Various studies have linked obesity to poor outcomes after organ transplantation: delayed allograft function, higher rates of acute rejection, and decreased survival. Some research suggests patients with obesity who undergo bariatric surgery before transplantation fare better.
Researchers at Brigham and Women’s Hospital previously reported in eLife that serum levels of a bile acid called taurodeoxycholic acid (TDCA) and the amino acid valine were depleted in obese mice and were restored when the animals underwent sleeve gastrectomy. They also observed significant weight loss and reversed insulin resistance in obese mice treated with TDCA and valine.
In a new animal study, published in the American Journal of Transplantation, Stefan G. Tullius, MD, PhD, chief of the Division of Transplant Surgery at the Brigham, Markus Quante, MD, of the University Hospital Tuebingen, Jasper Iske, of the Institute of Transplant Immunology at Hannover Medical School, and colleagues present evidence that TDCA/valine may be a noninvasive alternative to bariatric surgery for improving transplant outcomes in patients with obesity.
Bariatric Surgery Prolonged Graft Survival
The researchers began by performing sleeve gastrectomy just prior to skin transplantation in a mouse model of diet-induced obesity. As expected, skin grafts were rejected significantly more rapidly in obese mice than lean mice.
Graft survival in sham-operated obese mice was the same as in obese controls. This suggested the prolongation in graft survival after bariatric surgery reflects anti-inflammatory effects linked to weight loss and/or metabolic changes.
Effects of Bariatric Surgery on Alloimmunity
In exploring the anti-inflammatory effects of sleeve gastrectomy, the team found it attenuated T cell–mediated alloimmune responses, which is presumably what prolongs graft survival:
- Before graft rejection, obese mice exhibited significantly increased interferon-γ production by both splenic CD4+ and CD8+ T cells
- In contrast, obese mice that underwent sleeve gastrectomy displayed a dramatic decrease in IFN-γ expression, comparable with levels observed in lean controls, and increased levels of interleukin-10, which is well established to be anti-inflammatory
TDCA/Valine Prolonged Graft Survival
The researchers performed skin transplantation on obese mice, then gave them daily injections of either TDCA or the combination of TDCA and valine:
- Administration of TDCA alone prolonged skin graft survival significantly
- TDCA/valine treatment resulted in an even more pronounced prolongation of graft survival, comparable to that in obese mice that underwent sleeve gastrectomy
- TDCA/valine administered to lean animals did not affect graft survival
Immunomodulatory Effects of TDCA/Valine
Obese mice that were treated with TDCA/valine after transplantation consistently exhibited:
- Reduced CD4+ and CD8+ alloimmune responses
- Reduced levels of donor-specific antibodies
- Increased numbers of regulatory T cells
- Increased production of IL-10
Further experiments suggested the mechanism of the immunomodulatory effects of TDCA/valine: it affected the interaction of macrophages and T cells by restraining pro-inflammatory M1-macrophage polarization through TGR5 (a bile acid receptor) and cAMP signaling.
TDCA/valine treatment may represent a novel, noninvasive alternative to bariatric surgery for patients awaiting an organ transplant or for those who gain a substantial amount of weight after transplantation.