Jason Bishai’s research while affiliated with Broad Institute of MIT and Harvard and other places

Inflammatory bowel diseases (IBD) are associated with alterations in gut microbial abundances and lumenal metabolite concentrations, but the effects of specific metabolites on the gut microbiota in health and disease remain largely unknown. Here, we analysed the influences of metabolites that are differentially abundant in IBD on the growth and physiology of gut bacteria that are also differentially abundant in IBD. We found that N-acylethanolamines (NAEs), a class of endogenously produced signalling lipids elevated in the stool of IBD patients and a T-cell transfer model of colitis, stimulated growth of species over-represented in IBD and inhibited that of species depleted in IBD in vitro. Using metagenomic sequencing, we recapitulated the effects of NAEs in complex microbial communities ex vivo, with Proteobacteria blooming and Bacteroidetes declining in the presence of NAEs. Metatranscriptomic analysis of the same communities identified components of the respiratory chain as important for the metabolism of NAEs, and this was verified using a mutant deficient for respiratory complex I. In this study, we identified NAEs as a class of metabolites that are elevated in IBD and have the potential to shift gut microbiota towards an IBD-like composition. Inflammatory bowel diseases (IBD) are associated with increased faecal N-acylethanolamines (NAEs), which are primarily host-produced signalling lipids, in patients and a mouse model of colitis. These metabolites can enhance the growth of bacterial species enriched in IBD faecal samples and are associated with the expression of respiratory chain genes necessary for microbial metabolism of NAEs.

Background: Alterations in the microbiome have been postulated to drive inflammation in IBD. In this pilot randomized controlled trial, we evaluated the effectiveness of quadruple antibiotic cocktail in addition to intravenous-corticosteroids (IVCSs) in acute severe colitis (ASC). Methods: Hospitalized children with ASC (pediatric ulcerative colitis activity index [PUCAI] ≥65) were randomized into 2 arms: the first received antibiotics in addition to IVCS (amoxicillin, vancomycin, metronidazole, doxycycline/ciprofloxacin [IVCS+AB]), whereas the other received only IVCS for 14 days. The primary outcome was disease activity (PUCAI) at day 5. Microbiome was analyzed using 16S rRNA gene and metagenome. Results: Twenty-eight children were included: 16 in the AB + IVCS arm and 12 in the IVCS arm (mean age 13.9 ± 4.1 years and 23 [82%] with extensive colitis). The mean day-5 PUCAI was 25 ± 16.7 vs 40.4 ± 20.4, respectively (P = 0.037). Only 3 and 2 children, respectively, required colectomy during 1-year follow-up (P = 0.89). Microbiome data at time of admission were analyzed for 25 children, of whom 17 (68%) had a predominant bacterial species (>33% abundance); response was not associated with the specific species, whereas decreased microbiome diversity at admission was associated with day-5 response in the IVCS arm. Conclusion: Patients with ASC have alterations in the microbiome characterized by loss of diversity and presence of predominant bacterial species. Quadruple therapy in addition to IVCS improved disease activity on day 5, but larger studies are needed to determine whether this is associated with improved long-term outcomes (clinicaltrials.gov NCT02033408).

