Disruption of the Gut Ecosystem by Antibiotics

Abstract

The intestinal microbiota is a complex ecosystem consisting of various microorganisms that expands human genetic repertoire and therefore affects human health and disease. The metabolic processes and signal transduction pathways of the host and intestinal microorganisms are intimately linked, and abnormal progression of each process leads to changes in the intestinal environment. Alterations in microbial communities lead to changes in functional structures based on the metabolites produced in the gut, and these environmental changes result in various bacterial infections and chronic enteric inflammatory diseases. Here, we illustrate how antibiotics are associated with an increased risk of antibiotic-associated diseases by driving intestinal environment changes that favor the proliferation and virulence of pathogens. Understanding the pathogenesis caused by antibiotics would be a crucial key to the treatment of antibiotic-associated diseases by mitigating changes in the intestinal environment and restoring it to its original state.

Keywords: Microbiota; antibiotics; enteric pathogen; fecal microbiota transplantation (FMT); probiotics.

Fig. 1. Pathogens exploit the antibiotic-induced inflammatory conditions. Pathogens use sugars and inorganic compounds generated by the intestinal microbiota as carbon or energy sources and perform anaerobic respiration in the inflammatory conditions caused by antibiotics. (A) When the distribution of intestinal microorganisms is in a stable state, the invasion of pathogenic bacteria is suppressed by antimicrobial substances produced from intestinal bacteria and host cells and the inflammation is suitably controlled. (B) In an inflammatory condition, the colonization of E. coli and Salmonella expands through anaerobic respiration using ROS and RNS, which are released by DUOX2 and iNOS in epithelial cells. Hydrogen sulfide derived from sulfate-reducing bacteria such as Desulfovibrio spp. is converted to thiosulfate during cellular respiration in colonic epithelial cells. ROS generated by neutrophils convert the thiosulfate into tetrathionate that can be used as an electron acceptor. During this process, the generated tetrathionate boosts the growth of S. Typhimurium through tetrathionate respiration that converts tetrathionate to thiosulfate. E. coli reduces nitrate to nitrite through nitrate respiration. (C) Bacteroides thetaiotaomicron decomposes mucosal glycoconjugates to produce sialic acid. EHEC and Salmonella can use the sialic acid as a carbon source. Inflammatory conditions lead to release of fucose from host glycan and the liberated fucose is subsequently consumed by pathogens. As an example, EHEC are known to regulate the expression of virulence genes by sensing the fucose. (D) C. difficile, C. rodentium, and EHEC utilize succinate, which is produced by other intestinal microorganisms. SCFAs excreted during polysaccharide metabolism by aerobic bacteria and butyrate, propionate, and acetate are predominantly present in the intestinal environment. A commensal bacterium, Bacteroides spp., mainly distributes succinate, which is subsequently consumed by secondary fermentative microbes in a steady state and therefore rarely accumulates in the intestinal environment. However, succinate is not consumed under antibiotic treatment or inflammatory conditions, eventually leading to its accumulation in the intestinal lumen. Succinate promotes gluconeogenesis of EHEC. In addition, the colonization and proliferation of C. rodentium are enhanced, especially with expression of virulence genes of the LEE. C. difficile can couple succinate metabolism and convert it to butyrate with the fermentation of carbohydrates, thereby enhancing its colonization and virulence. (E) Antibiotics can trigger the growth of Enterobacteriaceae. ROS at high concentrations result in an expansion of E. coli harboring an extra catalase that are genetically generated through chromosomal modification and eventually favor intestinal colonization of Vibrio cholerae, a strain that is highly sensitive strain to ROS, by reducing the ROS that are excessively generated in inflammatory conditions. E. coli, Escherichia coli; ROS, reactive oxygen species; RNS, reactive nitrogen species; iNOS, inducible nitric oxide synthase; EHEC, Enterohemorrhagic Escherichia coli; C. difficile, Clostridium difficile; C. rodentium, Citrobacter rodentium; SCFAs, short-chain fatty acids; LEE, locus of enterocyte effacement.

Fig. 2. Effects of antibiotics on the hypoxia barrier of intestinal epithelial cells. (A) In normal conditions, oxygen tension decreases steadily from the intestinal submucosal layer to the lumen. Although the partial pressure of oxygen is approximately 100 mm Hg in the basal layer, it is almost 0 mm Hg in the lumen. Under antibiotic treatment or inflammatory conditions, Clostridia produce butyrate and colonic epithelial cells convert the butyrate to carbon dioxide, leading to maintenance of hypoxia in the lumen. (B) When butyrate is lacking in the intestine, the cells utilize glucose for cellular respiration and the lactate that is released during the process increases oxygenation within the lumen. S. Typhimurium can proliferate using cytochrome bd-II oxidase encoded in cyxB, which is highly expressed at low oxygen concentrations.