Ulcerative colitis (UC) is a chronic gastrointestinal inflammation with limited prevention or treatment options. Colonic dendritic cells (DCs), and macrophages express anti-inflammatory mechanisms that suppress inflammatory responses in the colon. Loss of these anti-inflammatory mechanisms leads to intestinal inflammation during UC. Therefore, enhancing the anti-inflammatory properties of APCs is an important approach for prevention and treatment of UC. A critical barrier to progress in the field is the identification o mechanisms that mediate induction of anti-inflammatory environment and promotion of colonic health, and most importantly, whether we can we harness these mechanisms to design interventions aimed at prevention and/or treatment of UC. Several studies have demonstrated that dietary fiber and specific gut bacteria suppress intestinal inflammations. Dietary fiber/gut microbiota effectors short chain fatty acids (SCFAs);acetate, propionate and butyrate have been speculated to promote colonic health. Among SCFAs, butyrate has received most attention for its anti-inflammatory effects. Therefore, strategies that stimulate butyrate-mediated anti-inflammatory pathways hold a promising approach to prevent and/or treat UC. Our preliminary data demonstrate that Gpr109a, a G- protein coupled receptor for butyrate (and niacin, vitamin B3) induces expression of IL-10, Aldh1a in colonic APCs and potentiate Treg induction and thus facilitates the suppression of colonic inflammation. Based on these findings, the objectives of current proposal are to identify components of the Gpr109a signaling pathway that mediates induction IL-10 and Aldh1a in colonic APCs, and demonstration that targeting of Gpr109a is an effective strategy for prevention and treatment of colonic inflammation in mouse models.
The specific aims of this proposal are as follows:
Aim 1 will test that peroxisome proliferator-activated receptor ? (PPAR?) plays an essential role in butyrate/niacin/Gpr109a-mediated induction of IL-10 and Aldh1a in colonic APCs, and induction of Tregs in colon and suppression of colonic inflammation.
Aim 2 will demonstrate that Gpr109a signaling mediated activation of PPAR? and induction of IL-10 and Aldh1a in colonic APCs and induction of Tregs in colon is ?-arrestin-1-dependent.
Aim 3 will test the hypothesis that Gpr109a ligand replaces role of dietary fiber in induction of Tregs in colon, protect colon against inflammation under dietary fiber deficiency and has a therapeutic value in prevention and treatment of UC. At successful completion, the proposed studies will uncover that Gpr109a is a key receptor that connects dietary fiber/gut bacteria to the biochemical pathways responsible for suppression of colonic inflammation and maintains a healthy colonic environment and the targeting of Gpr109a/butyrate signaling pathway can be utilized for the prevention and treatment of UC.
Dietary fiber and specific gut commensal bacteria (good bacteria) suppress intestinal inflammations. Gpr109a is a cell surface molecule that interacts with butyrate, a good bacteria derived by-product of dietary fiber. The proposed studies will uncover the mechanisms that connect dietary fiber and good bacteria to the biochemical pathways responsible for suppression of colonic inflammation and maintain a healthy colonic environment, and test whether targeting of these mechanisms is a novel therapeutic strategy for the prevention and treatment of intestinal inflammations.
|Bhatt, Brinda; Zeng, Peng; Zhu, Huabin et al. (2018) Gpr109a Limits Microbiota-Induced IL-23 Production To Constrain ILC3-Mediated Colonic Inflammation. J Immunol 200:2905-2914|
|Sharman, Sarah K; Islam, Bianca N; Hou, Yali et al. (2017) Sildenafil normalizes bowel transit in preclinical models of constipation. PLoS One 12:e0176673|
|Wang, Rui; Islam, Bianca N; Bridges, Allison et al. (2017) cGMP Signaling Increases Antioxidant Gene Expression by Activating Forkhead Box O3A in the Colon Epithelium. Am J Pathol 187:377-389|
|Zhu, Huabin; Lemos, Henrique; Bhatt, Brinda et al. (2017) Carbidopa, a drug in use for management of Parkinson disease inhibits T cell activation and autoimmunity. PLoS One 12:e0183484|
|Sivaprakasam, Sathish; Prasad, Puttur D; Singh, Nagendra (2016) Benefits of short-chain fatty acids and their receptors in inflammation and carcinogenesis. Pharmacol Ther 164:144-51|
|Sivaprakasam, S; Gurav, A; Paschall, A V et al. (2016) An essential role of Ffar2 (Gpr43) in dietary fibre-mediated promotion of healthy composition of gut microbiota and suppression of intestinal carcinogenesis. Oncogenesis 5:e238|
|Cai, Yafei; Pi, Wenhu; Sivaprakasam, Satish et al. (2015) UFBP1, a Key Component of the Ufm1 Conjugation System, Is Essential for Ufmylation-Mediated Regulation of Erythroid Development. PLoS Genet 11:e1005643|
|Gurav, Ashish; Sivaprakasam, Sathish; Bhutia, Yangzom D et al. (2015) Slc5a8, a Na+-coupled high-affinity transporter for short-chain fatty acids, is a conditional tumour suppressor in colon that protects against colitis and colon cancer under low-fibre dietary conditions. Biochem J 469:267-78|
|Zhang, M; Zhu, X; Zhang, Y et al. (2015) RCAD/Ufl1, a Ufm1 E3 ligase, is essential for hematopoietic stem cell function and murine hematopoiesis. Cell Death Differ 22:1922-34|
|Singh, Nagendra; Gurav, Ashish; Sivaprakasam, Sathish et al. (2014) Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40:128-39|