Background Acute severe ulcerative colitis (ASC) is one of the few medical emergencies of gastroenterology. We previously reported the clinical results of the PRASCO randomised controlled trial in which oral antibiotics (AB) improved disease activity after 5 days of treatment in children with ASC. This suggests that the microbiome is implicated in the aetiology and progression of ASC. We thus aimed to explore the microbiome of children enrolled in the PRASCO trial. Methods In the PRASCO trial, 26 children with ASC were randomised: 11 received IV corticosteroids (IVCS) and 15 received four oral AB's (amoxycillin, doxycillin/ciprofloxacin, metronidazole, vancomycin) in addition to IVCS. Stool samples were collected at regular intervals during admission. Metagenomic sequencing was performed using Illumina Nextera XT library preparation kit on a HiSeq platform. After filtering low quality and human reads using the KneadData pipeline, species-level taxonomic abundances were inferred for all samples using MetaPhlAn2. Results At baseline before treatment, 14/26 (54%) children harboured more than 30% of a single species: 9 (35%) with Escherichia coli, 2 (7.7%) Haemophilus species, and 1 (3.8%) each with Klebsiella pneumoniae, Barnesiella intestinihominis or Parabacteroides sp. (none with Fusobacterium varium). interestingly, of the 15 children in the AB arm, 11 (73%) had a transient relative bloom of >50% Enterobacteriaceae (mainly E. coli) after treatment, compared with only 3/11 in the IVCS only arm (p = 0.02). Despite this, disease activity at Day 5 was lower in the AB arm and time to remission was shorter (p = 0.049). When analysing all samples, several species of Lachnospiraceae family and Clostridium bartlettii were significantly and positively associated with remission. C. bartletti and R. torques (previously observed to be depleted in IBD and known butyrate producers) were lower in children with more severe disease. Conclusions This is the first report of microbiome pattern in ASC, showing provocative results. Over half of children with ASC have gut microbiomes highly enriched (>30%) at baseline with a specific species, mostly Enterobacteriaceae. This association may suggest that some ASC episodes are triggered by yet unknown enteric infections. While our antibiotic cocktail transiently exacerbated this enrichment it reduced disease activity, possibly due to niche availability after treatment, which can subsequently be filled by butyrate-producing microbes. In addition, the enrichment is relative to other species; it is possible that the absolute count was much lower in the AB group. Dysregulation of butyrate production may be associated with ASC in children. This study was supported by grants from: IOIBD, Helmsley Charitable Trust and Janssen

Background A previous case series suggested a benefit of antibiotic-cocktail in steroid-refractory paediatric UC. In this pilot randomised investigator-blinded controlled trial we aimed to evaluate the effectiveness of wide-spectrum antibiotic regimens in acute severe colitis (ASC) in addition to standard intravenous corticosteroid (IVCS) therapy. Methods Children 2–18 years with ASC (i.e. PUCAI ≥ 65) refractory to oral steroids were randomised into two arms: the first received antibiotics in addition to IVCS (amoxicillin, vancomycin, metronidazole, doxycyclin (or ciprofloxacin in those younger than 8 years of age)-AB+IVCS), while the other received only IVCS. Children with proctitis, infections, and those treated with antibiotics in the preceding 2 weeks were excluded. The primary outcome was total PUCAI score at Day 5 of treatment. Missing data for ITT analysis were imputed using the NRI method for categorical variables and LOCF for continuous variables. Results Thirty children were randomised and two were excluded (one positive for CMV and one salmonella): 16 in the AB+IVCS and 12 in the IVCS arms (mean age 14 ± 2.7 years, range 7–18, 15 (54%) males, 23 (82%) extensive colitis). Baseline variables were similar between groups (PUCAI 73.1 ± 6.6 vs. 75 ± 7.1, respectively). The mean Day 5 PUCAI was 25 ± 16.7 vs. 40.4 ± 20.4, respectively (p = 0.037). View largeDownload slide Total PUCAI score at Day 5 of therapy. View largeDownload slide Total PUCAI score at Day 5 of therapy. Bearing in mind that the trial was not powered for this, there were no differences in the need for second-line therapy during the admission nor in the colectomy rate 1 year following admission (19% vs. 17%; p = 0.89). Median admission days (IQR) was statistically similar (7.5 (5–10) vs. 9 (5.5–13); p = 0.35). Microbiome analysis upon admission was available for 22 children of whom 8 (36%) had a predominant bacterium (>33% abundance). Conclusions In this RCT, the first ever performed in children with ASC, antibiotic cocktail in addition to IVCS improved disease activity on Day 5. Further studies are needed to determine whether this is associated with improved long-term hard outcomes.