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Background The complex network of interactions occurring between gastrointestinal (GI) and extra-intestinal (EI) parasitic helminths of humans and animals and the resident gut microbial flora is attracting increasing attention from biomedical researchers, because of the likely implications for the pathophysiology of helminth infection and disease. Nevertheless, the vast heterogeneity of study designs and microbial community profiling strategies, and of bioinformatic and biostatistical approaches for analyses of metagenomic sequence datasets hinder the identification of bacterial targets for follow-up experimental investigations of helminth-microbiota cross-talk. Furthermore, comparative analyses of published datasets are made difficult by the unavailability of a unique repository for metagenomic sequence data and associated metadata linked to studies aimed to explore potential changes in the composition of the vertebrate gut microbiota in response to GI and/or EI helminth infections. Results Here, we undertake a meta-analysis of available metagenomic sequence data linked to published studies on helminth-microbiota cross-talk in humans and veterinary species using a single bioinformatic pipeline, and introduce the 'MICrobiome HELminth INteractions database' (MICHELINdb), an online resource for mining of published sequence datasets, and corresponding metadata, generated in these investigations. Conclusions By increasing data accessibility, we aim to provide the scientific community with a platform to identify gut microbial populations with potential roles in the pathophysiology of helminth disease and parasite-mediated suppression of host inflammatory responses, and facilitate the design of experiments aimed to disentangle the cause(s) and effect(s) of helminth-microbiota relationships. 3-P6fXwiUKUizQ4bBEnJ8w Video abstract.

Soil-transmitted helminths colonize more than 1.5 billion people worldwide, yet little is known about how they interact with bacterial communities in the gut microbiota. Differences in the gut microbiota between individuals living in developed and developing countries may be partly due to the presence of helminths, since they predominantly infect individuals from developing countries, such as the indigenous communities in Malaysia we examine in this work. We compared the composition and diversity of bacterial communities from the fecal microbiota of 51 people from two villages in Malaysia, of which 36 (70.6%) were infected by helminths. The 16S rRNA V4 region was sequenced at an average of nineteen thousand sequences per samples. Helminth-colonized individuals had greater species richness and number of observed OTUs with enrichment of Paraprevotellaceae, especially with Trichuris infection. We developed a new approach of combining centered log-ratio (clr) transformation for OTU relative abundances with sparse Partial Least Squares Discriminant Analysis (sPLS-DA) to enable more robust predictions of OTU interrelationships. These results suggest that helminths may have an impact on the diversity, bacterial community structure and function of the gut microbiota.

In this review, we examine the evidence that intestinal helminths can control harmful inflammatory responses and promote homeostasis by triggering systemic immune responses. Induction of separable components of immunity by helminths, which includes type 2 and immune regulatory responses, can both contribute toward the reduction in harmful type 1 immune responses that drive certain inflammatory diseases. Despite inducing type 2 responses, intestinal helminths may also downregulate harmful type 2 immune responses including allergic responses. We consider the possibility that intestinal helminth infection may indirectly affect inflammation by influencing the composition of the intestinal microbiome. Taken together, the studies reviewed herein suggest that intestinal helminth-induced responses have potent systemic effects on the immune system, raising the possibility that whole parasites or specific molecules produced by these metazoans may be an important resource for the development of future immunotherapies to control inflammatory diseases.

Investigations of the impact that patent infections by soil-transmitted gastrointestinal nematode parasites exert on the composition of the host gut commensal flora are attracting growing interest by the scientific community. However, information collected to date varies across experiments, and further studies are needed to identify consistent relationships between parasites and commensal microbial species. Here, we explore the qualitative and quantitative differences between the microbial community profiles of cohorts of human volunteers from Sri Lanka with patent infection by one or more parasitic nematode species (H+), as well as that of uninfected subjects (H-) and of volunteers who had been subjected to regular prophylactic anthelmintic treatment (Ht). High-throughput sequencing of the bacterial 16S rRNA gene, followed by bioinformatics and biostatistical analyses of sequence data revealed no significant differences in alpha diversity (Shannon) and richness between groups (P = 0.65, P = 0.13 respectively); however, beta diversity was significantly increased in H+ and Ht when individually compared to H-volunteers (P = 0.04). Among others, bacteria of the families Verrucomicrobiaceae and Enterobacteriaceae showed a trend towards increased abundance in H+, whereas the Leuconostocaceae and Bacteroidaceae showed a relative increase in H- and Ht respectively. Our findings add valuable knowledge to the vast, and yet little explored, research field of parasite-microbiota interactions and will provide a basis for the elucidation of the role such interactions play in pathogenic and immune-modulatory properties of parasitic nematodes in both human and animal hosts.

