Mucosal host-microbe interactions associate with clinical phenotypes in inflammatory bowel disease.

Disrupted host-microbe interactions at the mucosal level are key to the pathophysiology of IBD. This study aimed to comprehensively examine crosstalk between mucosal gene expression and microbiota in patients with IBD. To study tissue-specific interactions, we perform transcriptomic (RNA-seq) and microbial (16S-rRNA-seq) profiling of 697 intestinal biopsies (645 derived from 335 patients with IBD and 52 from 16 non-IBD controls). Mucosal gene expression patterns in IBD are mainly determined by tissue location and inflammation, whereas the mucosal microbiota composition shows a high degree of individual specificity. Analysis of transcript-bacteria interactions identifies six distinct groups of inflammation-related pathways that are associated with intestinal microbiota (adjusted P < 0.05). An increased abundance of Bifidobacterium is associated with higher expression of genes involved in fatty acid metabolism, while Bacteroides correlates with increased metallothionein signaling. In patients with fibrostenosis, a transcriptional network dominated by immunoregulatory genes is associated with Lachnoclostridium bacteria in non-stenotic tissue (adjusted P < 0.05), while being absent in CD without fibrostenosis. In patients using TNF-α-antagonists, a transcriptional network dominated by fatty acid metabolism genes is linked to Ruminococcaceae (adjusted P < 0.05). Mucosal microbiota composition correlates with enrichment of intestinal epithelial cells, macrophages, and NK-cells. Overall, these data demonstrate the presence of context-specific mucosal host-microbe interactions in IBD, revealing significantly altered inflammation-associated gene-taxa modules, particularly in patients with fibrostenotic CD and patients using TNF-α-antagonists. This study provides compelling insights into host-microbe interactions that may guide microbiota-directed precision medicine and fuels the rationale for microbiota-targeted therapeutics as a strategy to alter disease course in IBD.

Polygenetic risk scores do not add predictive power to clinical models for response to anti-TNFα therapy in inflammatory bowel disease.

BACKGROUND: Anti-tumour necrosis factor alpha (TNFα) therapy is widely used in the management of Crohn's disease (CD) and ulcerative colitis (UC). However, up to a third of patients do not respond to induction therapy and another third of patients lose response over time. To aid patient stratification, polygenetic risk scores have been identified as predictors of response to anti-TNFα therapy. We aimed to replicate the association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients, to establish its clinical validity. MATERIALS AND METHODS: Primary non-response, primary response, durable response and loss of response to anti-TNFα therapy was retrospectively assessed for each patient using stringent definitions. Genome wide genotyping was performed and previously described polygenetic risk scores for primary non-response and durable response were calculated. We compared polygenetic risk scores between patients with primary response and primary non-response, and between patients with durable response and loss of response, using separate analyses for CD and UC. RESULTS: Out of 334 patients with CD, 15 (4%) patients met criteria for primary non-response, 221 (66%) for primary response, 115 (34%) for durable response and 35 (10%) for loss of response. Out of 112 patients with UC, 12 (11%) met criteria for primary non-response, 68 (61%) for primary response, 19 (17%) for durable response and 20 (18%) for loss of response. No significant differences in polygenetic risk scores were found between primary non-responders and primary responders, and between durable responders and loss of responders. CONCLUSIONS: We could not replicate the previously reported association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients with CD or UC. Currently, there is insufficient evidence to use polygenetic risk scores to predict response to anti-TNFα therapy in patients with IBD.

Predicted efficacy of a pharmacogenetic passport for inflammatory bowel disease.

BACKGROUND: High inter-individual variability in therapeutic response to drugs used in the management of Inflammatory Bowel Disease (IBD) leads to high morbidity and high costs. Genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis and immunogenicity of Tumour Necrosis Factor alpha (TNFα) antagonists have been identified, but uptake of pre-treatment pharmacogenetic testing into clinical guidelines has been slow. AIM: To explore the efficacy of a pharmacogenetic passport for IBD that includes multiple pharmacogenetic predictors of response. METHODS: Patients with IBD exposed to thiopurines and/or TNFα antagonists were retrospectively evaluated for the presence of thiopurine toxicity and/or immunogenicity of TNFα antagonists. All patients were genotyped using both whole-exome sequencing and the Illumina Global Screening Array. An in-house-developed computational pipeline translated genetic data into an IBD pharmacogenetic passport that predicted risks for thiopurine toxicity and immunogenicity of TNFα antagonists per patient. Using pharmacogenetic-guided treatment guidelines, we calculated clinical efficacy estimates for pharmacogenetic testing for IBD. RESULTS: Among 710 patients with IBD exposed to thiopurines and/or TNFα antagonists, 150 adverse drug responses occurred and our pharmacogenetic passport would have predicted 54 (36%) of these. Using a pharmacogenetic passport for IBD that includes genetic variants predictive of thiopurine-induced myelosuppression, thiopurine-induced pancreatitis, and immunogenicity of TNFα antagonists, 24 patients need to be genotyped to prevent one of these adverse drug responses. CONCLUSIONS: This study highlights the clinical efficacy of a pharmacogenetic passport for IBD. Implementation of such a pharmacogenetic passport into clinical management of IBD may contribute to a reduction in adverse drug responses.

Predicting (side) effects for patients with inflammatory bowel disease: The promise of pharmacogenetics.

Inflammatory bowel disease (IBD) is a chronic and heterogeneous intestinal inflammatory disorder. The medical management of IBD aims for long-lasting disease remission to prevent complications and disease progression. Early introduction of immunosuppression forms the mainstay of medical IBD management. Large inter-individual variability in drug responses, in terms of both efficacy and toxicity, leads to high rates of therapeutic failure in the management of IBD. Better patient stratification is needed to maximize patient benefit and minimize the harm caused by adverse events. Pre-treatment pharmacogenetic testing has the potential to optimize drug selection and dose, and to minimize harm caused by adverse drug reactions. In addition, optimizing the use of cheap conventional drugs, and avoiding expensive ineffective drugs, will lead to a significant reduction in costs. Genetic variation in both TPMT and NUDT15, genes involved in thiopurine metabolism, is associated to an increased risk of thiopurine-induced myelosuppression. Moreover, specific HLA haplotypes confer risk to thiopurine-induced pancreatitis and to immunogenicity to tumor necrosis factor-antagonists, respectively. Falling costs and increased availability of genetic tests allow for the incorporation of pre-treatment genetic tests into clinical IBD management guidelines. In this paper, we review clinically useful pharmacogenetic associations for individualized treatment of patients with IBD and discuss the path from identification of a predictive pharmacogenetic marker to implementation into IBD clinical care.