title: Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis.
abstract: Antibiotic usage promotes intestinal colonization of antibiotic-resistant bacteria. However, whether resistant bacteria gain dominance in enteric microflora or disseminate to extraintestinal viscera remains unclear. Our aim was to investigate temporal diversity changes in microbiota and transepithelial routes of bacterial translocation after antibiotic-resistant enterobacterial colonization. Mice drinking water with or without antibiotics were intragastrically gavaged with ampicillin-resistant (Amp-r) nonpathogenic Escherichia coli (E. coli) and given normal water afterward. The composition and spatial distribution of intestinal bacteria were evaluated using 16S rDNA sequencing and fluorescence in situ hybridization. Bacterial endocytosis in epithelial cells was examined using gentamicin resistance assay and transmission electromicroscopy. Paracellular permeability was assessed by tight junctional immunostaining and measured by tissue conductance and luminal-to-serosal dextran fluxes. Our results showed that antibiotic treatment enabled intestinal colonization and transient dominance of orally acquired Amp-r E. coli in mice. The colonized Amp-r E. coli peaked on day 3 postinoculation and was competed out after 1 wk, as evidenced by the recovery of commensals, such as Escherichia, Bacteroides, Lachnospiraceae, Clostridium, and Lactobacillus. Mucosal penetration and extraintestinal dissemination of exogenous and endogenous enterobacteria were correlated with abnormal epithelial transcytosis but uncoupled with paracellular tight junctional damage. In conclusion, antibiotic-induced enteric dysbiosis predisposes to exogenous infection and causes systemic dissemination of both antibiotic-resistant and commensal enterobacteria through transcytotic routes across epithelial layers. These results may help explain the susceptibility to sepsis in antibiotic-resistant enteric bacterial infection.
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan;
authors: Linda Chia-Hui
authors: LC
authors: Yu
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan;
authors: Yi-An
authors: YA
authors: Shih
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan;
authors: Li-Ling
authors: LL
authors: Wu
authors: Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan;
authors: Yang-Ding
authors: YD
authors: Lin
authors: Graduate Institute of Physiology, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan;
authors: Wei-Ting
authors: WT
authors: Kuo
authors: Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan;
authors: Wei-Hao
authors: WH
authors: Peng
authors: Graduate Institute of Anatomy and Cell Biology, National Taiwan University College of Medicine, Taipei, Taiwan;
authors: Kuo-Shyan
authors: KS
authors: Lu
authors: Department of Internal Medicine, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan; and.
authors: Shu-Chen
authors: SC
authors: Wei
authors: Department of Pathology, University of Chicago, Chicago, Illinois.
authors: Jerrold R
authors: JR
authors: Turner
authors: Department of Pediatrics, National Taiwan University College of Medicine, Taipei, Taiwan; yhni@ntu.edu.tw.
authors: Yen-Hsuan
authors: YH
authors: Ni
mesh_terms: D000667:Ampicillin / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D004352:Drug Resistance, Microbial; D064806:Dysbiosis / Q000382:microbiology*; D004756:Enterobacteriaceae Infections / Q000188:drug therapy / Q000382:microbiology*; D004926:Escherichia coli / Q000187:drug effects / Q000472:pathogenicity; D007413:Intestinal Mucosa / Q000382:microbiology* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D064307:Microbiota; D013559:Symbiosis; D057900:Transcytosis
chemical_list: D000900:Anti-Bacterial Agents; D000667:Ampicillin
keywords: bacterial endocytosis; epithelial barrier; gut-derived sepsis; intestinal microbiota; superbug