The gut microbiome plays a central role in inflammatory bowel diseases (IBDs) pathogenesis and propagation. To determine whether the gut microbiome may predict responses to IBD therapy, we conducted ...a prospective study with Crohn’s disease (CD) or ulcerative colitis (UC) patients initiating anti-integrin therapy (vedolizumab). Disease activity and stool metagenomes at baseline, and weeks 14, 30, and 54 after therapy initiation were assessed. Community α-diversity was significantly higher, and Roseburia inulinivorans and a Burkholderiales species were more abundant at baseline among CD patients achieving week 14 remission. Several significant associations were identified with microbial function; 13 pathways including branched chain amino acid synthesis were significantly enriched in baseline samples from CD patients achieving remission. A neural network algorithm, vedoNet, incorporating microbiome and clinical data, provided highest classifying power for clinical remission. We hypothesize that the trajectory of early microbiome changes may be a marker of response to IBD treatment.
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•Stool metagenomes of IBD patients starting biologic therapy were prospectively assessed•Higher abundance of butyrate producers at baseline in therapy-responsive CD patients•Baseline enrichment of 13 microbial pathways in therapy-responsive CD patients•Early microbial changes at week 14 persist up to 1 year in responders
Gut microbiome may predict responses to clinical therapy. Ananthakrishnan et al. conducted a prospective study with IBD patients initiating anti-integrin therapy. Higher abundance of butyrate producers and enrichment of 13 microbial pathways at baseline in therapy-responsive CD patients was observed. Early microbial changes persist up to 1 year in responders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The inflammatory bowel diseases (IBDs), which include Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial chronic conditions of the gastrointestinal tract. While IBD has been ...associated with dramatic changes in the gut microbiota, changes in the gut metabolome-the molecular interface between host and microbiota-are less well understood. To address this gap, we performed untargeted metabolomic and shotgun metagenomic profiling of cross-sectional stool samples from discovery (n = 155) and validation (n = 65) cohorts of CD, UC and non-IBD control patients. Metabolomic and metagenomic profiles were broadly correlated with faecal calprotectin levels (a measure of gut inflammation). Across >8,000 measured metabolite features, we identified chemicals and chemical classes that were differentially abundant in IBD, including enrichments for sphingolipids and bile acids, and depletions for triacylglycerols and tetrapyrroles. While > 50% of differentially abundant metabolite features were uncharacterized, many could be assigned putative roles through metabolomic 'guilt by association' (covariation with known metabolites). Differentially abundant species and functions from the metagenomic profiles reflected adaptation to oxidative stress in the IBD gut, and were individually consistent with previous findings. Integrating these data, however, we identified 122 robust associations between differentially abundant species and well-characterized differentially abundant metabolites, indicating possible mechanistic relationships that are perturbed in IBD. Finally, we found that metabolome- and metagenome-based classifiers of IBD status were highly accurate and, like the vast majority of individual trends, generalized well to the independent validation cohort. Our findings thus provide an improved understanding of perturbations of the microbiome-metabolome interface in IBD, including identification of many potential diagnostic and therapeutic targets.
Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are ...heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database ( http://ibdmdb.org ), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Introduction
Poor sleep, depression, and anxiety are common in patients with inflammatory bowel diseases (IBD) and associated with increased risk of relapse and poor outcomes. The effectiveness of ...therapies in improving such psychosocial outcomes is unclear but is an important question to examine with increasing selectivity of therapeutic agents.
Methods
This prospective cohort enrolled patients with moderate-to-severe CD or UC starting biologic therapy with vedolizumab or anti-tumor necrosis factor α agents (anti-TNF). Sleep quality, depression, and anxiety were measured using validated short-form NIH PROMIS questionnaires assessing sleep and mood quality over the past 7 days. Disease activity was assessed using validated indices. Improvement in sleep and mood scores from baseline was assessed, and regression models were used to identify determinants of sleep quality.
Results
Our study included 160 patients with IBD (49 anti-TNF, 111 Vedolizumab) among whom half were women and the mean age was 40.2 years. In the combined cohort, we observed a statistically significant and meaningful decrease in mean scores from baseline (52.8) by week 6 (49.8,
p
= 0.002). Among vedolizumab users, sleep T-score improved from baseline (53.6) by week 6 (50.7) and persisted through week 54 (46.5,
p
= 0.009). Parallel reductions in depression and anxiety were also noted (
p
< 0.05 by week 6). We observed no difference in improvement in sleep, depression, and anxiety between vedolizumab and anti-TNF use at week 6.
