Translocation of Viable Gut Microbiota to Mesenteric Adipose Drives Formation of Creeping Fat in Humans

Connie W Y Ha; Anthony Martin; Gregory D Sepich-Poore; Baochen Shi; Yizhou Wang; Kenneth Gouin; Gregory Humphrey; Karenina Sanders; Yasiru Ratnayake; Kelvin S L Chan; Gustaf Hendrick; J R Caldera; Christian Arias; Jacob E Moskowitz; Shannan J Ho Sui; Shaohong Yang; David Underhill; Matthew J Brady; Simon Knott; Kelly Kaihara; Michael J Steinbaugh; Huiying Li; Dermot P B McGovern; Rob Knight; Phillip Fleshner; Suzanne Devkota

doi:10.1016/j.cell.2020.09.009

Translocation of Viable Gut Microbiota to Mesenteric Adipose Drives Formation of Creeping Fat in Humans

Cell. 2020 Oct 29;183(3):666-683.e17. doi: 10.1016/j.cell.2020.09.009. Epub 2020 Sep 28.

Authors

Connie W Y Ha¹, Anthony Martin¹, Gregory D Sepich-Poore², Baochen Shi³, Yizhou Wang⁴, Kenneth Gouin⁵, Gregory Humphrey⁶, Karenina Sanders⁶, Yasiru Ratnayake⁷, Kelvin S L Chan⁷, Gustaf Hendrick¹, J R Caldera⁸, Christian Arias¹, Jacob E Moskowitz¹, Shannan J Ho Sui⁹, Shaohong Yang¹, David Underhill¹⁰, Matthew J Brady¹¹, Simon Knott⁵, Kelly Kaihara¹², Michael J Steinbaugh⁹, Huiying Li³, Dermot P B McGovern¹, Rob Knight¹³, Phillip Fleshner¹⁴, Suzanne Devkota¹⁵

Affiliations

¹ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
² Department of Bioengineering, University of California San Diego, La Jolla, California 92093, USA.
³ Department of Molecular and Medical Pharmacology, Crump Institute for Molecular Imaging, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
⁴ Applied Genomics, Computation and Translational Core, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁵ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Applied Genomics, Computation and Translational Core, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁶ Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA.
⁷ Trabeya Pte. Ltd., Singapore 018989, Singapore.
⁸ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
⁹ Harvard Chan Bioinformatics Core, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
¹⁰ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹¹ Department of Medicine, Section of Endocrinology and Metabolism, The University of Chicago, Chicago, IL 60637, USA.
¹² Bio-Rad Genomics, Hercules, CA 94547, USA.
¹³ Department of Pediatrics, University of California San Diego, La Jolla, CA 92093, USA; Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA 92093, USA.
¹⁴ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Colorectal Surgery, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
¹⁵ F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. Electronic address: suzanne.devkota@cshs.org.

Abstract

A mysterious feature of Crohn's disease (CD) is the extra-intestinal manifestation of "creeping fat" (CrF), defined as expansion of mesenteric adipose tissue around the inflamed and fibrotic intestine. In the current study, we explore whether microbial translocation in CD serves as a central cue for CrF development. We discovered a subset of mucosal-associated gut bacteria that consistently translocated and remained viable in CrF in CD ileal surgical resections, and identified Clostridium innocuum as a signature of this consortium with strain variation between mucosal and adipose isolates, suggesting preference for lipid-rich environments. Single-cell RNA sequencing characterized CrF as both pro-fibrotic and pro-adipogenic with a rich milieu of activated immune cells responding to microbial stimuli, which we confirm in gnotobiotic mice colonized with C. innocuum. Ex vivo validation of expression patterns suggests C. innocuum stimulates tissue remodeling via M2 macrophages, leading to an adipose tissue barrier that serves to prevent systemic dissemination of bacteria.

Keywords: Crohn’s disease; adipogenesis; creeping fat; fibrosis; human microbiome; ileum; inflammatory bowel diseases; macrophages; mesenteric adipose; translocation.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / microbiology*
Adipose Tissue / pathology
Animals
Bacterial Translocation*
Biodiversity
Biomarkers / metabolism
Cell Polarity
Cells, Cultured
Colitis, Ulcerative / pathology
Crohn Disease / microbiology
Crohn Disease / pathology
Gastrointestinal Microbiome* / genetics
Gene Expression Regulation
Germ-Free Life
Humans
Ileum / microbiology
Ileum / pathology
Lipopolysaccharides / metabolism
Macrophages / metabolism
Mesentery / microbiology*
Metagenome
Metagenomics
Mice
Mice, Inbred C57BL
Phenotype
RNA, Ribosomal, 16S / genetics
Stem Cells / metabolism

Substances

Biomarkers
Lipopolysaccharides
RNA, Ribosomal, 16S

Abstract

Publication types

MeSH terms

Substances

Grants and funding