title: Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip.
abstract: A human gut-on-a-chip microdevice was used to coculture multiple commensal microbes in contact with living human intestinal epithelial cells for more than a week in vitro and to analyze how gut microbiome, inflammatory cells, and peristalsis-associated mechanical deformations independently contribute to intestinal bacterial overgrowth and inflammation. This in vitro model replicated results from past animal and human studies, including demonstration that probiotic and antibiotic therapies can suppress villus injury induced by pathogenic bacteria. By ceasing peristalsis-like motions while maintaining luminal flow, lack of epithelial deformation was shown to trigger bacterial overgrowth similar to that observed in patients with ileus and inflammatory bowel disease. Analysis of intestinal inflammation on-chip revealed that immune cells and lipopolysaccharide endotoxin together stimulate epithelial cells to produce four proinflammatory cytokines (IL-8, IL-6, IL-1β, and TNF-α) that are necessary and sufficient to induce villus injury and compromise intestinal barrier function. Thus, this human gut-on-a-chip can be used to analyze contributions of microbiome to intestinal pathophysiology and dissect disease mechanisms in a controlled manner that is not possible using existing in vitro systems or animal models.
authors.affiliation: Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115;
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115;
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.affiliation: Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115; Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; Synthetic Biology Center, Massachusetts Institute of Technology, Cambridge, MA 02139; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142; Harvard-Massachusetts Institute of Technology Program in Health Sciences and Technology, Cambridge, MA 02139; jimjc@mit.edu don.ingber@wyss.harvard.edu.
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
authors.affiliation: Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115; Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138 jimjc@mit.edu don.ingber@wyss.harvard.edu.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Ingber
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001419:Bacteria / Q000254:growth & development; D018938:Caco-2 Cells; D006801:Humans; D045823:Ileus / Q000188:drug therapy / Q000382:microbiology / Q000503:physiopathology; D066298:In Vitro Techniques; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000382:microbiology* / Q000503:physiopathology*; D053583:Interleukin-1beta / Q000276:immunology; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000276:immunology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000382:microbiology* / Q000503:physiopathology*; D056656:Lab-On-A-Chip Devices; D064307:Microbiota / Q000502:physiology*; D008954:Models, Biological; D010528:Peristalsis / Q000187:drug effects / Q000502:physiology*; D019936:Probiotics / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D000900:Anti-Bacterial Agents; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha
keywords: gut-on-a-chip; inflammatory bowel disease; intestine; mechanical; microbiome