Baseline Gut Microbiota Research Articles

Associations between acute gastrointestinal GvHD and the baseline gut microbiota of allogeneic hematopoietic stem cell transplant recipients and donors.

Growing evidence suggests that host-microbiota interactions influence GvHD risk following allogeneic hematopoietic stem cell transplant. However, little is known about the influence of the transplant recipient's pre-conditioning microbiota nor the influence of the transplant donor's microbiota. Our study examines associations between acute gastrointestinal GvHD (agGvHD) and 16S rRNA fecal bacterial profiles in a prospective cohort of N=57 recipients before preparative conditioning, as well as N=22 of their paired HLA-matched sibling donors. On average, recipients had lower fecal bacterial diversity (P=0.0002) and different phylogenetic membership (UniFrac P=0.001) than the healthy transplant donors. Recipients with lower phylogenetic diversity had higher overall mortality rates (hazard ratio=0.37, P=0.008), but no statistically significant difference in agGvHD risk. In contrast, high bacterial donor diversity was associated with decreased agGvHD risk (odds ratio=0.12, P=0.038). Further investigation is warranted as to whether selection of hematopoietic stem cell transplant donors with high gut microbiota diversity and/or other specific compositional attributes may reduce agGvHD incidence, and by what mechanisms.

105P - Baseline gut microbiota in metastatic melanoma patients treated with ipilimumab: Relation with clinical response and colitis

105P - Baseline gut microbiota in metastatic melanoma patients treated with ipilimumab: Relation with clinical response and colitis

Administration of two probiotic strains during early childhood does not affect the endogenous gut microbiota composition despite probiotic proliferation

BackgroundProbiotics are increasingly applied to prevent and treat a range of infectious, immune related and gastrointestinal diseases. Despite this, the mechanisms behind the putative effects of probiotics are poorly understood. One of the suggested modes of probiotic action is modulation of the endogenous gut microbiota, however probiotic intervention studies in adults have failed to show significant effects on gut microbiota composition. The gut microbiota of young children is known to be unstable and more responsive to external factors than that of adults. Therefore, potential effects of probiotic intervention on gut microbiota may be easier detectable in early life. We thus investigated the effects of a 6 month placebo-controlled probiotic intervention with Bifidobacterium animalis subsp. lactis (BB-12®) and Lactobacillus rhamnosus (LGG®) on gut microbiota composition and diversity in more than 200 Danish infants (N = 290 enrolled; N = 201 all samples analyzed), as assessed by 16S rRNA amplicon sequencing. Further, we evaluated probiotic presence and proliferation by use of specific quantitative polymerase chain reaction (qPCR).ResultsProbiotic administration did not significantly alter gut microbiota community structure or diversity as compared to placebo. The probiotic strains were detected in 91.3% of the fecal samples from children receiving probiotics and in 1% of the placebo treated children. Baseline gut microbiota was not found to predict the ability of probiotics to establish in the gut after the 6 month intervention. Within the probiotics group, proliferation of the strains LGG® and BB-12® in the gut was detected in 44.7% and 83.5% of the participants, respectively. A sub-analysis of the gut microbiota including only individuals with detected growth of the probiotics LGG® or BB-12® and comparing these to placebo revealed no differences in community structure or diversity.ConclusionSix months of probiotic administration during early life did not change gut microbiota community structure or diversity, despite active proliferation of the administered probiotic strains. Therefore, alteration of the healthy infant gut microbiota is not likely to be a prominent mechanism by which these specific probiotics works to exert beneficial effects on host health.Trial registrationNCT02180581. Registered 30 June 2014.

Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab

Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma (MM) but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity. Twenty-six patients with MM treated with ipilimumab were prospectively enrolled. Fecal microbiota composition was assessed using 16S rRNA gene sequencing at baseline and before each ipilimumab infusion. Patients were further clustered based on microbiota patterns. Peripheral blood lymphocytes immunophenotypes were studied in parallel. A distinct baseline gut microbiota composition was associated with both clinical response and colitis. Compared with patients whose baseline microbiota was driven by Bacteroides (cluster B, n = 10), patients whose baseline microbiota was enriched with Faecalibacterium genus and other Firmicutes (cluster A, n = 12) had longer progression-free survival (P = 0.0039) and overall survival (P = 0.051). Most of the baseline colitis-associated phylotypes were related to Firmicutes (e.g. relatives of Faecalibacterium prausnitzii and Gemmiger formicilis), whereas no colitis-related phylotypes were assigned to Bacteroidetes. A low proportion of peripheral blood regulatory T cells was associated with cluster A, long-term clinical benefit and colitis. Ipilimumab led to a higher inducible T-cell COStimulator induction on CD4+ T cells and to a higher increase in serum CD25 in patients who belonged to Faecalibacterium-driven cluster A. Baseline gut microbiota enriched with Faecalibacterium and other Firmicutes is associated with beneficial clinical response to ipilimumab and more frequent occurrence of ipilimumab-induced colitis.

Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab.

Ann Oncol 2017; 28(6): 1368–1379 (doi: 10.1093/annonc/mdx108) In the original article, there were errors in Figure 3B and the accompanying legend. These have been corrected online as below. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumabAnnals of OncologyVol. 28Issue 6PreviewIpilimumab, an immune checkpoint inhibitor targeting CTLA-4, prolongs survival in a subset of patients with metastatic melanoma (MM) but can induce immune-related adverse events, including enterocolitis. We hypothesized that baseline gut microbiota could predict ipilimumab anti-tumor response and/or intestinal toxicity. Full-Text PDF Open Archive

Influence of habitual dietary fibre intake on the responsiveness of the gut microbiota to a prebiotic: protocol for a randomised, double-blind, placebo-controlled, cross-over, single-centre study

IntroductionThe commensal gut microbiota have been shown to have an impact on human health as aberrant gut microbiota have been linked to disease. Dietary constituents are influential in shaping the...

Gut microbiota composition and relapse risk in pediatric MS: A pilot study

We explored the association between baseline gut microbiota (16S rRNA biomarker sequencing of stool samples) in 17 relapsing-remitting pediatric MS cases and risk of relapse over a mean 19.8months follow-up. From the Kaplan-Meier curve, 25% relapsed within an estimated 166days from baseline. A shorter time to relapse was associated with Fusobacteria depletion (p=0.001 log-rank test), expansion of the Firmicutes (p=0.003), and presence of the Archaea Euryarchaeota (p=0.037). After covariate adjustments for age and immunomodulatory drug exposure, only absence (vs. presence) of Fusobacteria was associated with relapse risk (hazard ratio=3.2 (95% CI: 1.2–9.0), p=0.024). Further investigation is warranted. Findings could offer new targets to alter the MS disease course.

Preventing Primate Gvhd Using a Novel Antagonistic Anti-CD28 Antibody Plus Rapamycin: Downregulation of CD8 Proliferation Predicts Gvhd-Free Survival

Results: Complete bacterial/fungal pyrosequencing and bacterial groupqPCRwasperformedon10patients (4 iGVHD, 6no GVHD). As evidenced by 16S rRNA sequencing, only patients with iGVHD developed significant expansion of ENTERO and a significant decrease in SCFA Clostridia prior to the diagnosis of iGVHD. Bacterial group qPCR confirmed these findings: patients with GVHD had significantly higher ENTERO (p< 0.01, Mann Whitney) and significantly lower EREC and CLEPT (subgroups of the SCFA Clostridia) (P<0.01) than non-GVHD counterparts. Of the clinical characteristics recorded, clindamycin treatment, which is effective against Clostrida spp, was the most strongly associated with the development of iGVHD Conclusion: Expansion of pro-inflammatory ENTERO and decreases in anti-inflammatory Clostridia (CLEPT and EREC) are associatedwith iGVHD in pediatric BMT patients. Medical therapies such as chemotherapy and/or antibiotics may disturb the baseline gut microbiota and make certain patients predisposed to the development of iGVHD. Realtimemonitoring of the gut microbiota (bacterial group qPCR) has great potential as a biomarker for iGVHD.