The gut microbiome has established importance in regulating many aspects of human health, including nutrition and immunity. While many internal and environmental factors are known to influence the microbiome, less is known about the effects of intestinal helminth parasites (worms), which together affect one-sixth of the world's population. High-throughput 16S rRNA sequencing has allowed the characterization of helminth-uninfected (HU) and helminth-infected (HI) gut microbiomes, revealing distinct profiles. However, there have been no qualitative or quantitative syntheses of these studies, which show marked variation in participant age, diet, pathogen of interest, and study location. A predefined minimally biased search strategy identified 23 studies in humans. For each of these studies, we qualitatively addressed the effects of helminth infection on within-individual (alpha) and between-individual (beta) fecal microbiome diversity, infection-associated microbial taxa, the effect of helminth clearance on microbiome composition, microbiome composition as a predictor of infection status or treatment outcome, and treatment-specific effects on the fecal microbiome. Concomitantly, we performed a meta-analysis on a subset of 7 of these studies containing raw, paired-end 16S reads and individual-level metadata, comprising 424 pretreatment or untreated HI individuals and 497 HU controls. After reducing the batch effect and adjusting for age, our data demonstrated that intestinal helminth parasites can alter the host gut microbiome by increasing alpha diversity and promoting taxonomic reassortment and gradient collapse. Most strongly influencing the microbiome composition were the helminths found in the large intestine, Enterobius vermicularis and Trichuris trichiura , suggesting that this influence appears to be specific to soil-transmitted helminths (STH) species and host anatomical niche. In summary, using a large and diverse sample set captured in the meta-analysis, we were able to evaluate the influence of individual helminth species as well as species-species interactions, each of which explained a significant portion of the variation in the microbiome. IMPORTANCE The gut microbiome has established importance in regulating many aspects of human health, including nutrition and immunity. While many internal and environmental factors are known to influence the microbiome, less is known about the effects of intestinal helminth parasites (worms), which together affect one-sixth of the world's population. Through a comprehensive qualitative systematic review and quantitative meta-analysis of existing literature, we provide strong evidence that helminth infection dynamically shifts the intestinal microbiome structure. Moreover, we demonstrated that such influence seems to be specific to helminth species and host anatomical niche. Our findings suggest that the gut microbiome may underlie some of the pathology associated with intestinal worm infection and support future work to understand the precise nature of the helminth-microbiome relationship.

Helminth infections and nutrition can independently alter the composition and abundance of the gastrointestinal microbiota, however, their combined effect is poorly understood. Here, we used the T. retortaeformis-rabbit system to examine how the helminth infection and host restriction from coprophagy/ready-to-absorb nutrients affected the duodenal microbiota, and how these changes related to the acquired immune response at the site of infection. A factorial experiment was performed where the bacterial community, its functionality and the immune response were examined in four treatments (Infect, Infect+Collar, Control+Collar and Control). Helminths reduced the diversity and abundance of the microbiota while the combination of parasites and coprophagic restriction led to a more diversified and abundant microbiota than infected cases, without significantly affecting the intensity of infection. Animals restricted from coprophagy and free from parasites exhibited the richest and most abundant bacterial community. By forcing the individuals to absorb nutrients from less digested food, the coprophagic restriction appears to have facilitated the diversity and proliferation of bacteria in the duodenum. Changes in the microbiota were more clearly associated with changes in the immune response for the infected than the nutrient restricted animals. The functional and metabolic characteristics of the duodenal microbiota were not significantly different between treatments. Overall, infection and diet affect the gut microbiota but their interactions and outcome can be complex. These findings can have important implications for the development of control measures to helminth infections where poor nutrition/malnutrition can also be a concern.

