Hypothesis: The gut microbiota regulates systemic immunity. Different characteristics of the microbiota can be defined that have pro- or anti-inflammatory effects. We tested the hypothesis that different gut microbiota influence the survival of completely MHC mismatched murine cardiac transplants.

Methods: BALB/c hearts were transplanted to C57BL/6 (B6) mice. Mice were fed antibiotics (kanamycin, gentamicin, colistin, metronidazole, vancomycin) in drinking water on d -6 to -1 before transplant. Fecal pellets from three groups of mice were suspended at 200 mg/mL in saline: healthy B6, female mice on d11 of pregnancy, and colitic T cell receptor transgenic mice that spontaneously develop colitis. Fecal microbiota transplantation (FMT) was performed on d0 by oral gavage of 200 μL of pellet suspension. Other groups received immunosuppression with anti-CD40L (250 μg iv d0) or tacrolimus (2 mg/kg/d sc d0-40) + FMT. Fecal pellets were collected after grafting from transplanted mice, and their microbiota analyzed using 16S rRNA gene sequencing. Cardiac allografts were assessed for survival, harvested at d40 or rejection, and stained with H&E and Masson's Trichrome.

Results: Antibiotics and FMT alone did not alter graft survival or histology. Among mice treated with antibiotics, FMT, and anti-CD40L, FMT with pregnant stool resulted in significantly better allograft survival and improved histology compared to FMT with colitic stool, antibiotics only, or anti-CD40L only. Among mice treated with antibiotics, FMT, and tacrolimus, mice that received colitic stool had significantly worse graft histology compared to mice that received pregnant or normal stool. 16S rRNA gene analysis of FMT source samples and transplant recipient samples revealed highly significant differences in the bacterial community structures of normal, colitic, and pregnant fecal samples as determined by bacterial composition and relative abundance, principle component analysis and hierarchical clustering. Bacteria from the genus Bifidobacterium were absent in colitic, yet present in normal and pregnant source samples and transplant recipient samples, indicating a possible anti-inflammatory effect of these bacteria.

Conclusion: The microbiota has a profound systemic effect on immunity with consequences for graft survival, rejection, and inflammation. Additionally, pro- and anti-inflammatory fecal microbiota and specific components of the microbiota can be defined and manipulated.μμμ

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