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Antibiotic-related gut dysbiosis induces lung immunodepression and worsens lung infection in mice.

ABSTRACT: BACKGROUND:Gut dysbiosis due to the adverse effects of antibiotics affects outcomes of lung infection. Previous murine models relied on significant depletion of both gut and lung microbiota, rendering the analysis of immune gut-lung cross-talk difficult. Here, we study the effects of antibiotic-induced gut dysbiosis without lung dysbiosis on lung immunity and the consequences on acute P. aeruginosa lung infection. METHODS:C57BL6 mice received 7?days oral vancomycin-colistin, followed by normal regimen or fecal microbial transplant or Fms-related tyrosine kinase 3 ligand (Flt3-Ligand) over 2?days, and then intra-nasal P. aeruginosa strain PAO1. Gut and lung microbiota were studied by next-generation sequencing, and lung infection outcomes were studied at 24?h. Effects of vancomycin-colistin on underlying immunity and bone marrow progenitors were studied in uninfected mice by flow cytometry in the lung, spleen, and bone marrow. RESULTS:Vancomycin-colistin administration induces widespread cellular immunosuppression in both the lung and spleen, decreases circulating hematopoietic cytokine Flt3-Ligand, and depresses dendritic cell bone marrow progenitors leading to worsening of P. aeruginosa lung infection outcomes (bacterial loads, lung injury, and survival). Reversal of these effects by fecal microbial transplant shows that these alterations are related to gut dysbiosis. Recombinant Flt3-Ligand reverses the effects of antibiotics on subsequent lung infection. CONCLUSIONS:These results show that gut dysbiosis strongly impairs monocyte/dendritic progenitors and lung immunity, worsening outcomes of P. aeruginosa lung infection. Treatment with a fecal microbial transplant or immune stimulation by Flt3-Ligand both restore lung cellular responses to and outcomes of P. aeruginosa following antibiotic-induced gut dysbiosis.

SUBMITTER: Dessein R

PROVIDER: S-EPMC7574210 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Antibiotic-related gut dysbiosis induces lung immunodepression and worsens lung infection in mice.

Dessein Rodrigue R Bauduin Marvin M Grandjean Teddy T Le Guern Rémi R Figeac Martin M Beury Delphine D Faure Karine K Faveeuw Christelle C Guery Benoit B Gosset Philippe P Kipnis Eric E

Critical care (London, England) 20201015 1

<h4>Background</h4>Gut dysbiosis due to the adverse effects of antibiotics affects outcomes of lung infection. Previous murine models relied on significant depletion of both gut and lung microbiota, rendering the analysis of immune gut-lung cross-talk difficult. Here, we study the effects of antibiotic-induced gut dysbiosis without lung dysbiosis on lung immunity and the consequences on acute P. aeruginosa lung infection.<h4>Methods</h4>C57BL6 mice received 7 days oral vancomycin-colistin, follo ...[more]

PMID: 33076936

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Project description:Antibiotics can be a double-edged sword. The application of broad-spectrum antibiotics leads to the suppression of microorganisms in the human body without selective targeting, including numerous non-pathogenic microorganisms within the gut. As a result, dysbiosis of the gut microbiota can occur. The gut microbiota is a vast and intricate ecosystem that has been connected with various illnesses. Significantly, the gut and liver function in a closely coupled anatomical and physiological relationship referred to as the "gut-liver axis". Consequently, metabolites stemming from the gut microbiota migrate via the portal vein to the liver, thereby influencing gene expression and proper physiological activity within the liver. This study aimed to investigate the dysbiosis of gut microbiota ecology and the disruption of gene expression resulting from oral antibiotics and their subsequent recovery. In the experiment, mice were tube-fed neomycin (0.5 mg/mL) and ampicillin (1 mg/mL) for 21 days (ABX group) to conduct 16s rRNA sequencing. By simultaneously analyzing public datasets PRJDB6615, which utilized the same antibiotics, it was found that nearly 50% of the total microbiota abundance was attributed to the f__Lactobacillaceae family. Additionally, datasets GSE154465 and GSE159761, using the same antibiotics, were used to screen for differentially expressed genes pre-and post-antibiotic treatment. Quantitative real-time PCR was employed to evaluate gene expression levels before and after antibiotic treatment. It was discovered that oral antibiotics significantly disrupted gene expression in the gut and liver, likely due to the dysregulation of the gut microbiota ecology. Fecal microbiota transplantation (FMT) was found to be an effective method for restoring gut microbiota dysbiosis. To further enhance the restoration of gut microbiota and gene expression, an antioxidant, vitamin C, was added to the FMT process to counteract the oxidative effect of antibiotics on microorganisms. The results showed that FMTs with vitamin C were more effective in restoring gut microbiota and gene expression to the level of the fecal transplant donor.

