Precision medicine in immune-mediated inflammatory diseases (IMIDs) requires an understanding of how cellular networks change following therapy. We describe a therapeutic atlas for Crohn’s disease (CD) and ulcerative colitis (UC) following anti-tumour necrosis factor (TNF) therapy. We generated ~1 million single-cell transcriptomes, organised into 109 cell states, from 216 gut biopsies from 38 patients and three controls, revealing disease- and therapy-specific differences. A systems-biology analysis identified distinct spatially-resolved cellular microenvironments: granuloma signatures in CD and interferon (IFN)-response signatures localising to T-cell aggregates and epithelial damage in CD and UC. Longitudinal comparisons demonstrated that disease progression in non-responders associated with myeloid and stromal cell perturbations in CD and increased multi-cellular IFN signalling in UC. IFN signalling was also observed in rheumatoid arthritis (RA) synovium with a lymphoid pathotype. Our therapeutic atlas informs drug positioning across IMIDs, and suggests a rationale for the use of janus kinase (JAK) inhibition following anti-TNF resistance.

Although intestinal epithelial cells (IECs) can express major histocompatibility complex class II (MHC II), especially during intestinal inflammation, it remains unclear if antigen presentation by IECs favours pro- or anti-inflammatory CD4 + T cell responses. Using selective gene ablation of MHC II in IECs and IEC organoid cultures, we assessed the impact of MHC II expression by IECs on CD4 + T cell responses and disease outcomes in response to enteric bacterial pathogens. We found that intestinal bacterial infections elicit inflammatory cues that greatly increase expression of MHC II processing and presentation molecules in colonic IECs. Whilst IEC MHC II expression had little impact on disease severity following Citrobacter rodentium or Helicobacter hepaticus infection, using a colonic IEC organoid-CD4 + T cell co-culture system, we demonstrate that IECs can activate antigen-specific CD4 + T cells in an MHC II-dependent manner, modulating both regulatory and effector Th cell subsets. Furthermore, we assessed adoptively transferred H. hepaticus -specific CD4 + T cells during intestinal inflammation in vivo and report that IEC MHC II expression dampens pro-inflammatory effector Th cells. Our findings indicate that IECs can function as non-conventional antigen presenting cells and that IEC MHC II expression fine-tunes local effector CD4 + T cell responses during intestinal inflammation.

The relationship between gastrointestinal tract infection, the host immune response, and the clinical outcome of disease is not well understood in COVID-19. We sought to understand the effect of intestinal immune responses to SARS-CoV-2 on patient outcomes including the magnitude of systemic antibody induction. Combining two prospective cohort studies, International Severe Acute Respiratory and emerging Infections Consortium Comprehensive Clinical Characterisations Collaboration (ISARIC4C) and Integrated Network for Surveillance, Trials and Investigations into COVID-19 Transmission (INSTINCT), we acquired samples from 88 COVID-19 cases representing the full spectrum of disease severity and analysed viral RNA and host gut cytokine responses in the context of clinical and virological outcome measures. There was no correlation between the upper respiratory tract and faecal viral loads. Using hierarchical clustering, we identified a group of fecal cytokines including Interleukin-17A, Granulocyte macrophage colony-stimulating factor, Tumor necrosis factorα, Interleukin-23, and S100A8, that were transiently elevated in mild cases and also correlated with the magnitude of systemic anti-Spike-receptor-binding domain antibody induction. Receiver operating characteristic curve analysis showed that expression of these gut cytokines at study enrolment in hospitalised COVID-19 cases was associated negatively with overall clinical severity implicating a protective role in COVID-19. This suggests that a productive intestinal immune response may be beneficial in the response to a respiratory pathogen and a biomarker of a successful barrier response.

Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte‐specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti‐inflammatory energy substrates. Instead, Atg7 ‐deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2‐mediated upregulation of Ephx1 . This shift reduced secretion of IL‐10 from adipose tissues, which was dependent on the cytochrome P450‐EPHX pathway, and lowered circulating levels of IL‐10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat‐gut crosstalk through an autophagy‐dependent regulation of anti‐inflammatory oxylipins via the cytochrome P450‐EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.

