title: Soluble bioactive microbial mediators regulate proteasomal degradation and autophagy to protect against inflammation-induced stress.
abstract: Bifidobacterium breve and other Gram-positive gut commensal microbes protect the gastrointestinal epithelium against inflammation-induced stress. However, the mechanisms whereby these bacteria accomplish this protection are poorly understood. In this study, we examined soluble factors derived from Bifidobacterium breve and their impact on the two major protein degradation systems within intestinal epithelial cells, proteasomes and autophagy. Conditioned media from gastrointestinal Gram-positive, but not Gram-negative, bacteria activated autophagy and increased expression of the autophagy proteins Atg5 and Atg7 along with the stress response protein heat shock protein 27. Specific examination of media conditioned by the Gram-positive bacterium Bifidobacterium breve (Bb-CM) showed that this microbe produces small molecules (<3 kDa) that increase expression of the autophagy proteins Atg5 and Atg7, activate autophagy, and inhibit proteasomal enzyme activity. Upregulation of autophagy by Bb-CM was mediated through MAP kinase signaling. In vitro studies using C2BBe1 cells silenced for Atg7 and in vivo studies using mice conditionally deficient in intestinal epithelial cell Atg7 showed that Bb-CM-induced cytoprotection is dependent on autophagy. Therefore, this work demonstrates that Gram-positive bacteria modify protein degradation programs within intestinal epithelial cells to promote their survival during stress. It also reveals the therapeutic potential of soluble molecules produced by these microbes for prevention and treatment of gastrointestinal disease.
authors: Department of Medicine, Inflammatory Bowel Disease Research Center, The University of Chicago, Chicago, Illinois; Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors: Yuhei
authors: Y
authors: Inaba
authors: Department of Medicine, Inflammatory Bowel Disease Research Center, The University of Chicago, Chicago, Illinois; Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors: Nobuhiro
authors: N
authors: Ueno
authors: Department of Medicine, Inflammatory Bowel Disease Research Center, The University of Chicago, Chicago, Illinois; Division of Life Style and Digestive Diseases, Kagoshima Medical University, Kagoshima, Japan.
authors: Masatsugu
authors: M
authors: Numata
authors: Department of Medicine, Inflammatory Bowel Disease Research Center, The University of Chicago, Chicago, Illinois.
authors: Xiaorong
authors: X
authors: Zhu
authors: Department of Medicine, Inflammatory Bowel Disease Research Center, The University of Chicago, Chicago, Illinois.
authors: Jeannette S
authors: JS
authors: Messer
authors: Department of Microbiology and Immunology, Indiana University School of Medicine-South Bend, South Bend, Indiana.
authors: David L
authors: DL
authors: Boone
authors: Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors: Mikihiro
authors: M
authors: Fujiya
authors: Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan.
authors: Yutaka
authors: Y
authors: Kohgo
authors: Department of Medicine, Inflammatory Bowel Disease Research Center, The University of Chicago, Chicago, Illinois.
authors: Mark W
authors: MW
authors: Musch
authors: Department of Medicine, Inflammatory Bowel Disease Research Center, The University of Chicago, Chicago, Illinois; echang@medicine.bsd.uchicago.edu.
authors: Eugene B
authors: EB
authors: Chang
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism; D000071193:Autophagy-Related Protein 7 / Q000235:genetics / Q000378:metabolism; D000069984:Bifidobacterium breve; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D007249:Inflammation / Q000378:metabolism / Q000382:microbiology; D007413:Intestinal Mucosa / Q000378:metabolism / Q000382:microbiology*; D051379:Mice; D018345:Mice, Knockout; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*
chemical_list: D000071187:Autophagy-Related Protein 5; D046988:Proteasome Endopeptidase Complex; D000071193:Autophagy-Related Protein 7
keywords: Atg5; Atg7; cell death; cell survival; host-microbe interaction; inflammatory bowel diseases; microbiota; microflora; mucosal inflammation; peptidoglycan