Cys34 Adductomics Links Colorectal Cancer with the Gut Microbiota and Redox Biology.

Chronic inflammation is an established risk factor for colorectal cancer (CRC). To study reactive products of gut inflammation and redox signaling on CRC development we used untargeted adductomics to detect adduct features in pre-diagnostic serum from the EPIC-Italy cohort. We focused on modifications to Cys34 in human serum albumin (HSA), which is responsible for scavenging small reactive electrophiles that might initiate cancers. Employing a combination of statistical methods, we selected seven Cys34 adducts associated with CRC, as well as BMI (a well-known risk factor). Five adducts were more abundant in CRC cases than controls and clustered with each other, suggesting a common pathway. Since two of these adducts were Cys34 modifications by methanethiol, a microbial-human co-metabolite, and crotonaldehyde, a product of lipid peroxidation, these findings further implicate infiltration of gut microbes into the intestinal mucosa and the corresponding inflammatory response as causes of CRC. The other two associated adducts were Cys34 disulfides of homocysteine that were less abundant in CRC cases than controls and may implicate homocysteine metabolism as another causal pathway. The selected adducts and BMI ranked higher as potentially causal factors than variables previously associated with CRC (smoking, alcohol consumption, physical activity and total meat consumption). Regressions of case-control differences in adduct levels on days to diagnosis showed no statistical evidence that disease progression, rather than causal factors at recruitment, contributed to the observed differences. These findings support the hypothesis that infiltration of gut microbes into the intestinal mucosa and the resulting inflammation are causal factors for CRC.