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TitleRapid environmental effects on gut nematode susceptibility in rewilded mice
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RESEARCH ARTICLE

Rapid environmental effects on gut nematode

susceptibility in rewilded mice

Jacqueline M. Leung
1*, Sarah A. Budischak1, Hao Chung The2, Christina Hansen1,

Rowann Bowcutt
3
, Rebecca Neill

1
, Mitchell Shellman

1
, P’ng Loke

3
, Andrea L. Graham

1*

1 Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United

States of America, 2 Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme,

Vo Van Kiet, Ho Chi Minh City, Viet Nam, 3 Department of Microbiology, New York University School of

Medicine, New York, New York, United States of America

* [email protected] (JML); [email protected] (ALG)

Abstract

Genetic and environmental factors shape host susceptibility to infection, but how and how

rapidly environmental variation might alter the susceptibility of mammalian genotypes

remains unknown. Here, we investigate the impacts of seminatural environments upon the

nematode susceptibility profiles of inbred C57BL/6 mice. We hypothesized that natural

exposure to microbes might directly (e.g., via trophic interactions) or indirectly (e.g., via

microbe-induced immune responses) alter the hatching, growth, and survival of nematodes

in mice housed outdoors. We found that while C57BL/6 mice are resistant to high doses of

nematode (Trichuris muris) eggs under clean laboratory conditions, exposure to outdoor

environments significantly increased their susceptibility to infection, as evidenced by

increased worm burdens and worm biomass. Indeed, mice kept outdoors harbored as many

worms as signal transducer and activator of transcription 6 (STAT6) knockout mice, which

are genetically deficient in the type 2 immune response essential for clearing nematodes.

Using 16S ribosomal RNA sequencing of fecal samples, we discovered enhanced microbial

diversity and specific bacterial taxa predictive of nematode burden in outdoor mice. We also

observed decreased type 2 and increased type 1 immune responses in lamina propria and

mesenteric lymph node (MLN) cells from infected mice residing outdoors. Importantly, in our

experimental design, different groups of mice received nematode eggs either before or after

moving outdoors. This contrasting timing of rewilding revealed that enhanced hatching of

worms was not sufficient to explain the increased worm burdens; instead, microbial

enhancement and type 1 immune facilitation of worm growth and survival, as hypothesized,

were also necessary to explain our results. These findings demonstrate that environment

can rapidly and significantly shape gut microbial communities and mucosal responses to

nematode infections, leading to variation in parasite expulsion rates among genetically simi-

lar hosts.

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