Evidence suggests that a significant interplay exists between the host gut microbiota and both the transmission and severity of malaria. Therefore, we explored the association between malaria and the gut microbiota across various geographic regions, considering host’s nutritional habits, helminth coinfections and age. This observational study was conducted in 3 malaria-endemic provinces of Rwanda: West, South and East. Demographic data, blood and fecal samples were collected from 169 participants (85 females and 84 males) aged between 2–78 years. We used questionnaire-derived qualitative data based on geographic regions, age, and nutrition. Malaria and soil-transmitted helminth diagnosis was assessed by microscopy. The gut microbial composition was analyzed based on bacterial 16S rRNA gene amplicon sequencing. We observed that preschool children had a significantly lower microbiota diversity compared to both school children (q = 0.027, K-Wallis) and adults (q = 0.011, K-Wallis). Unlike age, infection status (uninfected, malaria alone, soil-transmitted helminth alone or coinfection) was not significantly associated with the gut microbiota. However, using Bray-Curtis distances, we found a significantly differential gut microbial beta-diversity with a convergent distribution in the Western province compared to the other provinces (q = 0.0045, pairwise PERMANOVA). This geographic difference was not explained by any change in energy intake, protein, lipids, or carbohydrates consumption but was likely due to lower dietary fibre intake in the West compared to the South (q < 0.0001, ANOVA) and the East (q = 0.07, ANOVA). In conclusion, we have not found significant links between infection and gut microbiota. However, we showed a significant difference in the gut microbiota composition of people living in different geographic locations in Rwanda, possibly due to their nutritional habits.

Background Bidirectional signalling between the brain and the gastrointestinal tract is regulated at neural, hormonal, and immunological levels. Recent studies have shown that helminth infections can alter the normal gut microbiota. Studies have also shown that the gut microbiota is instrumental in the normal development, maturation and function of the brain. The pathophysiological pathways by which helminth infections contribute to altered cognitive function remain poorly understood. Discussion We put forward the hypothesis that gastrointestinal infections with parasitic worms, such as helminths, induce an imbalance of the gut-brain axis, which, in turn, can detrimentally manifest in brain development. Factors supporting this hypothesis are: 1) research focusing on intelligence and school performance in school-aged children has shown helminth infections to be associated with cognitive impairment, 2) disturbances in gut microbiota have been shown to be associated with important cognitive developmental effects, and 3) helminth infections have been shown to alter the gut microbiota structure. Evidence on the complex interactions between extrinsic (parasite) and intrinsic (host-derived) factors has been synthesised and discussed. Summary While evidence in favour of the helminth-gut microbiota-central nervous system hypothesis is circumstantial, it would be unwise to rule it out as a possible mechanism by which gastrointestinal helminth infections induce childhood cognitive morbidity. Further empirical studies are necessary to test an indirect effect of helminth infections on the modulation of mood and behaviour through its effects on the gut microbiota.

A plethora of data points towards a role of the gastrointestinal (GI) microbiota of neonatal and young vertebrates in supporting the development and regulation of the host immune system. However, knowledge of the impact that infections by GI helminths exert on the developing microbiota of juvenile hosts is, thus far, limited. This study investigates, for the first time, the associations between acute infections by GI helminths and the faecal microbial and metabolic profiles of a cohort of equine youngstock, prior to and following treatment with parasiticides (ivermectin). We observed that high versus low parasite burdens (measured via parasite egg counts in faecal samples) were associated with specific compositional alterations of the developing microbiome; in particular, the faecal microbiota of animals with heavy worm infection burdens was characterised by lower microbial richness, and alterations to the relative abundances of bacterial taxa with immune-modulatory functions. Amino acids and glucose were increased in faecal samples from the same cohort, which indicated the likely occurrence of intestinal malabsorption. These data support the hypothesis that GI helminth infections in young livestock are associated with significant alterations to the GI microbiota, which may impact on both metabolism and development of acquired immunity. This knowledge will direct future studies aimed to identify the long-term impact of infection-induced alterations of the GI microbiota in young livestock.

Helminth infection and dietary intake can affect the intestinal microbiota, as well as the immune system. Here we analyzed the relationship between fecal microbiota and blood profiles of indigenous Malaysians, referred to locally as Orang Asli, in comparison to urban participants from the capital city of Malaysia, Kuala Lumpur. We found that helminth infections had a larger effect on gut microbial composition than did dietary intake or blood profiles. Trichuris trichiura infection intensity also had the strongest association with blood transcriptional profiles. By characterizing paired longitudinal samples collected before and after deworming treatment, we determined that changes in serum zinc and iron levels among the Orang Asli were driven by changes in helminth infection status, independent of dietary metal intake. Serum zinc and iron levels were associated with changes in the abundance of several microbial taxa. Hence, there is considerable interplay between helminths, micronutrients and the microbiota on the regulation of immune responses in humans.