title: Critical role of microbiota within cecal crypts on the regenerative capacity of the intestinal epithelium following surgical stress.
abstract: Cecal crypts represent a unique niche that are normally occupied by the commensal microbiota. Due to their density and close proximity to stem cells, microbiota within cecal crypts may modulate epithelial regeneration. Here we demonstrate that surgical stress, a process that invariably involves a short period of starvation, antibiotic exposure, and tissue injury, results in cecal crypt evacuation of their microbiota. Crypts devoid of their microbiota display pathophysiological features characterized by abnormal stem cell activation as judged by leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) staining, expansion of the proliferative zone toward the tips of the crypts, and an increase in apoptosis. In addition, crypts devoid of their microbiota display loss of their regenerative capacity as assessed by their ability to form organoids ex vivo. When a four-member human pathogen community isolated from the stool of a critically ill patient is introduced into the cecum of mice with empty crypts, crypts become occupied by the pathogens and further disruption of crypt homeostasis is observed. Fecal microbiota transplantation restores the cecal crypts' microbiota, normalizes homeostasis within crypts, and reestablishes crypt regenerative capacity. Taken together, these findings define an emerging role for the microbiota within cecal crypts to maintain epithelial cell homeostasis in a manner that may enhance recovery in response to the physiological stress imposed by the process of surgery.
  This study provides novel insight into the process by which surgical injury places the intestinal epithelium at risk for colonization by pathogenic microbes and impairment of its regenerative capacity via loss of its microbiota. We show that fecal transplant restores crypt homeostasis in association with repopulation of the microbiota within cecal crypts.
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zaborin
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois.
authors.forename: Monika
authors.initials: M
authors.lastname: Krezalek
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Hyoju
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Defazio
authors.affiliation: Pathology, Pritzker School of Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Namrata
authors.initials: N
authors.lastname: Setia
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois.
authors.forename: Natalia
authors.initials: N
authors.lastname: Belogortseva
authors.affiliation: Integrated Light Microscopy Core Facility, University of Chicago, Chicago, Illinois; and.
authors.forename: Vytautas P
authors.initials: VP
authors.lastname: Bindokas
authors.affiliation: The James Franck Institute, University of Chicago, Chicago, Illinois.
authors.forename: Qiti
authors.initials: Q
authors.lastname: Guo
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois.
authors.forename: Olga
authors.initials: O
authors.lastname: Zaborina
authors.affiliation: Department of Surgery, University of Chicago, Chicago, Illinois; jalverdy@surgery.bsd.uchicago.edu.
authors.forename: John C
authors.initials: JC
authors.lastname: Alverdy
mesh_terms: D000818:Animals; D002432:Cecum / Q000382:microbiology* / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006706:Homeostasis; D007413:Intestinal Mucosa / Q000382:microbiology / Q000502:physiology* / Q000601:surgery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D064307:Microbiota; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism
chemical_list: C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: Lgr5; apoptosis; cecal crypt microbiota; epithelial regeneration; fecal microbial transplant; proliferative zone; surgical stress