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Complex responses to hydrogen peroxide and hypochlorous acid by the probiotic bacterium Lactobacillus reuteri

ABSTRACT: Inflammatory diseases of the gut are associated with increased intestinal oxygen concentrations and high levels of inflammatory oxidants, including hydrogen peroxide (H2O2) and hypochlorous acid (HOCl), which are antimicrobial compounds produced by the innate immune system. This contributes to dysbiotic changes in the gut microbiome, including increased populations of pro-inflammatory enterobacteria (Escherichia coli and related species) and decreased levels of health-associated anaerobic Firmicutes and Bacteroidetes. The pathways for H2O2 and HOCl resistance in E. coli have been well-studied, but little is known about how commensal and probiotic bacteria respond to inflammatory oxidants. In this work, we have characterized the transcriptomic response of the anti-inflammatory, gut colonizing Gram-positive probiotic Lactobacillus reuteri to both H2O2 and HOCl. L. reuteri mounts distinct responses to each of these stressors, and both gene expression and survival were strongly affected by the presence or absence of oxygen. Oxidative stress response in L. reuteri required several factors not found in enterobacteria, including the small heat shock protein Lo18, polyphosphate kinase 2, and RsiR, an L. reuteri-specific regulator of anti-inflammatory mechanisms. These results raise the intriguing possibility of developing treatments for inflammatory gut diseases that could sensitize pro-inflammatory enterobacteria to killing by the immune system while sparing anti-inflammatory, health-associated species.

ORGANISM(S): Limosilactobacillus reuteri

PROVIDER: GSE127961 | GEO | 2019/08/15

REPOSITORIES: GEO

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Project description:Purpose: The aim of this study was to determine the transcriptional response of P. aeruginosa PA14 to HOCl and HOSCN stress, and determine genes dependent on RclR (PA14_07340) regulation. Methods: PA14 WT and ∆rclR exponential phase cultures were exposed to sub-lethal amounts of HOCl or HOSCN (2.2 or 0.8 mM, respectively), or untreated, and after 20 minutes of exposure, RNA was extracted and gene expression analysed by RNA-seq. Reads Per Kilobase per Million mapped reads (RPKM) were determined and the log2 fold change of the RPKM values of treated WT compared to untreated WT, or treated WT compared to treated ∆rclR was calculated. Genes with a log2 fold change of >1.5 were considered upregulated and genes with a log2 fold change of <-1.5 were considered downregulated. Results: In the WT strain, HOCl exposure resulted in upregulation of 231 genes and downregulation of 20 genes, and HOSCN exposure caused upregulation of 105 genes and downregulation of 16 genes. There was considerable overlap in the transcriptional response to HOCl and HOSCN, with 74 genes being induced in response to both oxidants. Genes upregulated by HOCl and HOSCN included those involved in sulphur and taurine transport, those encoding the type 3 secretion system, the MexEF-OprN drug efflux pump, and the putative peroxiredoxin RclX (PA14_07355). Comparison of the treated WT and treated ∆rclR strains revealed that in the presence of HOCl RclR upregulated 42 genes and downregulated 7 genes, and in the presence of HOSCN upregulated 132 genes and downregulated 213 genes. In the presence of both HOCl and HOSCN, RclR was required for upregulation of rclX as well as pyocyanin biosynthesis genes. In the presence of HOSCN, RclR downregulated a large number of genes, including those encoding chaperones. Conclusions: Our data have identified that the transcriptional response of P. aeruginosa to HOCl and HOSCN is multifaceted and appears to be linked to antibiotic resistance and the virulence factors pyocyanin and type 3 secretion. Determination of the regulon of the transcriptional regulator RclR after HOCl and HOSCN exposure suggests RclR has a role in coordinating the P. aeruginosa response to these oxidants.

Project description:Familial Mediterranean fever (FMF) is an inflammatory genetic disease characterized by elevated systemic reactivity against commensal gut microbiota and high levels of gut Candida albicans. The current study investigated the effects of Lactobacillus acidophillus INMIA 9602 Er 317/402 strain (probiotic “Narine”) on the relative abundance of gut enteric bacteria, lactobacilli, Staphylococcus aureus, and Enteroccocus faecalis in Candida albicans-carrier and non-carrier FMF patients in remission with the main MEFV mutation patterns M694V/V726A- the prevalent MEFV gene mutation within FMF patients in the Armenian cohort. Our data revealed that M694V/V726A mutations in PURIN inflammasome leading to FMF disease brought to gender specific differences in microbial community structure in FMF patients. Possibly, long-term colchicine use suppresses the PURIN inflammasome/inhibits NLRP3 inflammasome-dependent IL-1β release influencing on overgrowth of C. albicans in gut microbiota of FMF patients. The comparison of Operational Taxonomic Units (OTUs) of enteric bacteria in C. albicans-carrier and non-carrier female patients revealed the statistically significant increase in OTUs of enterobacteria in C. albicans-carriers. In contrast to this, there were no differences in abundance of Enteroccocus faecalis between female FMF C. albicans-carriers compared with non-carriers, while male FMF C. albicans-carriers have increased abundance of E. faecalis in their gut microbiota compared with that of male patients with none carriers. The gut microbiota of FMF patients (both male and female) with C. albicans below baseline level contains high abundance of lactobacilli compared with C. albicans-carriers. The adoption of Lactobacillus acidophilus INMIA 9602 Er 317/402 leads to changes in gut microbiota composition of FMF patients. It reduces, in particularly, the abundance of enterobacteria in females, and Enteroccocus faecalis in men parallel with reducing the numbers of yeast in gut microbiota of FMF patients. We hypothesize that colchicine treatment changes the already-altered gut microbiota of FMF patients, thereby affecting the regulation of immune system by inhibition of NLRP3 inflammasome. Colchicine could lead to overgrowth of C. albicans in gut microbiota of FMF patients, whereas the Lactobacillus acidophilus INMIA 9602 Er 317/402 works on activation of inflammasome by new changes in gut microbiota of patients.

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Complex responses to hydrogen peroxide and hypochlorous acid by the probiotic bacterium Lactobacillus reuteri

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