Immunosuppressive Treatment Alters Secretion of Ileal Antimicrobial Peptides and Gut Microbiota, and Favors Subsequent Colonization by Uropathogenic Escherichia coli.
BACKGROUND
Transplant recipients are treated with immunosuppressive (IS) therapies, which impact host-microbial interactions. We examined the impact of IS drugs on gut microbiota and on the expression of ileal antimicrobial peptides.


METHODS
Mice were treated for 14 days with prednisolone, mycophenolate mofetil, tacrolimus, a combination of these 3 drugs, everolimus, or water. Feces were collected before and after treatment initiation. Ileal samples were collected after sacrifice. Fecal and ileal microbiota were analyzed by pyrosequencing of 16S rRNA genes and enumeration of selected bacteria by culture, and C-type lectins were assessed in ileal tissues by reverse transcriptase-quantitative polymerase chain reaction.


RESULTS
Prednisolone disrupted fecal microbiota community structure, decreased Bacteroidetes, and increased Firmicutes in the feces. Prednisolone, tacrolimus, and mycophenolate mofetil modified fecal microbiota at the family level in each experimental replicate, but changes were not consistent between the replicates. In ileal samples, the genus Clostridium sensu stricto was dramatically reduced in the prednisolone and combined IS drug groups. These modifications corresponded to an altered ileal expression of C-type lectins Reg3γ and Reg3β, and of interleukin 22. Interestingly, the combined IS treatment enabled a commensal Escherichia coli to flourish, and dramatically increased colonization by uropathogenic E. coli strain 536.


CONCLUSIONS
IS treatment alters innate antimicrobial defenses and disrupts the gut microbiota, which leads to overgrowth of indigenous E. coli and facilitates colonization by opportunistic pathogens.
1 Michael Smith Laboratories, University of British Columbia, Vancouver, Canada. 2 AP-HP, Kidney transplant department, Pitié-Salpêtrière Hospital, and Univ. Pierre et Marie Curie, Sorbonne Universités, Paris, France. 3 INSERM, IAME, UMR 1137, Paris, France. 4 Department of Agricultural, Food and Nutritional Science. University of Alberta, Edmonton, Canada. 5 Univ Paris Diderot, Sorbonne Paris Cité, Paris, France.
Jérôme
J
Tourret
Benjamin P
BP
Willing
Sara
S
Dion
Jayden
J
MacPherson
Erick
E
Denamur
Brett B
BB
Finlay
D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D004359:Drug Therapy, Combination; D004927:Escherichia coli Infections / Q000276:immunology / Q000382:microbiology; D005243:Feces / Q000382:microbiology; D000069196:Gastrointestinal Microbiome / Q000187:drug effects*; D054884:Host-Pathogen Interactions; D007082:Ileum / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents / Q000633:toxicity*; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009173:Mycophenolic Acid / Q000633:toxicity*; D009894:Opportunistic Infections / Q000276:immunology / Q000382:microbiology; D011239:Prednisolone / Q000633:toxicity*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D021521:Ribotyping; D016559:Tacrolimus / Q000633:toxicity*; D013997:Time Factors; D014552:Urinary Tract Infections / Q000276:immunology / Q000382:microbiology; D056689:Uropathogenic Escherichia coli / Q000254:growth & development* / Q000276:immunology / Q000472:pathogenicity
D023181:Antimicrobial Cationic Peptides; D007166:Immunosuppressive Agents; D037181:Lectins, C-Type; D011239:Prednisolone; D009173:Mycophenolic Acid; D016559:Tacrolimus