Musculoskeletal diseases affect up to 20% of adults worldwide. The gut microbiome has been implicated in inflammatory conditions, but large-scale metagenomic evaluations have not yet traced the routes by which immunity in the gut affects inflammatory arthritis. To characterize the community structure and associated functional processes driving gut microbial involvement in arthritis, the Inflammatory Arthritis Microbiome Consortium investigated 440 stool shotgun metagenomes comprising 221 adults diagnosed with rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis and 219 healthy controls and individuals with joint pain without an underlying inflammatory cause. Diagnosis explained about 2% of gut taxonomic variability, which is comparable in magnitude to inflammatory bowel disease. We identified several candidate microbes with differential carriage patterns in patients with elevated blood markers for inflammation. Our results confirm and extend previous findings of increased carriage of typically oral and inflammatory taxa and decreased abundance and prevalence of typical gut clades, indicating that distal inflammatory conditions, as well as local conditions, correspond to alterations to the gut microbial composition. We identified several differentially encoded pathways in the gut microbiome of patients with inflammatory arthritis, including changes in vitamin B salvage and biosynthesis and enrichment of iron sequestration. Although several of these changes characteristic of inflammation could have causal roles, we hypothesize that they are mainly positive feedback responses to changes in host physiology and immune homeostasis. By connecting taxonomic alternations to functional alterations, this work expands our understanding of the shifts in the gut ecosystem that occur in response to systemic inflammation during arthritis.

16S rRNA gene sequencing is a cost-effective method for profiling the bacterial component of a microbiome. Nevertheless, processing and analysis of the resulting sequencing data is often constrained by the availability of dedicated bioinformaticians - creating a bottleneck for biological interpretation. Multiple visualisation and analysis tools now exist for downstream analysis of 16S rRNA data. These tools are designed with biological scientists in mind and therefore consist of a graphical user interface that interacts with taxonomic counts tables to perform tasks such as alpha- and beta-diversity analysis and differential abundance. However, generating the input to these applications still relies on bioinformatics experience, creating a disconnect between data processing and data analysis. We aimed to bridge the gap between data processing and data analysis. To do this we have created two tools - OCMS_16S and OCMSlooksy - that perform data processing and data visualisation/analysis, respectively. OCMS_16S is a cgat-core based pipeline that wraps DADA2 functionality in order to facilitate processing of raw sequence reads into tables of amplicon sequence variant (ASV) counts using a simple command line interface. OCMSlooksy is an RShiny application that takes an OCMS_16S-generated SQLite database as input to facilitate data exploration and analysis. Combining these tools provides a simple, user-friendly workflow to facilitate 16S rRNA gene amplicon sequencing data analysis from raw reads to results.

Background: Patients with primary sclerosing cholangitis (PSC) frequently have co-ocurring ulcerative colitis (UC) and develop colorectal cancer. Colorectal cancer risk in patients with PSC-associated ulcerative colitis (PSC/UC) is elevated relative to patients with ulcerative colitis (UC) alone, reasons for which remain obscure. Understanding the molecular and microbial basis for differences between these two patient groups and how these vary across intestinal sites is important for the development of therapies to prevent colorectal cancer development in at-risk individuals. Methods: We employed ribonucleic acid sequencing (RNA-seq) analysis of biopsy samples across three intestinal tissue locations (ileum, caecum and rectum) in patients with PSC/UC (ileum n = 7, caecum n = 7, rectum n = 7), UC (ileum n = 9, caecum n = 10, rectum n = 10) and healthy controls (ileum n = 11, caecum n = 9, rectum n = 12) to determine tissue-dependent transcriptional alterations in PSC/UC. We also performed 16S ribosomal RNA (rRNA) amplicon sequencing to determine bacterial associations with PSC/UC. Results: Tissue-defining transcriptional signatures revealed that the ileum was enriched for genes involved in lipid and drug metabolism, the caecum for activated immune cells and the rectum for enteric neurogenesis. Transcriptional alterations relative to healthy control samples were largely shared between patients with PSC/UC or UC although were distinct across tissue locations. Nevertheless, we observed reduced expression of gamma-glutamyl transferase 1 (GGT1) specifically in the ileum and caecum of patients with PSC/UC. Analysis of the bacterial component of the microbiome revealed high inter-individual variability of microbiome composition and little evidence for tissue-dependency. We observed a reduction in Parabacteroides relative abundance in the rectum of patients with PSC/UC. Conclusions: The role of gamma-glutamyl transferase in maintaining the redox environment through the glutathione salvage pathway makes our observed alterations a potential pathway to PSC-associated colorectal cancer.

