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Persistent Systemic Microbial Translocation, Inflammation, and Intestinal Damage During Clostridioides difficile Infection.

ABSTRACT: Background:Clostridioides difficile infection (CDI) might be complicated by the development of nosocomial bloodstream infection (n-BSI). Based on the hypothesis that alteration of the normal gut integrity is present during CDI, we evaluated markers of microbial translocation, inflammation, and intestinal damage in patients with CDI. Methods:Patients with documented CDI were enrolled in the study. For each subject, plasma samples were collected at T0 and T1 (before and after CDI therapy, respectively), and the following markers were evaluated: lipopolysaccharide-binding protein (LPB), EndoCab IgM, interleukin-6, intestinal fatty acid binding protein (I-FABP). Samples from nonhospitalized healthy controls were also included. The study population was divided into BSI+/BSI- and fecal microbiota transplantation (FMT) +/FMT- groups, according to the development of n-BSI and the receipt of FMT, respectively. Results:Overall, 45 subjects were included; 8 (17.7%) developed primary n-BSI. Markers of microbial translocation and intestinal damage significantly decreased between T0 and T1, however, without reaching values similar to controls (P < .0001). Compared with BSI-, a persistent high level of microbial translocation in the BSI+ group was observed. In the FMT+ group, markers of microbial translocation and inflammation at T1 tended to reach control values. Conclusions:CDI is associated with high levels of microbial translocation, inflammation, and intestinal damage, which are still present at clinical resolution of CDI. The role of residual mucosal perturbation and persistence of intestinal cell damage in the development of n-BSI following CDI, as well as the possible effect of FMT in the restoration of mucosal integrity, should be further investigated.

SUBMITTER: Oliva A

PROVIDER: S-EPMC6954488 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:BackgroundDespite effective antiretroviral therapy (ART), patients with chronic human immunodeficiency virus (HIV) infection have increased microbial translocation and systemic inflammation. Alterations in the intestinal microbiota may play a role in microbial translocation and inflammation.MethodsWe profiled the fecal microbiota by pyrosequencing the gene encoding 16S ribosomal RNA (rRNA) and measured markers of microbial translocation and systemic inflammation in 21 patients who had chronic HIV infection and were receiving suppressive ART (cases) and 16 HIV-uninfected controls.ResultsThe fecal microbial community composition was significantly different between cases and controls. The relative abundance of Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae, Erysipelotrichi, Erysipelotrichales, Erysipelotrichaceae, and Barnesiella was significantly enriched in cases, whereas that of Rikenellaceae and Alistipes was depleted. The plasma soluble CD14 level (sCD14) was significantly higher and the endotoxin core immunoglobulin M (IgM) level lower in cases, compared with controls. There were significant positive correlations between the relative abundances of Enterobacteriales and Enterobacteriaceae and the sCD14 level; the relative abundances of Gammaproteobacteria, Enterobacteriales, and Enterobacteriaceae and the interleukin 1β (IL-1β) level; the relative abundances of Enterobacteriales and Enterobacteriaceae and the interferon γ level; and the relative abundances of Erysipelotrichi and Barnesiella and the TNF-α level. There were negative correlations between endotoxin core IgM and IL-1β levels.ConclusionsPatients who have chronic HIV infection and are receiving suppressive ART display intestinal dysbiosis associated with increased microbial translocation and significant associations between specific taxa and markers of microbial translocation and systemic inflammation. This was an exploratory study, the findings of which need to be confirmed.

Project description:While Clostridioides difficile is recognized as an important human pathogen, it is also a significant cause of gastroenteritis and associated diarrhea in neonatal pigs. Since clinical disease is rarely diagnosed in piglets older than 1 week of age, it is hypothesized that natural resistance is associated with the increased complexity of the intestinal microbiota as the animals age. To test this, piglets were challenged with C. difficile (ribotype 078/toxinotype V) at times ranging from 2 to 14 days of age, and the severity of disease and microbial diversity of the cecal microbiota were assessed. Half of the piglets that were challenged with C. difficile at 2 and 4 days of age developed clinical signs of disease. The incidence of disease decreased rapidly as the piglets aged, to a point where none of the animals challenged after 10 days of age showed clinical signs. The cecal microbial community compositions of the piglets also clustered by age, with those of animals 2 to 4 days old showing closer relationships to one another than to those of older piglets (8 to 14 days). This clustering occurred across litters from 4 different sows, providing further evidence that the resistance to C. difficile disease in piglets greater than 1 week old is directly related to the diversity and complexity of the intestinal microbiota. IMPORTANCE C. difficile is an important bacterial pathogen that is the most common cause of infections associated with health care in the United States. It also causes significant morbidity and mortality in neonatal pigs, and currently there are no preventative treatments available to livestock producers. This study determined the age-related susceptibility of piglets to C. difficile over the first 2 weeks of life, along with documenting the natural age-related changes that occurred in the intestinal microbiota over the same time period in a controlled environment. We observed that the populations of intestinal bacteria within individual animals of the same age, regardless of litter, showed the highest degree of similarity. Identifying bacterial species associated with the acquisition of natural resistance observed in older pigs could lead to the development of new strategies to prevent and or treat disease caused by C. difficile infection.

Project description:The gastrointestinal microbiome plays an important role in limiting susceptibility to infection with Clostridioides difficile To better understand the ecology of bacteria important for C. difficile colonization resistance, we developed an experimental platform to simplify complex communities of fecal bacteria through dilution and rapidly screen for their ability to resist C. difficile colonization after challenge, as measured by >100-fold reduction in levels of C. difficile in challenged communities. We screened 76 simplified communities diluted from cultures of six fecal donors and identified 24 simplified communities that inhibited C. difficile colonization in vitro Sequencing revealed that simplified communities were composed of 19 to 67 operational taxonomic units (OTUs) and could be partitioned into four distinct community types. One simplified community could be further simplified from 56 to 28 OTUs through dilution and retain the ability to inhibit C. difficile We tested the efficacy of seven simplified communities in a humanized microbiota mouse model. We found that four communities were able to significantly reduce the severity of the initial C. difficile infection and limit susceptibility to disease relapse. Analysis of fecal microbiomes from treated mice demonstrated that simplified communities accelerated recovery of indigenous bacteria and led to stable engraftment of 19 to 22 OTUs from simplified communities. Overall, the insights gained through the identification and characterization of these simplified communities increase our understanding of the microbial dynamics of C. difficile infection and recovery.IMPORTANCE Clostridioides difficile is the leading cause of antibiotic-associated diarrhea and a significant health care burden. Fecal microbiota transplantation is highly effective at treating recurrent C. difficile disease; however, uncertainties about the undefined composition of fecal material and potential long-term unintended health consequences remain. These concerns have motivated studies to identify new communities of microbes with a simpler composition that will be effective at treating disease. This work describes a platform for rapidly identifying and screening new simplified communities for efficacy in treating C. difficile infection. Four new simplified communities of microbes with potential for development of new therapies to treat C. difficile disease are identified. While this platform was developed and validated to model infection with C. difficile, the underlying principles described in the paper could be easily modified to develop therapeutics to treat other gastrointestinal diseases.

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Persistent Systemic Microbial Translocation, Inflammation, and Intestinal Damage During Clostridioides difficile Infection.

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