Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner
Marianne R. Spalinger, … , Gerhard Rogler, Michael Scharl
Marianne R. Spalinger, … , Gerhard Rogler, Michael Scharl
Published May 20, 2019
Citation Information: J Clin Invest. 2019;129(6):2527-2541. https://doi.org/10.1172/JCI123263.
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Research Article Gastroenterology

Protein tyrosine phosphatase non-receptor type 22 modulates colitis in a microbiota-dependent manner

Abstract

The gut microbiota is crucial for our health, and well-balanced interactions between the host’s immune system and the microbiota are essential to prevent chronic intestinal inflammation, as observed in inflammatory bowel diseases (IBD). A variant in protein tyrosine phosphatase non-receptor type 22 (PTPN22) is associated with reduced risk of developing IBD, but promotes the onset of autoimmune disorders. While the role of PTPN22 in modulating molecular pathways involved in IBD pathogenesis is well studied, its impact on shaping the intestinal microbiota has not been addressed in depth. Here, we demonstrate that mice carrying the PTPN22 variant (619W mice) were protected from acute dextran sulfate sodium (DSS) colitis, but suffered from pronounced inflammation upon chronic DSS treatment. The basal microbiota composition was distinct between genotypes, and DSS-induced dysbiosis was milder in 619W mice than in WT littermates. Transfer of microbiota from 619W mice after the first DSS cycle into treatment-naive 619W mice promoted colitis, indicating that changes in microbial composition enhanced chronic colitis in those animals. This indicates that presence of the PTPN22 variant affects intestinal inflammation by modulating the host’s response to the intestinal microbiota.

Authors

Marianne R. Spalinger, Thomas S.B. Schmidt, Marlene Schwarzfischer, Larissa Hering, Kirstin Atrott, Silvia Lang, Claudia Gottier, Annelies Geirnaert, Christophe Lacroix, Xuezhi Dai, David J. Rawlings, Andrew C. Chan, Christian von Mering, Gerhard Rogler, Michael Scharl

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Figure 6

Genotype-specific effects of DSS treatment on the gut microbiota.

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Genotype-specific effects of DSS treatment on the gut microbiota. (A) Di...
(A) Distinct compositional shifts in each genotype relative to H2O-treated controls were observed upon 1 cycle of DSS treatment (acute colitis), following a 10-day recovery phase, and upon 4 DSS cycles (chronic colitis). (B) These shifts were conferred to WT mice cohoused with PTPN22–/– or 619W mice, but not vice versa. Note that mice in A were not cohoused, whereas in B, WT mice were cohoused with PTPN22–/– or 619W, and vice versa. (C) Compositional shifts could be differentially attributed to the factors genotype, treatment, and time point, as indicated by R2 values in PERMANOVA tests on data subsets. Note that for illustration purposes, only 1 of several replicate experiments is shown in A; the total number of mice per group used in statistical tests is reported on the right and in Supplemental Table 2.