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Therapeutic Potential of the Gut Microbiota in the Prevention and Treatment of Sepsis.

ABSTRACT: Alongside advances in understanding the pathophysiology of sepsis, there have been tremendous strides in understanding the pervasive role of the gut microbiota in systemic host resistance. In pre-clinical models, a diverse and balanced gut microbiota enhances host immunity to both enteric and systemic pathogens. Disturbance of this balance increases susceptibility to sepsis and sepsis-related organ dysfunction, while restoration of the gut microbiome is protective. Patients with sepsis have a profoundly distorted composition of the intestinal microbiota, but the impact and therapeutic potential of the microbiome is not well-established in human sepsis. Modulation of the microbiota consists of either resupplying the pool of beneficial microbes by administration of probiotics, improving the intestinal microenvironment to enhance the growth of beneficial species by dietary interventions and prebiotics, or by totally recolonizing the gut with a fecal microbiota transplantation (FMT). We propose that there are three potential opportunities to utilize these treatment modalities over the course of sepsis: to decrease sepsis incidence, to improve sepsis outcome, and to decrease late mortality after sepsis. Exploring these three avenues will provide insight into how disturbances of the microbiota can predispose to, or even perpetuate the dysregulated immune response associated with this syndrome, which in turn could be associated with improved sepsis management.

SUBMITTER: Haak BW

PROVIDER: S-EPMC6139316 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Therapeutic Potential of the Gut Microbiota in the Prevention and Treatment of Sepsis.

Haak Bastiaan W BW Prescott Hallie C HC Wiersinga W Joost WJ

Frontiers in immunology 20180910

Alongside advances in understanding the pathophysiology of sepsis, there have been tremendous strides in understanding the pervasive role of the gut microbiota in systemic host resistance. In pre-clinical models, a diverse and balanced gut microbiota enhances host immunity to both enteric and systemic pathogens. Disturbance of this balance increases susceptibility to sepsis and sepsis-related organ dysfunction, while restoration of the gut microbiome is protective. Patients with sepsis have a pr ...[more]

PMID: 30250472

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Project description:The effects of using gut microbiota metabolites instead of live microorganisms to modulate sepsis-induced gut dysbiosis remain largely unknown. We assessed the effects of microbiota metabolite indole-3-propionic acid (IPA) on gut microbiota in mice during sepsis. Sepsis models were constructed by cecal ligation and puncture (CLP) methods. Fecal microbiota composition analysis was performed to characterize the gut microbiota composition. Fecal microbiota transplantation was performed to validate the roles of gut microbiota on sepsis progression. IPA-treated mice exhibited lower serum inflammatory mediator levels and a higher survival rate than those of saline-treated mice after modeling of sepsis, which were negated in the presence of antibiotics. Compared with saline-treated mice after modeling, IPA-treated mice showed a markedly different intestinal microbiota composition, with an enrichment of Bifidobacteriaceae family and a depletion of Enterobacteriaceae family. Mice gavaged with postoperative feces from IPA-treated animals displayed better survival than mice gavaged with feces from saline-treated animals. Overall, these data suggest that IPA offers a microbe-modulated survival advantage in septic mice, indicating that some microbiota metabolites could replace live microorganisms as potential options for regulation of sepsis-induced gut dysbiosis. IMPORTANCE The role of gut microbiota in the pathophysiology of sepsis is gaining increasing attention and developing effective and safe sepsis therapies targeting intestinal microorganisms is promising. Given the safety of probiotic supplementation or fecal microbiota transplantation in critically ill patients, identifying an abiotic agent to regulate the intestinal microbiota of septic patients is of clinical significance. This study revealed that IPA, a microbiota-generated tryptophan metabolite, ameliorated sepsis-induced mortality and decreased the serum levels of proinflammatory cytokines by modulating intestinal microbiota. Although IPA did not increase the abundance and diversity of the microbiota of septic mice, it significantly decreased the number of Enterobacteriaceae family. These findings indicate that a specific microbiota metabolite (e.g., IPA) can mediate the intestinal microbiota apart from FMT or probiotics.

Project description:BackgroundIt is unclear what the causal relationship is between the gut microbiota and sepsis. Therefore, we employed Mendelian randomization (MR) to determine whether a causal link exists between the two.MethodsThis study used publicly available genome-wide association studies (GWAS) summary data of gut microbiota, sepsis, sepsis (critical care), and sepsis (28-day death in critical care) to perform a two-sample MR analysis. To ensure the robustness of the results, we also conducted a sensitivity analysis.ResultsFor sepsis susceptibility, inverse variance weighted (IVW) estimates revealed that Victivallales (OR = 0.86, 95% CI, 0.78-0.94, p = 0.0017) was protective against sepsis, while Lentisphaerae (OR = 0.89, 95% CI, 0.80-0.99), Gammaproteobacteria (OR = 1.37, 95% CI, 1.08-1.73), Clostridiaceae1 (OR = 1.21, 95% CI, 1.04-1.40), RuminococcaceaeUCG011 (OR = 1.10, 95% CI, 1.01-1.20), Dialister (OR = 0.85, 95% CI, 0.74-0.97), and Coprococcus2 (OR = 0.81, 95% CI, 0.69-0.94) presented a suggestive association with the development of sepsis (all p < 0.05). For sepsis (critical care), IVW estimates indicated that Lentisphaerae (OR = 0.70, 95% CI, 0.53-0.93), Victivallales (OR = 0.67, 95% CI, 0.50-0.91), Anaerostipes (OR = 0.49, 95% CI, 0.31-0.76), LachnospiraceaeUCG004 (OR = 0.51, 95% CI, 0.34-0.77), and Coprococcus1 (OR = 0.66, 95% CI, 0.44-0.99) showed a suggestive negative correlation with sepsis (critical care) (all p < 0.05). For sepsis (28-day death in critical care), IVW estimates suggested that four bacterial taxa had a normally significant negative correlation with the risk of sepsis-related death, including Victivallales (OR = 0.54, 95% CI, 0.30-0.95), Coprococcus2 (OR = 0.34, 95% CI, 0.14-0.83), Ruminiclostridium6 (OR = 0.43, 95% CI, 0.22-0.83), and Coprococcus1 (OR = 0.45, 95% CI, 0.21-0.97), while two bacterial taxa were normally significantly positively linked to the risk of sepsis-related death, namely, Mollicutes (OR = 2.03, 95% CI, 1.01-4.08) and Bacteroidales (OR = 2.65, 95% CI, 1.18-5.96) (all p < 0.05). The robustness of the above correlations was verified by additional sensitivity analyses.ConclusionThis MR research found that several gut microbiota taxa were causally linked to the risk of sepsis, sepsis in critical care, and sepsis-related 28-day mortality in critical care.

Dataset Information

Therapeutic Potential of the Gut Microbiota in the Prevention and Treatment of Sepsis.

Publications

Therapeutic Potential of the Gut Microbiota in the Prevention and Treatment of Sepsis.

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