Incidence of pediatric inflammatory bowel disease (IBD) is increasing worldwide. The causative mechanisms involved in the disease pathogenesis are currently elusive. However, induced pathogenic inflammation due to malnutrition, impacting the ileal epithelium homeostasis, may contribute to disease manifestation. Thus, understanding the dietary risk factors involved in pediatric IBD is urgent. Diet containing micronutrients (e.g., vitamins) functionally controls the genomic mechanisms of the neonatal intestinal cells. Deficiency in host nutritional circuitry, notably during the pre and postnatal periods of pregnancy may not only impair the host- bacteria interaction controlling the gut homeostasis but also deteriorate the metabolic networks required for bacterial syntrophic growth. Vitamin B12 (VB12) is synthesized by some intestinal bacteria. VB12 deficiency may dysfunction ileal epithelial cells (iECs) expressing VB12 receptors (e.g., cubilin, megalin) with severe intestinal disorders post-birth. We recently reported that the newly discovered Propionibacterium strain, P. UF1, regulates phagocytic and protective T cell responses to intestinal pathogen infection in newborn and adult mice. Further, P. UF1 produces VB12 and crucially controls the biosynthesis of this vitamin through a novel putative riboswitch, cbiMCbl. We now demonstrate that VB12 critically controls ileal epithelial cell (iEC) molecular and metabolic homeostasis, particularly the mitochondrial respiration, to potentially limit aerobic Salmonella (STm) infection in newborn mice. The objectives of this research proposal are to further elucidate that (a) VB12 functionally sustains iEC function during STm infection, (b) VB12 regulates oxygen levels in iECs resulting in luminal hypoxia that controls aerobic STm infection and (c) VB12 fortifies ileal epithelium integrity and supports effector T helper (Th) cell response to STm challenge. The overarching hypotheses are: (1) VB12 reprograms the molecular machinery of iECs during STm infection, (2) regulation of ileal oxygenation by VB12 induces the luminal hypoxia that limits the aerobic STm infection and (3) controlling iEC-function by VB12 contributes to epithelial integrity and protective Th cell response to aerobic STm infection. The following Specific Aims will test these hypotheses: 1. Elucidate the molecular mechanisms sustaining iEC function by VB12 during STm infection. 2. Elaborate on the mitochondrial oxygen regulation in iECs by VB12 controlling aerobic STm infection. And 3. Investigate barrier integrity regulation by VB12 and protective Th cell response to STm infection. Results obtained from the proposed mechanistic studies will be the first in-depth report underscoring VB12 potency in regulating iEC function for a sustainable therapeutic strategy that could potentially improve neonatal health.
We will explore the relevance of vitamin B12 (VB12) in the regulation of the ileal epithelium homeostasis that may control pathogen infection causing intestinal tissue damage. The proposed research studies may provide important insights into VB12 ability to potentially improve the health of newborns through a sustainable therapeutic regimen.
| Colliou, Natacha; Ge, Yong; Gong, Minghao et al. (2018) Regulation of Th17 cells by P. UF1 against systemic Listeria monocytogenes infection. Gut Microbes 9:279-287 |
| Colliou, Natacha; Ge, Yong; Sahay, Bikash et al. (2017) Commensal Propionibacterium strain UF1 mitigates intestinal inflammation via Th17 cell regulation. J Clin Invest 127:3970-3986 |
