Enhanced citrate consumption increases colon permeability in C57BL/6J mice by affecting gut microbiota and activating HIF-1α

Citrate is a ubiquitously used food additive added to almost all industrialized alimentary product regardless the degree of processing. Indeed, citrate consumption has increased over the years since it is classified as a “generally recognized as safe” product, with no limitations to its use. Recently, we have shown that enhanced citrate consumption by mice impact physiology, impairing glucose tolerance and promoting low-grade systemic inflammation. Here, we treated mice for 24 hours or 12 weeks with standard chow diet enhanced with 40 mg citrate per gram of food, doubling its standard amount, and evaluated the colon of these animals and gut microbiota. Enhance citrate consumption for both 24 hours or 12 weeks promoted similar outcomes on mouse, as impairing glucose tolerance, thinning mucosal barrier and augmenting colon permeability and inflammation. Moreover, there is a robust change in gut microbiota population, that increased total bacteria with decreased variability, showing an obesogenic-like profile. Furthermore, enhanced citrate consumption upregulated the plasma membrane citrate transporter SLC13a5, HIF-1α and ATP: citrate lyase, boosting cytosolic citrate metabolism. In the end, we propose that enhanced citrate consumption increases cytosolic Acetyl-CoA formation, promoting lipid synthesis and acetylation of proteins and nucleic acids, and thus favoring epigenetic modifications.