Project description:Antibiotics disrupt normal gut microbiota and cause dysbiosis, leading to a reduction in intestinal epithelial barrier function. Disruption of the intestinal epithelial barrier, which is known as "leaky gut", results in increased intestinal permeability and contributes to the development or exacerbation of gastrointestinal diseases such as inflammatory bowel disease and irritable bowel syndrome. We have previously reported on a murine model of intestinal epithelial barrier dysfunction associated with dysbiosis induced by the administration of ampicillin and vancomycin. Saireito, a traditional Japanese herbal medicine, is often used to treat autoimmune disorders including ulcerative colitis; the possible mechanism of action and its efficacy, however, remains unclear. In this study, we examined the efficacy of Saireito in our animal model for leaky gut associated with dysbiosis. C57BL/6 mice were fed a Saireito diet for the entirety of the protocol (day1-28). To induce colitis, ampicillin and vancomycin were administered in drinking water for the last seven consecutive days (day22-28). As previously demonstrated, treatment with antibiotics caused fecal occult bleeding, cecum enlargement with black discoloration, colon inflammation with epithelial cell apoptosis, and upregulation of pro-inflammatory cytokines. Oral administration of Saireito significantly improved antibiotics-induced fecal occult bleeding and cecum enlargement by suppressing inflammation in the colon. Furthermore, Saireito treatment ensured the integrity of the intestinal epithelial barrier by suppressing apoptosis and inducing cell adhesion proteins including ZO-1, occludin, and E-cadherin in intestinal epithelial cells, which in turn decreased intestinal epithelial permeability. Moreover, the reduced microbial diversity seen in the gut of mice treated with antibiotics was remarkably improved with the administration of Saireito. In addition, Saireito altered the composition of gut microbiota in these mice. These results suggest that Saireito alleviates leaky gut caused by antibiotic-induced dysbiosis. Our findings provide a potentially new therapeutic strategy for antibiotic-related gastrointestinal disorders.

Project description:Dietary heme can be used by colonic bacteria equipped with heme-uptake systems as a growth factor and thereby impact on the microbial community structure. The impact of heme on the gut microbiota composition may be particularly pertinent in chronic inflammation such as in inflammatory bowel disease (IBD), where a strong association with gut dysbiosis has been consistently reported. In this study we investigated the influence of dietary heme on the gut microbiota and inferred metagenomic composition, and on chemically induced colitis and colitis-associated adenoma development in mice. Using 16S rRNA gene sequencing, we found that mice fed a diet supplemented with heme significantly altered their microbiota composition, characterized by a decrease in α-diversity, a reduction of Firmicutes and an increase of Proteobacteria, particularly Enterobacteriaceae. These changes were similar to shifts seen in dextran sodium sulfate (DSS)-treated mice to induce colitis. In addition, dietary heme, but not systemically delivered heme, contributed to the exacerbation of DSS-induced colitis and facilitated adenoma formation in the azoxymethane/DSS colorectal cancer (CRC) mouse model. Using inferred metagenomics, we found that the microbiota alterations elicited by dietary heme resulted in non-beneficial functional shifts, which were also characteristic of DSS-induced colitis. Furthermore, a reduction in fecal butyrate levels was found in mice fed the heme supplemented diet compared to mice fed the control diet. Iron metabolism genes known to contribute to heme release from red blood cells, heme uptake, and heme exporter proteins, were significantly enriched, indicating a shift toward favoring the growth of bacteria able to uptake heme and protect against its toxicity. In conclusion, our data suggest that luminal heme, originating from dietary components or gastrointestinal bleeding in IBD and, to lesser extent in CRC, directly contributes to microbiota dysbiosis. Thus, luminal heme levels may further exacerbate colitis through the modulation of the gut microbiota and its metagenomic functional composition. Our data may have implications in the development of novel targets for therapeutic approaches aimed at lowering gastrointestinal heme levels through heme chelation or degradation using probiotics and nutritional interventions.

Dataset Information

Antibiotic-related gut dysbiosis induces lung immunodepression and worsens lung infection in mice.

Publications

Antibiotic-related gut dysbiosis induces lung immunodepression and worsens lung infection in mice.

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