse model to extensively characterize the impact of intestinal helminth infection on intestinal bacterial communities along the intestinal tract. Based on our main results, we hypothesized that the worm-induced mucus secretion may favor the growth of SCFA-producing bacteria in the intestine, which in turn down-regulates the host immunity by promoting regulatory T cells. As part of this work, I also developed a web-based platform to assist scientists in analyzing data from high-throughput nucleic-acid sequencing, a method commonly used to characterize microbial communities but for which data analysis remains particularly challenging.

Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota

Eva Sabrina Gollwitzer, Nicola Harris, Benjamin John Marsland

BACKGROUND: Helminth parasites have been reported to have beneficial immunomodulatory effects in patients with allergic and autoimmune conditions and detrimental consequences in patients with tuberculosis and some viral infections. Their role in coinfection with respiratory viruses is not clear. OBJECTIVE: Here we investigated the effects of strictly enteric helminth infection with Heligmosomoides polygyrus on respiratory syncytial virus (RSV) infection in a mouse model. METHODS: A murine helminth/RSV coinfection model was developed. Mice were infected by means of oral gavage with 200 stage 3 H polygyrus larvae. Ten days later, mice were infected intranasally with either RSV or UV-inactivated RSV. RESULTS: H polygyrus-infected mice showed significantly less disease and pulmonary inflammation after RSV infection associated with reduced viral load. Adaptive immune responses, including TH2 responses, were not essential because protection against RSV was maintained in Rag1-/- and Il4rα-/- mice. Importantly, H polygyrus infection upregulated expression of type I interferons and interferon-stimulated genes in both the duodenum and lung, and its protective effects were lost in both Ifnar1-/- and germ-free mice, revealing essential roles for type I interferon signaling and microbiota in H polygyrus-induced protection against RSV. CONCLUSION: These data demonstrate that a strictly enteric helminth infection can have remote protective antiviral effects in the lung through induction of a microbiota-dependent type I interferon response.

Elsevier2017

The interaction of commensal intestinal bacteria with helminth parasites

Nicola Harris, Mario Michael Zaiss

Throughout evolution, both helminths and bacteria have inhabited our intestines. As intestinal helminths and bacteria inhabit the same environmental niche, it is likely that these organisms interact with, and impact on, each other. In addition, intestinal helminths are well known to alter intestinal physiology, permeability, mucous secretion and the production of antimicrobial peptides - all of which may impact on bacterial survival and spatial organization. Yet despite rapid advances in our understanding of host-intestinal bacteria interactions, the impact of helminths on this relationship has remained largely unexplored. Moreover, although intestinal helminths are generally accepted to possess potent immuno-modulatory activity, it is unknown whether this capacity requires interactions with intestinal bacteria. We propose that this 'menage a trois' situation is likely to have exerted a strong selective pressure on the development of our metabolic and immune systems. Whilst such pressures remain in developing countries, the eradication of helminths in industrialized countries has shifted this evolutionary balance, possibly underlying the increased development of chronic inflammatory diseases. Thus, helminth-bacteria interactions may represent a key determinant of healthy homoeostasis.

Wiley-Blackwell2016

The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

Lalit Kumar Dubey, Nicola Harris, Luc Xavier Marie Lebon, Andrew J. Macpherson, Benjamin John Marsland, Laure Menin, Ilaria Mosconi, Alessandra Piersigilli, Alexis Rapin, Jacques Rougemont, Mario Michael Zaiss

Intestinal helminths are potent regulators of their host's immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions.

Elsevier2015