Helminth-Induced Human Gastrointestinal Dysbiosis: a Systematic Review and Meta-Analysis Reveals Insights into Altered Taxon Diversity and Microbial Gradient Collapse

Abstract

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.

Keywords: helminth; intestinal bacteria; intestinal parasites; microbiome; nematodes; soil-transmitted helminth.

FIG 1

PRISMA flow diagram of the study selection process. Study selection was performed according to the most recent Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. *, Exclusion criteria included nonhuman host, nonintestinal helminth, intestinal comorbidity, focus exclusively on helminth’s microbiome, and no experimentation or data collection. **, Inclusion criteria included publication between 1 January 1975 and 3 August 2020, helminth infection with intestinal involvement, and human studies with ≥10 participants.

FIG 2

Study population. World map highlighting the countries where the 23 studies selected for the systematic review and 7 studies selected for the meta-analysis obtained their data. Buendía et al., 2018 (32) was used just for the systematic review.

FIG 3

Effects of helminth infection on measures of microbiome diversity, richness, and evenness. (A to D) Measures across all age groups. (A) Shannon alpha diversity. (B) InvSimpson alpha diversity. (C) Species evenness. (D) Species richness (Chao1). (E) Shannon alpha diversity nested by age and helminth infection status. HookwormA, Ancylostoma sp.; HookwormN, Necator sp.; HookwormNA, either Ancylostoma or Necator sp.

FIG 4

Beta diversity of HU and HI cohorts. PCoA plots of the (A) HU and (B) HI gut microbiomes. The relative contribution (Eigenvalue) of each axis to the total inertia of the data is indicated in the percent values on the axes. HookwormA, Ancylostoma sp.; HookwormN, Necator sp.; HookwormNA, either Ancylostoma or Necator sp.

FIG 5

Microbiome gradient analysis. (A and B) Continuously variable community configurations (gradients) visualized through PCoA plots of HU and HI microbiomes, respectively. (C and D) Bar plots of the most significant taxonomic trade-offs defining the gradients of HU and HI microbiomes, respectively.

FIG 6

Profiles of the dominant microbial communities in HU and HI cohorts. Microbial profile heatmap representing the 35 most prevalence taxonomies (presented at the species level) within all samples per age category, segregated by individual helminth species. Red indicates greater abundance, while blue indicates lower abundance. Numbers indicate the percentage of 16S rRNA reads made up of the various taxa. HookwormA, Ancylostoma sp.; HookwormN, Necator sp.; HookwormNA, either Ancylostoma or Necator sp.

FIG 7

Correlation circle plot of helminth-microbiome interactions. Angles represent the strength and direction of correlation, and distance from the center represents significance of the correlation. The top 20 most significant bacterial taxonomies (blue) and associated factors of interest (red; age, number of helminths, and helminth species) are included. Negative cosine interactions are negative correlations; cosine (0) (90° angle) indicates no interaction. The inner circle represents a mark for significance (0.05 threshold), where points outside are significant. HookwormA, Ancylostoma sp.; HookwormN, Necator sp.; HookwormNA, either Ancylostoma or Necator sp.