947 Aspiration of Gastric Contents Can Occur in the Presence of an Intact Swallow Mechanism

Background: A LFSD has demonstrated efficacy in reducing gastrointestinal (GI) symptoms in adults with IBS, though not all respond. The efficacy of a LFSD in children with IBS is unknown. We sought to determine whether a LFSD decreases abdominal pain frequency in children with IBS and factors determining efficacy of the diet. Methods: Children with Pediatric Rome III-defined IBS completed a 1-wk baseline period on their habitual diet followed by a 1-wk LFSD intervention. Participants were informed they would be taught one of two potential diets, although all participants were taught the same LFSD by a dietitian. Measurements during baseline and LFSD intervention included: A Pain/Stool Diary (capturing the number of pain episodes, stool frequency, and stool form using the modified Bristol Stool Form Scale for children), breath hydrogen/methane production, whole intestinal transit time, and stool microbiome composition analysis. Responders were defined as having ≥ 50% decrease in abdominal pain frequency. Results: Eight children (4 girls), mean age 9.0 ± 3.6 yrs were enrolled and completed the LFSD. Baseline vs LFSD Diet: As a group, overall pain frequency, pain severity, and pain related interference with activities decreased, with a trend toward fewer bowel movements but no differences in stool form (Table). There were no changes in breath hydrogen or methane production, or intestinal transit time. Trends toward increased abundances of Clostridiales and decreased abundance of Bacteroidetes were observed during the LFSD. Responders vs Non-responders: Four children (50%) were identified as responders. There were no differences between responders and non-responders with respect to baseline pain frequency, stool frequency, stool form, hydrogen, or methane production. During the LFSD, responders produced less hydrogen than non-responders (P,0.05), without differences between the groups in stooling characteristics or methane production. Responders (n=3) and non-responders (n=3) with constipation-predominant IBS could be separated by principal components analysis based on the relative species abundance of their baseline gut microbiota. Responders were characterized by increased abundance of taxa belonging to the genera Sporobacter (P ,0.05) and Subdoligranulum (P,0.02) and decreased abundance of taxa belonging to Bacteroides (P,0.05) relative to nonresponders. In addition, other differences in microbiome composition between responders vs. non-responders were identified during the LFSD. Conclusions: A LFSD was effective in decreasing abdominal pain frequency in children with IBS. Those children who had ≥ 50% reduction in pain frequency had less hydrogen production and a different stool microbiome composition vs. those who did not respond to the LFSD suggesting that gut microbiome makeup may predict LFSD efficacy in childhood IBS. Pain and stool characteristics (baseline vs. LFSD*)

946 Low Fermentable Substrate Diet (LFSD) in Children With Irritable Bowel Syndrome (IBS): Pilot Efficacy and Microbiological Predictors of Response

Background: A LFSD has demonstrated efficacy in reducing gastrointestinal (GI) symptoms in adults with IBS, though not all respond. The efficacy of a LFSD in children with IBS is unknown. We sought to determine whether a LFSD decreases abdominal pain frequency in children with IBS and factors determining efficacy of the diet. Methods: Children with Pediatric Rome III-defined IBS completed a 1-wk baseline period on their habitual diet followed by a 1-wk LFSD intervention. Participants were informed they would be taught one of two potential diets, although all participants were taught the same LFSD by a dietitian. Measurements during baseline and LFSD intervention included: A Pain/Stool Diary (capturing the number of pain episodes, stool frequency, and stool form using the modified Bristol Stool Form Scale for children), breath hydrogen/methane production, whole intestinal transit time, and stool microbiome composition analysis. Responders were defined as having ≥ 50% decrease in abdominal pain frequency. Results: Eight children (4 girls), mean age 9.0 ± 3.6 yrs were enrolled and completed the LFSD. Baseline vs LFSD Diet: As a group, overall pain frequency, pain severity, and pain related interference with activities decreased, with a trend toward fewer bowel movements but no differences in stool form (Table). There were no changes in breath hydrogen or methane production, or intestinal transit time. Trends toward increased abundances of Clostridiales and decreased abundance of Bacteroidetes were observed during the LFSD. Responders vs Non-responders: Four children (50%) were identified as responders. There were no differences between responders and non-responders with respect to baseline pain frequency, stool frequency, stool form, hydrogen, or methane production. During the LFSD, responders produced less hydrogen than non-responders (P,0.05), without differences between the groups in stooling characteristics or methane production. Responders (n=3) and non-responders (n=3) with constipation-predominant IBS could be separated by principal components analysis based on the relative species abundance of their baseline gut microbiota. Responders were characterized by increased abundance of taxa belonging to the genera Sporobacter (P ,0.05) and Subdoligranulum (P,0.02) and decreased abundance of taxa belonging to Bacteroides (P,0.05) relative to nonresponders. In addition, other differences in microbiome composition between responders vs. non-responders were identified during the LFSD. Conclusions: A LFSD was effective in decreasing abdominal pain frequency in children with IBS. Those children who had ≥ 50% reduction in pain frequency had less hydrogen production and a different stool microbiome composition vs. those who did not respond to the LFSD suggesting that gut microbiome makeup may predict LFSD efficacy in childhood IBS. Pain and stool characteristics (baseline vs. LFSD*)