Abstract Background Obesity, metabolic disease and some psychiatric conditions are associated with changes to relative abundance of bacterial species and specific genes in the faecal microbiome. Little is known about the impact of pharmacologically induced weight loss on distinct microbiome species and their respective gene programs in obese individuals. Methodology Using shotgun metagenomics, the composition of the microbiome was obtained for two cohorts of obese female Wistar rats (n = 10–12, total of 82) maintained on a high fat diet before and after a 42-day treatment with a panel of four investigatory or approved anti-obesity drugs (tacrolimus/FK506, bupropion, naltrexone and sibutramine), alone or in combination. Results Only sibutramine treatment induced consistent weight loss and improved glycaemic control in the obese rats. Weight loss was associated with reduced food intake and changes to the faecal microbiome in multiple microbial taxa, genes, and pathways. These include increased β-diversity, increased relative abundance of multiple Bacteroides species, increased Bacteroides/Firmicutes ratio and changes to abundance of genes and species associated with obesity-induced inflammation, particularly those encoding components of the flagellum and its assembly. Conclusions Sibutramine-induced weight loss in obese rats is associated with improved metabolic health, and changes to the faecal microbiome consistent with a reduction in obesity-induced bacterially-driven inflammation.

Background: Pleural infection is a common and severe disease with high morbidity and mortality worldwide. Knowledge of pleural infection bacteriology remains incomplete. The TORPIDS study was designed to discover the microbiome of pleural infection and assess correlation of bacterial patterns with clinically important outcomes. Methods: Pleural fluid samples (n=243) from the Pleural Infection Longitudinal Outcome Study (PILOT) were subjected to 16S rRNA next generation sequencing. Multivariate regression analysis was applied to investigate the link between bacterial patterns and clinical outcomes. Results: Pleural infection was predominately polymicrobial (79% of samples) with diverse bacterial patterns observed in monomicrobial and polymicrobial disease. Mixed anaerobes and other Gram-negative bacteria predominated in polymicrobial infection whereas Streptococcus pneumoniae prevailed in monomicrobial cases. The presence of anaerobes (HR=0.46, P=0.02) or bacteria of the Streptococcus anginosus group (HR=0.43, P=0.04) was associated with better survival, while the presence (HR=5·80, P<0·001) or dominance (HR=3.97, P=0.02) of Staphylococcus aureus was linked with higher mortality. Dominance of Enterobacteriaceae was associated with higher risk of death (HR=2.79, P=0.04). No differences were detected for duration of hospitalisation and the need for surgery. Conclusion: Polymicrobiality in pleural infection explains the requirement for broad spectrum antibiotic cover in most individuals. High mortality infection associated with Staphylococcus aureus and Enterobacteriaceae favours more aggressive but narrower spectrum antibiotic strategies.

Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu.

