Butyrate Protects Mice from Clostridium difficile-Induced Colitis through an HIF-1-Dependent Mechanism
José Luís Fachi,
Jaqueline de Souza Felipe,
Laís Passariello Pral,
Bruna Karadi da Silva,
Renan Oliveira Corrêa,
Mirella Cristiny Pereira de Andrade,
Denise Morais da Fonseca,
Paulo José Basso,
Niels Olsen Saraiva Câmara,
Éricka Lorenna de Sales e Souza,
Flaviano dos Santos Martins,
Suzana Eiko Sato Guima,
Andrew Maltez Thomas,
João Carlos Setubal,
Yuli Thamires Magalhães,
Fábio Luis Forti,
Thamiris Candreva,
Hosana Gomes Rodrigues,
Marcelo Bispo de Jesus,
Sílvio Roberto Consonni,
Alessandro dos Santos Farias,
Patrick Varga-Weisz,
Marco Aurélio Ramirez Vinolo
Affiliations
José Luís Fachi
Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
Jaqueline de Souza Felipe
Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
Laís Passariello Pral
Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
Bruna Karadi da Silva
Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
Renan Oliveira Corrêa
Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
Mirella Cristiny Pereira de Andrade
Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
Denise Morais da Fonseca
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-900, Brazil
Paulo José Basso
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-900, Brazil
Niels Olsen Saraiva Câmara
Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP 05508-900, Brazil
Éricka Lorenna de Sales e Souza
Laboratory of Biotherapeutics Agents, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG 31270-901, Brazil
Flaviano dos Santos Martins
Laboratory of Biotherapeutics Agents, Department of Microbiology, Institute of Biological Sciences, Federal University of Minas Gerais, Belo Horizonte, MG 31270-901, Brazil
Suzana Eiko Sato Guima
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-000, Brazil
Andrew Maltez Thomas
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-000, Brazil
João Carlos Setubal
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-000, Brazil; Biocomplexity Institute, Virginia Polytechnic Institute, Blacksburg, VA 24061, USA
Yuli Thamires Magalhães
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-000, Brazil
Fábio Luis Forti
Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP 05508-000, Brazil
Thamiris Candreva
Laboratory of Nutrients and Tissue Repair, School of Applied Sciences, University of Campinas, Limeira, SP 13484-350, Brazil
Hosana Gomes Rodrigues
Laboratory of Nutrients and Tissue Repair, School of Applied Sciences, University of Campinas, Limeira, SP 13484-350, Brazil
Marcelo Bispo de Jesus
Nano-Cell Interactions Lab, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
Sílvio Roberto Consonni
Laboratory of Citochemistry and Immunocitochemistry, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
Alessandro dos Santos Farias
Laboratory of Neuroimmunology, Department of Genetics, Evolution Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil
Patrick Varga-Weisz
Nuclear Dynamics Programme, Babraham Institute, Cambridge CB22 3AT, UK; School of Biological Sciences, University of Essex, Colchester CO4 3SQ, UK
Marco Aurélio Ramirez Vinolo
Laboratory of Immunoinflammation, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, University of Campinas, Campinas, SP 13083-862, Brazil; Corresponding author
Summary: Antibiotic-induced dysbiosis is a key factor predisposing intestinal infection by Clostridium difficile. Here, we show that interventions that restore butyrate intestinal levels mitigate clinical and pathological features of C. difficile-induced colitis. Butyrate has no effect on C. difficile colonization or toxin production. However, it attenuates intestinal inflammation and improves intestinal barrier function in infected mice, as shown by reduced intestinal epithelial permeability and bacterial translocation, effects associated with the increased expression of components of intestinal epithelial cell tight junctions. Activation of the transcription factor HIF-1 in intestinal epithelial cells exerts a protective effect in C. difficile-induced colitis, and it is required for butyrate effects. We conclude that butyrate protects intestinal epithelial cells from damage caused by C. difficile toxins via the stabilization of HIF-1, mitigating local inflammatory response and systemic consequences of the infection. : Fachi et al. demonstrate that butyrate is able to protect the intestinal epithelium from the damage caused by Clostridium difficile toxins by stabilizing HIF-1 and increasing tight junctions, which reduces intestinal epithelial permeability, thus inhibiting intestinal inflammation and bacterial translocation. Keywords: short chain fatty acids, microbiota, hypoxia, colitis, intestinal epithelial cells, infection
