Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4β7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.

Emerging data indicate a correlation between gut microbial composition and cardiovascular disease including hypertension. The host’s diet greatly affects microbial composition and metabolite production. Short chain fatty acids (SCFAs) are products of microbial fermentation, which can be utilized by the host. It has been suggested that SCFAs play a pivotal role as mediators in a microbiome host: microbial interactions occur in health and disease. The aim of this study was to evaluate the effect of a high salt diet (HSD) on microbial variation and to determine whether this effect is accompanied by an alteration in fecal SCFAs. To this end, Dahl salt-sensitive rats were divided into two groups (n = 10 each): (A) Control: fed regular chow; and (B) Fed HSD. High-throughput pyrosequencing of the 16S rRNA amplicon sequencing was used for microbiome characterizing. Chromatography-mass spectrometry was used to measure the levels of SCFAs: acetic acid, propionic acid, butyric acid, and isobutyric acid in fecal samples. Differences in microbial composition were noted between groups. Principal Coordinate Analysis (PCoA) principal coordinate 1 (PC1) primarily separated controls from the HSD. Four taxa displayed significant differences between HSD and controls. Taxa from the Erwinia genus, the Christensenellaceae and Corynebacteriaceae families, displayed an increased abundance in HSD versus control. In contrast, taxa from the Anaerostipes genus displayed a decreased abundance in HSD. We were able to identify seven unique taxa that were significantly associated with blood pressure. There was a significant difference in fecal acetic acid, as well as propionic and isobutyric acid, but not in the butyric acid composition between groups. Adding salt to a diet impacts the gut’s microbial composition, which may alter fecal SCFA production.

We systematically define differentially expressed lncRNA in the ileum of newly diagnosed pediatric CD. We show lncRNA utility to correctly classify disease or healthy states and demonstrate their regulation in response to an inflammatory signal. These lncRNAs, after mechanistic exploration, may serve as potential new tissue-specific targets for RNA-based interventions.

No abstract

OBJECTIVES: Crohn's disease (CD) is a chronic relapsing-remitting gut inflammatory disorder with a heterogeneous unpredictable course. Dysbiosis occurs in CD; however, whether microbial dynamics in quiescent CD are instrumental in increasing the risk of a subsequent flare remains undefined. METHODS: We analyzed the long-term dynamics of microbial composition in a prospective observational cohort of patients with quiescent CD (45 cases, 217 samples) over 2 years or until clinical flare occurred, aiming to identify whether changes in the microbiome precede and predict clinical relapse. Machine learning was used to prioritize microbial and clinical factors that discriminate between relapsers and nonrelapsers in the quiescent phase. RESULTS: Patients with CD in clinical, biomarker, and mucosal remission showed significantly reduced microbial richness and increased dysbiosis index compared with healthy controls. Of the 45 patients with quiescent CD, 12 (27%) flared during follow-up. Samples in quiescent patients preceding flare showed significantly reduced abundance of Christensenellaceae and S24.7, and increased abundance of Gemellaceae compared with those in remission throughout. A composite flare index was associated with a subsequent flare. Notably, higher individualized microbial instability in the quiescent phase was associated with a higher risk of a subsequent flare (hazard ratio 11.32, 95% confidence interval 3–42, P = 0.0035) using two preflare samples. Importantly, machine learning prioritized the flare index and the intrapersonal instability over clinical factors to best discriminate between relapsers and nonrelapsers. DISCUSSION: Individualized microbial variations in quiescent CD significantly increase the risk of future exacerbation and may provide a model to guide personalized preemptive therapy intensification.

No abstract

The coronavirus disease 2019 (COVID-19) has rapidly spread around the world, impacting the lives of many individuals. Growing evidence suggests that the nasopharyngeal and respiratory tract microbiome are influenced by various health and disease conditions, including the presence and the severity of different viral disease. To evaluate the potential interactions between Severe Acute Respiratory Syndrome Corona 2 (SARS-CoV-2) and the nasopharyngeal microbiome. Microbial composition of nasopharyngeal swab samples submitted to the clinical microbiology lab for suspected SARS-CoV-2 infections was assessed using 16S amplicon sequencing. The study included a total of 55 nasopharyngeal samples from 33 subjects, with longitudinal sampling available for 12 out of the 33 subjects. 21 of the 33 subjects had at least one positive COVID-19 PCR results as determined by the clinical microbiology lab. Inter-personal variation was the strongest factor explaining > 75% of the microbial variation, irrespective of the SARS-CoV-2 status. No significant effect of SARS-CoV-2 on the nasopharyngeal microbial community was observed using multiple analysis methods. These results indicate that unlike some other viruses, for which an effect on the microbial composition was noted, SARS-CoV-2 does not have a strong effect on the nasopharynx microbial habitants.

Celiac disease is provoked by gluten exposure, but the complete pathogenic process in the duodenum and the loss of tolerance to gluten is not well understood. We aimed to define the core celiac transcriptomic signature and pathologic pathways in pre-treatment formalin-fixed paraffin-embedded (FFPE) duodenum biopsies used for clinical diagnosis. We use mRNAseq to define pre-treatment diagnostic duodenum gene expression in 54 pediatric celiac patients and non-celiac controls, and we validate our key findings in two independent cohorts of 67 adults and pediatric participants that used fresh frozen biopsies. We further define similar and divergent genes and pathways in 177 small bowel Crohn disease patients and controls. We observe a marked suppression of mature epithelial metabolic functions in celiac patients, overlapping substantially with the Crohn disease signature. A marked adaptive immune response was noted for the up-regulated signature including interferon response, alpha-beta, and gamma-delta T-cells that overlapped to some extent with the Crohn disease signature. However, we also identified a celiac disease specific signature linked to increased cell proliferation, nuclear division, and cell cycle activity that was localized primarily to the epithelia as noted by CCNB1 and Ki67 staining. Lastly, we demonstrate the utility of the transcriptomic date to correctly classify disease or healthy states in the discovery and validation cohorts. Our data supplement recently published datasets providing insights into celiac pathogenesis using clinical pathology FFPE samples, and can stimulate new approaches to address this highly prevalent condition.