Contribution of microbially synthesized vitamers to folate status and impact on inflammatory bowel diseases

• Applicant: Professor Dr. Michael Blaut, since 3/2016
• Subject Area: Nutritional Sciences ; Gastroenterology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249021683

Inflammatory bowel diseases (IBD) are characterized by an undulating course of activity, with a low rate of spontaneous remission of the lesions and a constant threat of relapsing attacks. Incidence rates of IBD increased dramatically in parallel with social development but etiology of the disease is unclear. Although genetic predisposition in IBD patients has been clearly established, environmental factors are necessary contributors to IBD pathogenesis. Microbial dysbiosis is a hallmark in IBD subjects. Folate is one of the key vitamins involved in normal cellular function, growth, and development. Subclinical but biochemically relevant folate deficiency occurs in 40% of IBD patients. Folate deficiency may be directly related to the extent of the mucosal damage or result from inadequate intake, increased nutritional requirements due to the inflammatory condition, intake of medication, or genetic abnormalities. Dysregulation of the expression of the FOLH1 gene involved in folate metabolism has been suggested to be a predictive biomarker for the ileal Crohn s disease (CD) phenotype. Although evidence is accumulating that bacterially derived folates could impact the folate status of the host, their production in the gut has been largely ignored. Preliminary study in a mouse model of colitis inoculated with a folate producer bacterial commensal indicated that bacterially synthesized folates could be linked to the reduction of inflammation, but mechanisms of action were not elucidated. Our hypothesis is that serum folate deficiency in ileal CD subjects reflects an altered folate metabolism in the gastrointestinal tract due to a host and/or a gastrointestinal microbiota component. Furthermore, we hypothesize that altered folate metabolism in the gastrointestinal tract contribute to microbial dysbiosis and increased inflammation in ileal CD patients.With the present project, we will use a top down-approach, to first define the quantity as well as the different forms of fecal folate vitamers obtained from ileal CD patients with different serum folate status, and to characterize microbiota composition using Next Generation sequencing technologies. In a second stage, we will investigate the potential of the fecal microbiota of ileal CD patients with high and low serum folate status to synthesize folate vitamers by performing fermentation of fecal samples inoculated with different folate precursors and characterize microbial changes by pyrosequencing. Possible follow up of this study include the use of a mouse model of ileal CD inoculated with fecal microbiota from previously enrolled patients, in order to evaluate the impact of the fecal microbiota on both folate status and inflammation. The results should lead to a greater understanding of the role of bacterially synthesized folates and will facilitate the development of strategies to alter the gut microbiota in an effort to improve folate status and to prevent or suppress host inflammation.

• DFG Programme: Research Grants
• International Connection: USA
• Participating Persons: Dr. Wolfram Engst; Bärbel Gruhl; Privatdozent Dr. Gunnar Loh; Ruth Ann Luna, Ph.D.; Professorin Dr. Britta Siegmund; Professor Dr. James Versalovic
• Ehemalige Antragstellerin: Delphine Saulnier, Ph.D., until 2/2016