Pruritogenic activity of these compounds was assessed by intradermal injection in wild type and TRPA1-deficient mice.Results: Several fractions from bile activated the TRPA1 receptor (and several other receptors) in vitro.One of these fractions contained a compound with m/z 311.22 which could be identified as a hydrophilic isomer of hydroperoxylinoleic acid (HpODE).We could also show that in bile HpODE is rapidly converted into a hydrophilic isomer.Upon biliary diversion of a BRIC type 1 patient we could show that the initial excretion of HpODE and its metabolites is very high with gradual decrease concomitant with the disappearance of itch.In plasma of pruritic cholestatic patients HpODE concentrations were significantly increased compared to cholestatic patients without itch and healthy controls.Wild type mice exhibited scratching behavior upon intradermal injection of HpODE, whereas TRPA1 deficient mice did not.Conclusion: HpODE, a pruritogen in vitro and in vivo is present in elevated levels in cholestatic patients who experience itch.This compound, and its metabolites is highly secreted into bile upon biliary diversion.Pruriceptor antagonists may be useful in the treatment of cholestatic pruritus.

Pathobionts are members of the gut microbiota with the capacity to cause disease when there is malfunctioning intestinal homeostasis. These organisms are thought to be major contributors to the pathogenesis of inflammatory bowel disease (IBD), a group of chronic inflammatory disorders driven by dysregulated responses towards the microbiota. Over two decades have passed since the discovery of Helicobacter hepaticus, a mouse pathobiont which causes colitis in the context of immune deficiency. During this time, we have developed a detailed understanding of the cellular players and cytokine networks which drive H. hepaticus immunopathology. However, we are just beginning to understand the microbial factors that enable H. hepaticus to interact with the host and influence colonic health and disease. Here we review key H. hepaticus-host interactions, their relevance to other exemplar pathobionts and how when maladapted they drive colitis. Further understanding of these pathways may offer new therapeutic approaches for IBD.

Background Pleural infection is a common and severe disease with high morbidity and mortality worldwide. The knowledge of pleural infection bacteriology remains incomplete, as pathogen detection methods based on culture have insufficient sensitivity and are biased to selected microbes. We designed a study with the aim to discover and investigate the total microbiome of pleural infection and assess the correlation between bacterial patterns and 1-year survival of patients. Methods We assessed 243 pleural fluid samples from the PILOT study, a prospective observational study on pleural infection, with 16S rRNA next generation sequencing. 20 pleural fluid samples from patients with pleural effusion due to a non-infectious cause and ten PCR-grade water samples were used as controls. Downstream analysis was done with the DADA2 pipeline. We applied multivariate Cox regression analyses to investigate the association between bacterial patterns and 1-year survival of patients with pleural infection. Findings Pleural infection was predominately polymicrobial (192 [79%] of 243 samples), with diverse bacterial frequencies observed in monomicrobial and polymicrobial disease and in both community-acquired and hospital-acquired infection. Mixed anaerobes and other Gram-negative bacteria predominated in community-acquired polymicrobial infection whereas Streptococcus pneumoniae prevailed in monomicrobial cases. The presence of anaerobes (hazard ratio 0.46, 95% CI 0.24-0-86, p=0.015) or bacteria of the Streptococcus anginosus group (0.43, 0.19-0.97, p=0.043) was associated with better patient survival, whereas the presence (5.80, 2.37-14.21, p<0.0001) or dominance (3.97, 1-20-13.08, p=0.024) of Staphylococcus aureus was linked with lower survival. Moreover, dominance of Enterobacteriaceae was associated with higher risk of death (2.26,1.03-4.93,0.041). Interpretation Pleural infection is a predominantly polymicrobial infection, explaining the requirement for broad spectrum antibiotic cover in most individuals. High mortality infection associated with Saureus and Enterobacteriaceae favours more aggressive, with a narrower spectrum, antibiotic strategies. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd.

Pathobionts are members of the gut microbiota with the capacity to cause disease when there is malfunctioning intestinal homeostasis. These organisms are thought to be major contributors to the pathogenesis of inflammatory bowel disease (IBD), a group of chronic inflammatory disorders driven by dysregulated responses towards the microbiota. Over two decades have passed since the discovery of Helicobacter hepaticus, a mouse pathobiont which causes colitis in the context of immune deficiency. During this time, we have developed a detailed understanding of the cellular players and cytokine networks which drive H. hepaticus immunopathology. However, we are just beginning to understand the microbial factors that enable H. hepaticus to interact with the host and influence colonic health and disease. Here we review key H. hepaticus-host interactions, their relevance to other exemplar pathobionts and how when maladapted they drive colitis. Further understanding of these pathways may offer new therapeutic approaches for IBD.