Conclusions
Both vedolizumab and anti-TNF biologic therapies were associated with improvement in sleep and mood quality in IBD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background
Sleep disruption is common in inflammatory bowel diseases (IBD). However, studies demonstrating a similar prevalence in irritable bowel syndrome suggest that nighttime disruption due to ...diarrhea and abdominal pain may be key drivers of poor sleep quality. Whether inflammation is associated with poor sleep independently has not been examined previously.
Methods
This single-center study included subjects with IBD recruited to an ongoing prospective registry who completed a questionnaire assessing sleep quality and mood. Inflammatory marker levels C-reactive protein (CRP), erythrocyte sedimentation rate and clinical disease activity including nighttime disruption on the day of enrollment were obtained from the medical record. Logistic regression models were used to identify predictors of sleep quality.
Results
The study included 131 subjects (72 women) with a median age of IBD diagnosis of 25 years. Twenty-three subjects (19 %) had a high C-reactive protein level (≥8 mg/dL). Poor sleep was more common in those with high CRP levels than with normal values (70 vs. 39 %,
p
= 0.009). This association remained significant on multivariate analysis Odds ratio (OR) 4.12, 95 % confidence interval (CI) 1.38–12.29. Adjusting for the presence of nighttime disruption did not significant alter this association (OR 3.16, 95 % CI 1.01–9.90). High CRP correlated with poor sleep even in patients not experiencing nocturnal symptoms (
n
= 101, OR 4.89, 95 % CI 1.24–19.36).
Conclusion
High CRP is associated with poor sleep quality in IBD independent of the presence of nighttime disruptions, suggesting that a relationship exists between circulating inflammatory markers and sleep.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Early life exposures may modify risk of inflammatory bowel diseases (IBD; Crohn's disease (CD), ulcerative colitis (UC)). However, the relationship between early life exposures and natural history of ...IBD has not been previously examined.
This single center study included patients with CD or UC recruited in a prospective IBD registry. Enrolled patients completed a detailed environmental questionnaire that assessed various early life environmental exposures. Our primary outcome was requirement for disease-related surgery in CD and UC. Logistic regression models defined independent effect of early life exposures, adjusting for potential confounders.
Our study included 333 CD and 270 UC patients. Just over half were female with a median age at diagnosis of 25 years. One-third of the cohort had history of bowel surgery (31%) and nearly half had used at least one biologic agent (47%). Among those with CD, being breastfed was associated with reduced risk of CD-related surgery (34% vs. 55%), while childhood cigarette smoke exposure was associated with increased risk. On multivariate analysis, history of being breastfed (odds ratio (OR) 0.21, 95% confidence interval CI 0.09-0.46) and cigarette smoke exposure as a child (OR 2.17, 95% CI 1.10-4.29) remained independently associated with surgery. None of the early life variables influenced disease phenotype or outcome in UC.
A history of being breastfed was associated with a decreased risk while childhood cigarette smoke exposure was associated with an increased risk of surgery in patients with CD. Further investigation to examine biological mechanisms is warranted.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Inflammatory bowel disease (IBD) is a group of chronic diseases of the digestive tract that affects millions of people worldwide. Genetic, environmental and microbial factors have been implicated in ...the onset and exacerbation of IBD. However, the mechanisms associating gut microbial dysbioses and aberrant immune responses remain largely unknown. The integrative Human Microbiome Project seeks to close these gaps by examining the dynamics of microbiome functionality in disease by profiling the gut microbiomes of >100 individuals sampled over a 1-year period. Here, we present the first results based on 78 paired faecal metagenomes and metatranscriptomes, and 222 additional metagenomes from 59 patients with Crohn's disease, 34 with ulcerative colitis and 24 non-IBD control patients. We demonstrate several cases in which measures of microbial gene expression in the inflamed gut can be informative relative to metagenomic profiles of functional potential. First, although many microbial organisms exhibited concordant DNA and RNA abundances, we also detected species-specific biases in transcriptional activity, revealing predominant transcription of pathways by individual microorganisms per host (for example, by Faecalibacterium prausnitzii). Thus, a loss of these organisms in disease may have more far-reaching consequences than suggested by their genomic abundances. Furthermore, we identified organisms that were metagenomically abundant but inactive or dormant in the gut with little or no expression (for example, Dialister invisus). Last, certain disease-specific microbial characteristics were more pronounced or only detectable at the transcript level, such as pathways that were predominantly expressed by different organisms in patients with IBD (for example, Bacteroides vulgatus and Alistipes putredinis). This provides potential insights into gut microbial pathway transcription that can vary over time, inducing phenotypical changes that are complementary to those linked to metagenomic abundances. The study's results highlight the strength of analysing both the activity and the presence of gut microorganisms to provide insight into the role of the microbiome in IBD.
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