A Role for Folate in Microbiome-Linked Control of Autoimmunity

Figure 2

Bacterial route of de novo folic acid synthesis. Certain commensals of the human colonic flora produce folate de novo through the chorismate pathway (from phosphoenolpyruvate + guanosine triphosphate, GTP)₁. Further, 77% of the bacterial genome is capable of synthesizing folate using freely available p-aminobenzoic acid (pABA) and dihydropteroate diphosphate (pteridine)₂ [84]. The pathway engages a series of enzymatic reactions (red protein symbols) including dihydropteroate synthetase and dihydrofolate synthetase. The resulting dihydrofolate (via the dihydropteroate intermediate) must be enzymatically reduced (through dihydrofolate reductase) to generate biologically active tetrahydrofolate. This process can be blocked by the folate antagonist methotrexate (Mtx), used for controlling some forms of autoimmune disease including anterior uveitis. Folate metabolites synthesized by commensals are used by the bacteria themselves (e.g., for DNA-synthesis or anabolic pathways such as generation of amino acids, AA). The remaining unused folates are released into the gut lumen and absorbed in a receptor-mediated fashion absorption into the circulation.