Intestinal epithelium represents a dynamic and diverse cellular system that continuously interacts with gut commensals and external cues. Intestinal stem cells, which lie at the heart of epithelial renewal and turnover, proliferate to maintain a steady stem cell population and differentiate to form functional epithelial cell types. This rather sophisticated assembly-line is maintained by an elaborate micro-environment, sculpted by a myriad of host and gut microbiota-derived signals, forming an intestinal stem cell niche. This complex, yet crucial signaling niche undergoes dynamic changes during homeostasis and chronic intestinal inflammation. Inflammatory bowel disease refers to a chronic inflammatory response toward pathogenic or commensal microbiota, in a genetically susceptible host. Compositional and functional alterations in gut microbiota are pathognomonic of IBD.The present review highlights the modulatory role of gut microbiota on the intestinal stem cell niche during homeostasis and inflammatory bowel disease. We discuss the mechanisms of direct action of gut commensals (through microbiota-derived or microbiota-influenced metabolites) on ISCs, followed by their effects via other epithelial and immune cell types.

Background: Obesity, metabolic disease and some psychiatric conditions are associated with changes to relative abundance of bacterial species and specific genes in the fecal microbiome. Little is known about the impact of pharmacologically induced weight loss on distinct gut microbiome species and their respective gene programs in obese individuals. Results: Using shotgun metagenomics, the composition of the microbiome was obtained for two cohorts of obese female Wistar rats (n=10-12, total of 82) maintained on a high fat diet before and after a 42-day treatment with a panel of four investigatory or approved anti-obesity drugs (tacrolimus/FK506, bupropion, naltrexone and sibutramine), alone or in combination. We found that sibutramine treatment induced consistent weight loss through reducing food intake. Weight loss in sibutramine-treated rats was associated with changes to the gut microbiome that included increased beta-diversity, increased Bacteroides/Firmicutes ratio and increased relative abundance of multiple Bacteroides species. In addition, the relative abundance of multiple genes was found to be differentially abundant, including significant reductions in components of flagellum and genes involved in flagellum assembly. Conclusions: This study provides a large resource comprising complete shotgun metagenomics datasets of the fecal microbiome coupled with weight change and food intake at day 3, day 15 and day 42 from 82 obese rats treated with a range of compounds used for weight loss, which are available to the community for detailed analysis. Furthermore, by conducting a detailed analysis of the microbiome associated with sibutramine-induced weight loss, we have identified multiple weight-loss associated microbial taxa and pathways. These include a reduction in components of flagellum and the flagellum assembly pathway that points to a potential role of sibutramine-induced weight-loss on regulating bacterially driven anti-inflammatory responses.

This folder contains data required to re-run the data analysis. It is annotations data that includes:c2.cp.reactome.v6.1.symbols.tsv - reactome pathways (MSigDB)gene_id2gene_name - Ensembl gene id to gene name mappingc3.tft.v6.1.symbols.tsv - transcription factor gene sets (MSigDB)geneset_all.gtf.gz - Ensembl hg38 build 91 gtf annotationc5.bp.v6.1.symbols.tsv - GO biological pathway genesets (MSigDB)teichmann_fractions.txt - Cell fractions estimated usig scRNAseq from https://www.gutcellatlas.org/

