Loss of PTPN22 abrogates the beneficial effect of cohousing-mediated fecal microbiota transfer in murine colitis

Marianne R Spalinger,Larissa Hering,Claudia Gottier,Marlene Schwarzfischer,Annelies Geirnaert,Silvia Lang,Anica Sayoc,Michael Scharl,David Rawlings,Declan F Mccole,Ali Shawki,Xuezhi Dai,Andrew A Chan,Alina Santos,Gerhard Rogler,Gabriel E Leventhal,Katharina Bäbler,Christophe Lacroix

doi:10.1038/s41385-019-0201-1

Abstract

Fecal microbiota transfer (FMT) is a very efficient approach for the treatment of severe and recurring C. difficile infections. However, the beneficial effect of FMT in other disorders such as ulcerative colitis (UC) or Crohn’s disease remains unclear. Furthermore, it is currently unknown how disease-associated genetic variants in donors or recipients influence the effect of FMT. We found that bacteria-transfer from wild-type (WT) donors via cohousing was efficient in inducing recovery from colitis in WT mice, but not in mice deficient in protein-tyrosine phosphatase non-receptor type 22 (PTPN22), a known risk gene for several chronic inflammatory diseases. Also cohousing of PTPN22-deficient mice with diseased WT mice failed to induce faster recovery. Our data indicate that the genetic background of the donor and the recipient influences the outcome of microbiota transfer, and offers a potential explanation why transfer of fecal microbes from some, but not all donors is efficient in UC patients.

Highlights

The human intestine is populated with up to 1014 bacteria that form a complex ecosystem and have a tremendous impact on our health.[1,2] For several diseases, including obesity, diabetes, rheumatoid arthritis, liver diseases, and inflammatory bowel disease (IBD), shifts in the intestinal microbiota composition and a reduction in overall bacterial diversity as compared with healthy individuals have been described.[3,4] it is still unclear whether those changes are the result of the underlying condition or if they functionally contribute to disease development/ progression.[5]Therapeutic transfer of fecal microbiota from healthy subjects to patients suffering from mainly intestinal diseases is increasingly attempted
This suggests that cohousing results in transfer of microbiota, which might crucially contribute to the observed faster recovery
In this study, we investigated the therapeutic concept of microbiota transfer via cohousing using mouse colitis models and assessed how transfer of healthy microbiota affects recovery from intestinal inflammation

Summary

Introduction

The human intestine is populated with up to 1014 bacteria that form a complex ecosystem and have a tremendous impact on our health.[1,2] For several diseases, including obesity, diabetes, rheumatoid arthritis, liver diseases, and inflammatory bowel disease (IBD), shifts in the intestinal microbiota composition and a reduction in overall bacterial diversity as compared with healthy individuals have been described.[3,4] it is still unclear whether those changes are the result of the underlying condition or if they functionally contribute to disease development/ progression.[5]Therapeutic transfer of fecal microbiota from healthy subjects to patients suffering from mainly intestinal diseases is increasingly attempted. In severe cases of recurring Clostridium difficile infections, fecal microbiota transplantation (FMT) has been shown to be very efficient,[6,7,8] but the therapeutic value of FMT in other intestinal and non-intestinal disorders is still unresolved,[9] and conflicting data from clinical trials using FMT in IBD have been reported.[10,11,12,13,14] There is evidence that in the IBD subform ulcerative colitis (UC), the successful outcome of FMT might depend on the microbial composition of the donor,[15] leading to the phenomenon of so-called “super-donors” that induce remission in more than 90% of transplanted cases, while most donors have success rates below 50%.10–14,16. Given the impact of genetic variants on IBD pathogenesis, the genetic background of the host as well as of the donor might exert a prominent role in therapeutic success

Methods

Results

Conclusion