title: 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.
abstract: Mammalian colon harbours trillions of bacteria under physiological conditions; this symbiosis is made possible because of a tolerized response from the mucosal immune system. The mechanisms underlying this tolerogenic phenomenon remain poorly understood. In the present study we show that Slc5a8 (solute carrier gene family 5a, member 8), a Na(+)-coupled high-affinity transporter in colon for the bacterial fermentation product butyrate, plays a critical role in this process. Among various immune cells in colon, dendritic cells (DCs) are unique not only in their accessibility to luminal contents but also in their ability to induce tolerogenic phenotype in T-cells. We found that DCs exposed to butyrate express the immunosuppressive enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and aldehyde dehydrogenase 1A2 (Aldh1A2), promote conversion of naive T-cells into immunosuppressive forkhead box P3(+) (FoxP3(+)) Tregs (regulatory T-cells) and suppress conversion of naive T-cells into pro-inflammatory interferon (IFN)-γ-producing cells. Slc5a8-null DCs do not induce IDO1 and Aldh1A2 and do not generate Tregs or suppress IFN-γ-producing T-cells in response to butyrate. We also provide in vivo evidence for an obligatory role for Slc5a8 in suppression of IFN-γ-producing T-cells. Furthermore, Slc5a8 protects against colitis and colon cancer under conditions of low-fibre intake but not when dietary fibre intake is optimal. This agrees with the high-affinity nature of the transporter to mediate butyrate entry into cells. We conclude that Slc5a8 is an obligatory link between dietary fibre and mucosal immune system via the bacterial metabolite butyrate and that this transporter is a conditional tumour suppressor in colon linked to dietary fibre content.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, U.S.A.
authors.forename: Ashish
authors.initials: A
authors.lastname: Gurav
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, U.S.A.
authors.forename: Sathish
authors.initials: S
authors.lastname: Sivaprakasam
authors.affiliation: Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A.
authors.forename: Yangzom D
authors.initials: YD
authors.lastname: Bhutia
authors.affiliation: Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Ludwigstr 43, Bad Nauheim, D-61231, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Boettger
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, U.S.A.
authors.forename: Nagendra
authors.initials: N
authors.lastname: Singh
authors.affiliation: Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, U.S.A. vadivel.ganapathy@ttuhsc.edu.
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000276:immunology; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology; D027682:Cation Transport Proteins / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D004043:Dietary Fiber / Q000494:pharmacology*; D005227:Fatty Acids / Q000235:genetics / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D006633:Histamine Antagonists / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects / Q000235:genetics; D018928:Immunity, Mucosal; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D027501:Monocarboxylic Acid Transporters; D050697:Retinal Dehydrogenase; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D027682:Cation Transport Proteins; D004043:Dietary Fiber; D005227:Fatty Acids; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006633:Histamine Antagonists; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D027501:Monocarboxylic Acid Transporters; C507459:Slc5a8 protein, mouse; D025521:Tumor Suppressor Proteins; D020148:Butyric Acid; D007371:Interferon-gamma; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C512722:Aldh1a2 protein, mouse; D050697:Retinal Dehydrogenase
keywords: 3-dioxygenase 1; bacterial metabolites; butyrate transporter; colitis; colon cancer; dendritic cell; dietary fibre; histone deacetylase; indoleamine 2; member 8 (Slc5a8)-null mouse; solute carrier gene family 5a