Whipworm Infection Promotes Bacterial Invasion, Intestinal Microbiota Imbalance, and Cellular Immunomodulation

Abstract

Infections with Trichuris trichiura are among the most common causes of intestinal parasitism in children worldwide, and the diagnosis is based on microscopic egg identification in the chronic phase of the infection. During parasitism, the adult worm of the trichurid nematode maintains its anterior region inserted in the intestinal mucosa, which causes serious damage and which may open access for gut microorganisms through the intestinal tissue. The immune-regulatory processes taking place during the evolution of the chronic infection are still not completely understood. By use of the Swiss Webster outbred mouse model, mice were infected with 200 eggs, and tolerance to the establishment of a chronic Trichuris muris infection was induced by the administration of a short pulse of dexamethasone during nematode early larval development. The infected mice presented weight loss, anemia, an imbalance of the microbiota, and intense immunological cell infiltration in the large intestine. It was found that mice have a mixed Th1/Th2/Th17 response, with differences being found among the different anatomical locations. After 45 days of infection, the parasitism induced changes in the microbiota composition and bacterial invasion of the large intestine epithelium. In addition, we describe that the excretory-secretory products from the nematode have anti-inflammatory effects on mouse macrophages cultured in vitro, suggesting that T. muris may modulate the immune response at the site of insertion of the worm inside mouse tissue. The data presented in this study suggest that the host immune state at 45 days postinfection with T. muris during the chronic phase of infection is the result of factors derived from the worm as well as alterations to the microbiota and bacterial invasion. Taken together, these results provide new information about the parasite-host-microbiota relationship and open new treatment possibilities.

Whipworm-Associated Intestinal Microbiome Members Consistent Across Both Human and Mouse Hosts

“…(i) Bacteroides (Figure 8), for which many OTUs and the entire genus were significantly more abundant in the mice. In a previous mouse whipworm infection experiment, uninfected mice had undetectable levels of Bacteroides, but infected mice exhibited large amounts (200-egg infection in Swiss Webster outbred mice, 45 days post-infection) (Schachter et al, 2020), and Bacteroides is one of the major components of the T. muris microbiome (White et al, 2018). Here, we also identified two Bacteroides OTUs that were also significantly higher in whipworm-infected humans.…”

“…(i) Escherichia/Shigella ( Figure 4 ) was represented by a single OTU in mice (species Escherichia coli Xuzhou21), but several OTUs in human. In a previous mouse whipworm infection study, Escherichia was one of just four genera significantly associated with infection (200-egg infection in Swiss Webster outbred mice, 45 days post-infection) ( Schachter et al., 2020 ), and in another, Escherichia was only detectable following infection (20-egg infection, C57BL/6 mice, 35 days post-infection) ( Holm et al., 2015 ). Here, we observed that it not only increased with infection in both mice and humans (at both the OTU and genera level), but also decreased following deworming in mice (OTU and genera levels) and humans (OTU level).…”

“…A study from Sri Lanka identified several taxa significantly associated with hookworm, whipworm, or roundworm infection ( Jenkins et al., 2017 ). Animal models have also proven useful for studying whipworm infections, and previous studies have utilized mice models to study microbiome interactions with the mouse whipworm ( T. muris ) ( Holm et al., 2015 ; Houlden et al., 2015 ; White et al., 2018 ; Schachter et al., 2020 ).…”

The interplay between Trichuris and the microbiota

“…The importance of the microbiota during helminth infection is becoming increasingly recognized, and is also the start of an exciting and crucial area of parasitological research. Microbial changes have been reported for multiple intestinal helminths including infections with Ascaris lumbricoides (Ramírez-Carrillo et al ., 2020 ), H. polygyrus (Walk et al ., 2010 ; Kreisinger et al , 2015 ), Necator americanus (hookworm; Cantacessi et al ., 2014 ) and of interest for this review T. trichiura (Lee et al ., 2014 ; Chen et al ., 2021 ) and T. muris (Holm et al ., 2015 ; Houlden et al ., 2015 ; Schachter et al ., 2020 ).…”

“…Using a well-established model of chronic worm infection, when laboratory wild-type mice are given a single low dose of embryonated eggs (20–30 T. muris eggs) upon transition from larvae to adult worms (day 28 post infection), the gut microbiota undergo compositional changes (Houlden et al ., 2015 ; Schachter et al ., 2020 ). Specifically, bacterial taxa like Firmicutes , Mucispirillum and Proteobacteria increase as a result of infection; whilst Parabacteroides and Prevotella decrease in abundance (Holm et al ., 2015 ; Houlden et al ., 2015 ; Schachter et al ., 2020 ). The observed changes in microbial composition from infection appear to be parasite-dependent and transient in nature.…”