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Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration.

ABSTRACT:

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Treatment with streptomycin enhances the growth of human commensal Escherichia coli isolates in the mouse intestine, suggesting that the resident microbial community (microbiota) can inhibit the growth of invading microbes, a phenomenon known as "colonization resistance." However, the precise mechanisms by which streptomycin treatment lowers colonization resistance remain obscure. Here we show that streptomycin treatment rendered mice more susceptible to the development of chemically induced colitis, raising the possibility that the antibiotic might lower colonization resistance by changing mucosal immune responses rather than by preventing microbe-microbe interactions. Investigation of the underlying mechanism revealed a mild inflammatory infiltrate in the cecal mucosa of streptomycin-treated mice, which was accompanied by elevated expression of Nos2, the gene that encodes inducible nitric oxide synthase. In turn, this inflammatory response enhanced the luminal growth of E. coli by nitrate respiration in a Nos2-dependent fashion. These data identify low-level intestinal inflammation as one of the factors responsible for the loss of resistance to E. coli colonization after streptomycin treatment.

Importance

Our intestine is host to a complex microbial community that confers benefits by educating the immune system and providing niche protection. Perturbation of intestinal communities by streptomycin treatment lowers "colonization resistance" through unknown mechanisms. Here we show that streptomycin increases the inflammatory tone of the intestinal mucosa, thereby making the bowel more susceptible to dextran sulfate sodium treatment and boosting the Nos2-dependent growth of commensal Escherichia coli by nitrate respiration. These data point to the generation of alternative electron acceptors as a by-product of the inflammatory host response as an important factor responsible for lowering resistance to colonization by facultative anaerobic bacteria such as E. coli.

SUBMITTER: Spees AM

PROVIDER: S-EPMC3705454 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration.

Spees Alanna M AM Wangdi Tamding T Lopez Christopher A CA Kingsbury Dawn D DD Xavier Mariana N MN Winter Sebastian E SE Tsolis Renée M RM Bäumler Andreas J AJ

mBio 20130702 4

<h4>Unlabelled</h4>Treatment with streptomycin enhances the growth of human commensal Escherichia coli isolates in the mouse intestine, suggesting that the resident microbial community (microbiota) can inhibit the growth of invading microbes, a phenomenon known as "colonization resistance." However, the precise mechanisms by which streptomycin treatment lowers colonization resistance remain obscure. Here we show that streptomycin treatment rendered mice more susceptible to the development of che ...[more]

PMID: 23820397

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Project description:Oral antibiotic treatment is often applied in animal studies in order to allow establishment of an introduced antibiotic-resistant bacterium in the gut. Here, we compared the application of streptomycin dosed orally in microcontainers to dosage through drinking water. The selective effect on a resistant bacterial strain, as well as the effects on fecal, luminal, and mucosal microbiota composition, were investigated. Three groups of rats (n = 10 per group) were orally dosed with microcontainers daily for 3 days. One of these groups (STR-M) received streptomycin-loaded microcontainers designed for release in the distal ileum, while the other two groups (controls [CTR] and STR-W) received empty microcontainers. The STR-W group was additionally dosed with streptomycin through the drinking water. A streptomycin-resistant Escherichia coli strain was orally inoculated into all animals. Three days after inoculation, the resistant E. coli was found only in the cecum and colon of animals receiving streptomycin in microcontainers but in all intestinal compartments of animals receiving streptomycin in the drinking water. 16S rRNA amplicon sequencing revealed significant changes in the fecal microbiota of both groups of streptomycin-treated animals. Investigation of the inner colonic mucus layer by confocal laser scanning microscopy and laser capture microdissection revealed no significant effect of streptomycin treatment on the mucus-inhabiting microbiota or on E. coli encroachment into the inner mucus. Streptomycin-loaded microcontainers thus enhanced proliferation of an introduced streptomycin-resistant E. coli in the cecum and colon without affecting the small intestine environment. While improvements of the drug delivery system are needed to facilitate optimal local concentration and release of streptomycin, the application of microcontainers provides new prospects for antibiotic treatment. IMPORTANCE Delivery of antibiotics in microcontainer devices designed for release at specific sites of the gut represents a novel approach which might reduce the amount of antibiotic needed to obtain a local selective effect. We propose that the application of microcontainers may have the potential to open novel opportunities for antibiotic treatment of humans and animals with fewer side effects on nontarget bacterial populations. In the current study, we therefore elucidated the effects of streptomycin, delivered in microcontainers coated with pH-sensitive lids, on the selective effect on a resistant bacterium, as well as on the surrounding intestinal microbiota in rats.

Project description:Respiration is a fundamental process that has to optimally respond to metabolic demand and environmental changes. We previously showed that nitrate respiration, crucial for gut colonization by enterobacteria, is controlled by polar clustering of the nitrate reductase increasing the electron flux through the complex. Here, we show that the formate dehydrogenase electron-donating complex, FdnGHI, also clusters at the cell poles under nitrate-respiring conditions. Its proximity to the nitrate reductase complex was confirmed by its identification in the interactome of the latter, which appears to be specific to the nitrate-respiring condition. Interestingly, we have identified a multiprotein complex dedicated to handle nitric oxide resulting from the enhanced activity of the electron transport chain terminated by nitrate reductase. We demonstrated that the cytoplasmic NADH-dependent nitrite reductase NirBD and the hybrid cluster protein Hcp are key contributors to regulation of the nitric oxide level during nitrate respiration. Thus, gathering of actors involved in respiration and NO homeostasis seems to be critical to balancing maximization of electron flux and the resulting toxicity.IMPORTANCE Most bacteria rely on the redox activity of respiratory complexes embedded in the cytoplasmic membrane to gain energy in the form of ATP and of an electrochemical gradient established across the membrane. Nevertheless, production of harmful and toxic nitric oxide by actively growing bacteria as either an intermediate or side-product of nitrate respiration challenges how homeostasis control is exerted. Here, we show that components of the nitrate electron transport chain are clustered, likely influencing the kinetics of the process. Nitric oxide production from this respiratory chain is controlled and handled through a multiprotein complex, including detoxifying systems. These findings point to an essential role of compartmentalization of respiratory components in bacterial cell growth.

Dataset Information

Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration.

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Importance

Publications

Streptomycin-induced inflammation enhances Escherichia coli gut colonization through nitrate respiration.

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