AbstractBackgroundIdentifying which taxa are targeted by immunoglobulins can uncover important host-microbe interactions. Immunoglobulin binding of commensal taxa can be assayed by sorting bound bacteria from samples and using amplicon sequencing to determine their taxonomy, a technique most widely applied to study Immunoglobulin A (IgA-Seq). Previous experiments have scored taxon binding in IgA-Seq datasets by comparing abundances in the IgA bound and unbound sorted fractions. However, as these are relative abundances, such scores are influenced by the levels of the other taxa present and represent an abstract combination of these effects. Diversity in the practical approaches of prior studies also warrants benchmarking of the individual stages involved. Here, we provide a detailed description of the design strategy for an optimised IgA-Seq protocol. Combined with a novel scoring method for IgA-Seq datasets that accounts for the aforementioned effects, this platform enables accurate identification and quantification of commensal gut microbiota targeted by host immunoglobulins.ResultsUsing germ-free andRag1−/−mice as negative controls, and a strain-specific IgA antibody as a positive control, we determine optimal reagents and fluorescence activated cell sorting (FACS) parameters for IgA-Seq. Using simulated IgA-Seq data, we show that existing IgA-Seq scoring methods are influenced by pre-sort relative abundances. This has consequences for the interpretation of case-control studies where there are inherent differences in microbiota composition between groups. We show that these effects can be addressed using a novel scoring approach based on posterior probabilities. Finally, we demonstrate the utility of both the IgA-Seq protocol and probability-based scores by examining both novel and published data fromin vivodisease models.ConclusionsWe provide a detailed IgA-Seq protocol to accurately isolate IgA-bound taxa from intestinal samples. Using simulated and experimental data, we demonstrate novel probability-based scores that adjust for the compositional nature of relative abundance data to accurately quantify taxon-level IgA binding. All scoring approaches are made available in the IgAScores R package. These methods should improve the generation and interpretation of IgA-Seq datasets and could be applied to study other immunoglobulins and sample types.

One of the ways in which the human microbiome interacts with its host is via the vast array of chemically diverse metabolites it produces. The importance of the microbiome 'metabolome' to the host is underscored by its associations with a diverse range of host biological processes as well as an increasing number of chronic disease states such as obesity, inflammatory bowel disease, liver disease and metabolic syndrome. These associations are often complex and, in many cases, mechanistic links remain unclear. Metabolomics is a state-of-the-art analytical technique used to identify metabolic changes in biochemical systems and can reveal mechanistic links between microbiome composition, host homoeostasis and aberrant disease states. Here, we provide an overview of current metabolomics applications investigating important human diseases linked to the microbiome. In addition, we introduce recent technical developments in metabolomics that have the potential to lead to a greater understanding of how microbiome metabolism contributes to the manifestation of host pathophysiology.

ObjectiveDysregulated immune responses are the cause of IBDs. Studies in mice and humans suggest a central role of interleukin (IL)-23-producing mononuclear phagocytes in disease pathogenesis. Mechanistic insights into the regulation of IL-23 are prerequisite for selective IL-23 targeting therapies as part of personalised medicine.DesignWe performed transcriptomic analysis to investigate IL-23 expression in human mononuclear phagocytes and peripheral blood mononuclear cells. We investigated the regulation of IL-23 expression and used single-cell RNA sequencing to derive a transcriptomic signature of hyperinflammatory monocytes. Using gene network correlation analysis, we deconvolved this signature into components associated with homeostasis and inflammation in patient biopsy samples.ResultsWe characterised monocyte subsets of healthy individuals and patients with IBD that express IL-23. We identified autosensing and paracrine sensing of IL-1α/IL-1β and IL-10 as key cytokines that control IL-23-producing monocytes. Whereas Mendelian genetic defects in IL-10 receptor signalling induced IL-23 secretion after lipopolysaccharide stimulation, whole bacteria exposure induced IL-23 production in controls via acquired IL-10 signalling resistance. We found a transcriptional signature of IL-23-producing inflammatory monocytes that predicted both disease and resistance to antitumour necrosis factor (TNF) therapy and differentiated that from an IL-23-associated lymphocyte differentiation signature that was present in homeostasis and in disease.ConclusionOur work identifies IL-10 and IL-1 as critical regulators of monocyte IL-23 production. We differentiate homeostatic IL-23 production from hyperinflammation-associated IL-23 production in patients with severe ulcerating active Crohn’s disease and anti-TNF treatment non-responsiveness. Altogether, we identify subgroups of patients with IBD that might benefit from IL-23p19 and/or IL-1α/IL-1β-targeting therapies upstream of IL-23.