Laparoscopic Roux-en-Y gastric bypass (RYGB) modulates the low-grade inflammatory state associated with morbid obesity. It is unclear what molecular mechanisms underpin this modulation, given the difficulty in disentangling the changes that occur following RYGB (e.g. weight loss, malabsorption, hormonal changes). We sought to investigate whether weight loss is causally implicated with changes in serum levels of inflammatory molecules.


Using the largest genome-wide association study, we curated five genetic variants associated with weight loss following RYGB. We performed phenome-wide association studies (PheWAS) to identify other phenotypes associated with these variants. Subsequently, we used two-sample Mendelian Randomization (2SMR) to study the causal effects of weight loss on the serum levels of 382 inflammatory proteins. This is the first systematic quasi-causal investigation of weight loss following RYGB and serum markers of inflammation.


Our PheWAS analysis revealed that 4 of the 5 variants are associated with phenotypes relating to metabolism and inflammation, including insulin response and levels of C-reactive protein. After correcting for the number of tests, 2SMR of the 382 serum inflammatory markers reveals that weight loss following RYGB increases serum levels of IL-22 (beta = 0.021, p < 10-3; 95% CI, 0.010 to 0.031). Sensitivity analyses further supported the results and the causal direction.


Weight loss following RYGB causes an increase in IL-22 serum levels, suggesting that weight loss directly contributes to immune modulation following bypass. This is a proof-of-concept study highlighting the utility of genetic studies in disentangling molecular cause-and-effect following bariatric surgery.