title: Chronically Elevated Levels of Short-Chain Fatty Acids Induce T Cell-Mediated Ureteritis and Hydronephrosis.
abstract: Short-chain fatty acids (SCFAs) are major products of gut microbial fermentation and profoundly affect host health and disease. SCFAs generate IL-10(+) regulatory T cells, which may promote immune tolerance. However, SCFAs can also induce Th1 and Th17 cells upon immunological challenges and, therefore, also have the potential to induce inflammatory responses. Because of the seemingly paradoxical SCFA activities in regulating T cells, we investigated, in depth, the impact of elevated SCFA levels on T cells and tissue inflammation in mice. Orally administered SCFAs induced effector (Th1 and Th17) and regulatory T cells in ureter and kidney tissues, and they induced T cell-mediated ureteritis, leading to kidney hydronephrosis (hereafter called acetate-induced renal disease, or C2RD). Kidney hydronephrosis in C2RD was caused by ureteral obstruction, which was, in turn, induced by SCFA-induced inflammation in the ureteropelvic junction and proximal ureter. Oral administration of all major SCFAs, such as acetate, propionate, and butyrate, induced the disease. We found that C2RD development is dependent on mammalian target of rapamycin activation, T cell-derived inflammatory cytokines such as IFN-γ and IL-17, and gut microbiota. Young or male animals were more susceptible than old or female animals, respectively. However, SCFA receptor (GPR41 or GPR43) deficiency did not affect C2RD development. Thus, SCFAs, when systemically administered at levels higher than physiological levels, cause dysregulated T cell responses and tissue inflammation in the renal system. The results provide insights into the immunological and pathological effects of chronically elevated SCFAs.
authors.affiliation: Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907;
authors.forename: Jeongho
authors.identifier: http://orcid.org/0000-0002-0340-9181
authors.initials: J
authors.lastname: Park
authors.affiliation: Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907; and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907.
authors.forename: Craig J
authors.identifier: http://orcid.org/0000-0001-8883-7953
authors.initials: CJ
authors.lastname: Goergen
authors.affiliation: Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907;
authors.forename: Harm
authors.identifier: http://orcid.org/0000-0002-2738-9189
authors.initials: H
authors.lastname: HogenEsch
authors.affiliation: Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907; Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907; and Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907 chkim@purdue.edu.
authors.forename: Chang H
authors.identifier: http://orcid.org/0000-0003-4618-9134
authors.initials: CH
authors.lastname: Kim
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005232:Fatty Acids, Volatile / Q000378:metabolism*; D005260:Female; D005355:Fibrosis; D000069196:Gastrointestinal Microbiome; D020869:Gene Expression Profiling; D006869:Hydronephrosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D006965:Hyperplasia; D018836:Inflammation Mediators; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012737:Sex Factors; D015398:Signal Transduction; D019346:Sodium Acetate / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome; D014526:Urethritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: D016207:Cytokines; D005232:Fatty Acids, Volatile; D018836:Inflammation Mediators; D019346:Sodium Acetate; D058570:TOR Serine-Threonine Kinases
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