Taurodeoxycholic acid and valine reverse obesity-associated augmented alloimmune responses and prolong allograft survival.
Am J Transplant
; 22(2): 402-413, 2022 02.
Article
in En
| MEDLINE
| ID: mdl-34551205
ABSTRACT
Obesity initiates a chronic inflammatory network linked to perioperative complications and increased acute rejection rates in organ transplantation. Bariatric surgery is the most effective treatment of obesity recommended for morbidly obese transplant recipients. Here, we delineated the effects of obesity and bariatric surgery on alloimmunity and transplant outcomes in diet-induced obese (DIO) mice. Allograft survival was significantly shorter in DIO-mice. When performing sleeve gastrectomies (SGx) prior to transplantation, we found attenuated T cell-derived alloimmune responses resulting in prolonged allograft survival. Administering taurodeoxycholic acid (TDCA) and valine, metabolites depleted in DIO-mice and restored through SGx, prolonged graft survival in DIO-mice comparable with SGx an dampened Th1 and Th17 alloimmune responses while Treg frequencies and CD4+ T cell-derived IL-10 production were augmented. Moreover, in recipient animals treated with TDCA/valine, levels of donor-specific antibodies had been reduced. Mechanistically, TDCA/valine restrained inflammatory M1-macrophage polarization through TGR5 that compromised cAMP signaling and inhibited macrophage-derived T cell activation. Consistently, administering a TGR5 agonist to DIO-mice prolonged allograft survival. Overall, we provide novel insights into obesity-induced inflammation and its impact on alloimmunity. Furthermore, we introduce TDCA/valine as a noninvasive alternative treatment for obese transplant patients.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Obesity, Morbid
/
Heart Transplantation
Type of study:
Etiology_studies
/
Risk_factors_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Am J Transplant
Journal subject:
TRANSPLANTE
Year:
2022
Document type:
Article