Inhibiting antibiotic-resistant Enterobacteriaceae by microbiota-mediated intracellular acidification

Abstract

Klebsiella pneumoniae, Escherichia coli, and other members of the Enterobacteriaceae family are common human pathogens that have acquired broad antibiotic resistance, rendering infection by some strains virtually untreatable. Enterobacteriaceae are intestinal residents, but generally represent <1% of the adult colonic microbiota. Antibiotic-mediated destruction of the microbiota enables Enterobacteriaceae to expand to high densities in the colon, markedly increasing the risk of bloodstream invasion, sepsis, and death. Here, we demonstrate that an antibiotic-naive microbiota suppresses growth of antibiotic-resistant clinical isolates of Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis by acidifying the proximal colon and triggering short chain fatty acid (SCFA)–mediated intracellular acidification. High concentrations of SCFAs and the acidic environment counter the competitive edge that O2 and NO3 respiration confer upon Enterobacteriaceae during expansion. Reestablishment of a microbiota that produces SCFAs enhances clearance of Klebsiella pneumoniae, Escherichia coli, and Proteus mirabilis from the intestinal lumen and represents a potential therapeutic approach to enhance clearance of antibiotic-resistant pathogens.

Variations in microbiota composition of laboratory mice influence Citrobacter rodentium infection via variable short-chain fatty acid production

“…Measuring the OD of C. rodentium over time, we noticed significantly impaired growth at higher concentrations of butyrate at a pH value of 6.0, whereas acetate and propionate did only partially reduce the growth of C. rodentium at pH 6.0 at high physiological concentrations. No significant effect for any SCFA was visible at neutral pH in line with findings on other Enterobacteriaceae [26] (Fig 6B). These results indicated that higher concentrations of SCFAs, especially butyrate, as seen in the SPF-R mice are able to abrogate growth of C. rodentium in vitro.…”

“…It is widely acknowledged that the intestinal microbiota has enormous impact on the individual susceptibility against invading pathogens and the severity of intestinal inflammation via direct and immune-mediated mechanisms [1]. Especially reduction of the colonization resistance against certain Enterobacteriaceae such as Salmonella [5], E. coli or K. pneumoniae [26] after antibiotic treatment has been linked with a reduction of SCFA-producing bacteria. In the present study, we focus on the impact of naturally occurring variations in the microbiota composition of laboratory mice and the influence of specific members in the microbiota in murine C. rodentium infection without any antibiotic interventions.…”

“…Based on the strongly altered SCFA concentrations and their previous association to growth inhibition of Enterobacteriaceae such as Salmonella Typhimurium [5], E. coli and K. pneumoniae [26], we tested the inhibitory properties of different SCFAs against C. rodentium in vitro.…”

Rice Bran and Quercetin Produce a Positive Synergistic Effect on Human Gut Microbiota, Elevate the Level of Propionate, and Reduce the Population ofEnterobacteriaceaefamily when Determined using a Bioreactor Model

“…SCFAs production by microbiota has been associated with pathogen inhibition to benefit the host (50). Physiological levels of SCFAs are reported to reduce Enterobacteriaceae members by pH mediated action (51). Specifically, propionate production by a propionate producing consortium has been shown to reduce antibiotic induced dysbiosis (52).…”

Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

“…81 Indeed, the functional metabolic capabilities of certain commensals confer protection against pathogen infection, which is attributable to the intracellular acidification of pathogens mediated by SCFAs. 82 High concentrations of SCFAs and the acidic environment reverse or counteract the competitive advantage that O 2 and NO 3 respiration provide to facultative anaerobes such as Enterobacteriaceae. 82 Conversely, antibiotic treatment elicits gut dysbiosis and SCFA exhaustion, which further inhibits the PPAR-γ signaling pathway and induces metabolic reprogramming.…”