Chronic Trichuris muris Infection in C57BL/6 Mice Causes Significant Changes in Host Microbiota and Metabolome: Effects Reversed by Pathogen Clearance

Abstract

Trichuris species are a globally important and prevalent group of intestinal helminth parasites, in which Trichuris muris (mouse whipworm) is an ideal model for this disease. This paper describes the first ever highly controlled and comprehensive investigation into the effects of T. muris infection on the faecal microbiota of mice and the effects on the microbiota following successful clearance of the infection. Communities were profiled using DGGE, 454 pyrosequencing, and metabolomics. Changes in microbial composition occurred between 14 and 28 days post infection, resulting in significant changes in α and β- diversity. This impact was dominated by a reduction in the diversity and abundance of Bacteroidetes, specifically Prevotella and Parabacteroides. Metabolomic analysis of stool samples of infected mice at day 41 showed significant differences to uninfected controls with a significant increase in the levels of a number of essential amino acids and a reduction in breakdown of dietary plant derived carbohydrates. The significant reduction in weight gain by infected mice probably reflects these metabolic changes and the incomplete digestion of dietary polysaccharides. Following clearance of infection the intestinal microbiota underwent additional changes gradually transitioning by day 91 towards a microbiota of an uninfected animal. These data indicate that the changes in microbiota as a consequence of infection were transitory requiring the presence of the pathogen for maintenance. Interestingly this was not observed for all of the key immune cell populations associated with chronic T. muris infection. This reflects the highly regulated chronic response and potential lasting immunological consequences of dysbiosis in the microbiota. Thus infection of T. muris causes a significant and substantial impact on intestinal microbiota and digestive function of mice with affects in long term immune regulation.

Immunity to gastrointestinal nematode infections

“…Indeed, chronic T. muris infection results in the accumulation of interferon-g þ T cells in the bone marrow, 213 and does not appear to protect against the development of colitis. 214,215 Furthermore, depending on the strain, chronically infected mice gain less weight than their uninfected counterparts, 216 and in some cases even acquire colitis-like symptoms, thus losing weight, 217 mirroring the malnutrition and wasting of some infected humans. In contrast, lung pathology appears to be decreased in response to papain challenge, 218 illustrating that worm-induced protection against inflammatory disorders is highly context specific.…”

The colonic mucus protection depends on the microbiota

“…14 The importance of a mucus niche for this bacterium can be seen as its abundance is increased during mucus overproduction in helminth infections. 15,16 Mucispirillum has been suggested to be associated with a healthy gut. 17 Comparison of the microbiota composition in the two colonies revealed differences but only a few candidates possibly contributing to the formation of an impenetrable mucus layer were identified.…”

“…14 The importance of a mucus niche for this bacterium can be seen as its abundance is increased during mucus overproduction in helminth infections. 15,16 Mucispirillum has been suggested to be associated with a healthy gut. 17…”

Macrobiota — helminths as active participants and partners of the microbiota in host intestinal homeostasis

“…For example, 3 independent laboratories reported that infection with the mouse duodenal parasite Heligmosomoides polygyrus expanded the proportion of Lactobacillaceae and Enterobacteriaceae in the gut [3–5 • ]. Moreover, while chronic infection with the mouse whipworm Trichuris muris similarly raised Lacto-bacillaceae representation, it also reduced overall microbiota diversity, a factor often associated with poorer homeostatic control, reflecting an ecological imbalance in the intestinal microbial community [6,7 • ]. Intriguingly, removal of parasites restored the ‘naïve’ flora observed in uninfected mice, suggesting that helminth-induced changes in the microbiota are reversible by clearance of the macrobiota [7 • ].…”

“…Moreover, while chronic infection with the mouse whipworm Trichuris muris similarly raised Lacto-bacillaceae representation, it also reduced overall microbiota diversity, a factor often associated with poorer homeostatic control, reflecting an ecological imbalance in the intestinal microbial community [6,7 • ]. Intriguingly, removal of parasites restored the ‘naïve’ flora observed in uninfected mice, suggesting that helminth-induced changes in the microbiota are reversible by clearance of the macrobiota [7 • ]. Likewise, in wild mice ( Apodemus flavicollis ) a correlation was observed between increased bacterial microbiota richness and helminth infections and different types of helminths elicited characteristic changes in the composition and abundance of microbiota species [8].…”