A Role for Folate in Microbiome-Linked Control of Autoimmunity
Christine Mölzer, Heather M. Wilson, Lucia Kuffová, John V. Forrester
Abstract
The microbiome exerts considerable control over immune homeostasis and influences susceptibility to autoimmune and autoinflammatory disease (AD/AID) such as inflammatory bowel disease (IBD), multiple sclerosis (MS), type 1 diabetes (T1D), psoriasis, and uveitis. In part, this is due to direct effects of the microbiome on gastrointestinal (GI) physiology and nutrient transport, but also to indirect effects on immunoregulatory controls, including induction and stabilization of T regulatory cells ( <a:math xmlns:a="http://www.w3.org/1998/Math/MathML" id="M1"><a:msub><a:mrow><a:mi>T</a:mi></a:mrow><a:mrow><a:mtext>reg</a:mtext></a:mrow></a:msub></a:math> ). Secreted bacterial metabolites such as short-chain fatty acids (SCFA) are under intense investigation as mediators of these effects. In contrast, folate (vitamin B9), an essential micronutrient, has attracted less attention, possibly because it exerts global physiological effects which are difficult to differentiate from specific effects on the immune system. Here, we review the role of folate in AD/AID with some emphasis on sight-threatening autoimmune uveitis. Since folate is required for the generation and maintenance of <c:math xmlns:c="http://www.w3.org/1998/Math/MathML" id="M2"><c:msub><c:mrow><c:mi>T</c:mi></c:mrow><c:mrow><c:mtext>reg</c:mtext></c:mrow></c:msub></c:math> , we propose that one mechanism for microbiome-based control of AD/AID is via folate-dependent induction of GI tract <e:math xmlns:e="http://www.w3.org/1998/Math/MathML" id="M3"><e:msub><e:mrow><e:mi>T</e:mi></e:mrow><e:mrow><e:mtext>reg</e:mtext></e:mrow></e:msub></e:math> , particularly colonic <g:math xmlns:g="http://www.w3.org/1998/Math/MathML" id="M4"><g:msub><g:mrow><g:mi>T</g:mi></g:mrow><g:mrow><g:mtext>reg</g:mtext></g:mrow></g:msub></g:math> , via anergic T cells ( <i:math xmlns:i="http://www.w3.org/1998/Math/MathML" id="M5"><i:msub><i:mrow><i:mi>T</i:mi></i:mrow><i:mrow><i:mtext>an</i:mtext></i:mrow></i:msub></i:math> ). Hence, folate supplementation has potential prophylactic and/or therapeutic benefit in AID/AD.