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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. The Inflammatory Bowel Disease Multi’omics Database includes longitudinal data encompassing a multitude of analyses of stool, blood and biopsies of more than 100 individuals, and provides a comprehensive description of host and microbial activities in inflammatory bowel diseases.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown aetiology affecting the colon and rectum. Multiple factors, such as genetic background, environmental and luminal factors, and mucosal immune dysregulation, have been suggested to contribute to UC pathogenesis. UC has evolved into a global burden given its high incidence in developed countries and the substantial increase in incidence in developing countries. An improved understanding of the mechanisms underlying UC has led to the emergence of new treatments. Since the early 2000s, anti-tumour necrosis factor (TNF) treatment has significantly improved treatment outcomes. Advances in medical treatments have enabled a paradigm shift in treatment goals from symptomatic relief to endoscopic and histological healing to achieve better long-term outcomes and, consequently, diagnostic modalities have also been improved to monitor disease activity more tightly. Despite these improvements in patient care, a substantial proportion of patients, for example, those who are refractory to medical treatment or those who develop colitis-associated colorectal dysplasia or cancer, still require restorative proctocolectomy. The development of novel drugs and improvement of the treatment strategy by implementing personalized medicine are warranted to achieve optimal disease control. However, delineating the aetiology of UC is necessary to ultimately achieve disease cure. Ulcerative colitis is a chronic inflammatory bowel disease affecting the rectum and the colon. This Primer describes the epidemiology, the current understanding of ulcerative colitis pathophysiology and its diagnosis. In addition, Hibi and colleagues highlight the current and emerging therapeutic strategies and discuss the most pressing questions in the field.

Rinse Weersma, Carl Anderson and colleagues report the results of a trans-ancestry association study of inflammatory bowel disease. They implicate 38 new susceptibility loci, and show that the variance explained by each IBD risk locus is consistent across diverse ancestries, with a few notable exceptions. Ulcerative colitis and Crohn's disease are the two main forms of inflammatory bowel disease (IBD). Here we report the first trans-ancestry association study of IBD, with genome-wide or Immunochip genotype data from an extended cohort of 86,640 European individuals and Immunochip data from 9,846 individuals of East Asian, Indian or Iranian descent. We implicate 38 loci in IBD risk for the first time. For the majority of the IBD risk loci, the direction and magnitude of effect are consistent in European and non-European cohorts. Nevertheless, we observe genetic heterogeneity between divergent populations at several established risk loci driven by differences in allele frequency ( NOD2 ) or effect size ( TNFSF15 and ATG16L1 ) or a combination of these factors ( IL23R and IRGM ). Our results provide biological insights into the pathogenesis of IBD and demonstrate the usefulness of trans-ancestry association studies for mapping loci associated with complex diseases and understanding genetic architecture across diverse populations.

B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n  = 145; validation cohort 1, n  = 664; and validation cohort 2, n  = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG + plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvβ6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis. Multi-modal profiling reveals major alterations in colonic B cells in patients with ulcerative colitis, including reduced clonal diversity of plasma cells, and suggests that circulating gut-homing plasmablasts could serve as a biomarker for disease activity.

Damage to the colon mucus barrier, the first line of defense against microorganisms, is an important determinant of intestinal diseases such as inflammatory bowel disease and colorectal cancer, and disorder in extraintestinal organs. The mucus layer has attracted the attention of the scientific community in recent years, and with the discovery of new mucosal components, it has become increasingly clear that the mucosal barrier is a complex system composed of many components. Moreover, certain components are jointly involved in regulating the structure and function of the mucus barrier. Therefore, a comprehensive and systematic understanding of the functional components of the mucus layer is clearly warranted. In this review, we summarize the various functional components of the mucus layer identified thus far and describe their unique roles in shaping mucosal structure and function. Furthermore, we detail the mechanisms underlying mucus secretion, including baseline and stimulated secretion. In our opinion, baseline secretion can be categorized into spontaneous Ca 2+ oscillation-mediated slow and continuous secretion and stimulated secretion, which is mediated by massive Ca 2+ influx induced by exogenous stimuli. This review extends the current understanding of the intestinal mucus barrier, with an emphasis on host defense strategies based on fortification of the mucus layer. Gut health: Mucus barrier is key to intestinal defences The intestine’s mucus barrier is a multi-component system that, aided by a continual flow of mucus secretions, helps to protect the gut from pathogens. Xiaohong Zhang, Yuping Zhou and colleagues from Ningbo University, China, review the mucin proteins, antimicrobial peptides and other proteins that collectively determine the structure and function of the thick gel-like mucus that covers the surface of the gut. Specialized secretory cells in the gut lining produce this intestinal mucus, both through a continuous steady baseline process and in response to stress and other stimuli. Impaired secretion or loss of the protective mucus layer can expose intestinal cells to pathogenic microbes that contribute to inflammatory bowel disease, colorectal cancer and other gut disorders. A better understanding of mucosal components and turnover could therefore lead to new therapies for these diseases.

A key challenge for the effective treatment of gastrointestinal diseases including inflammatory bowel disease is to develop an orally administered drug delivery system capable of prolonged retention in the gastrointestinal tract. Herein we report a bioadhesive liquid coacervate based on hydrogen bonding-driven nanoparticle assembly. Free from electrostatic interactions, our fluid nanoparticle-assembled coacervate demonstrates significant pH- and salt-independent structural stability and forms a physically adhesive coating on a large surface area of intestinal tract with an extended residence time of more than 2 days to mediate the sustained release of preloaded water-soluble small molecule drugs in vivo. The orally administered drug-laden nanoparticle-assembled coacervate significantly mitigates the symptoms of inflammatory bowel disease, restores the diversity of gut microbiota, reduces systemic drug exposure, and improves the therapeutic efficacy in a rat acute colitis model compared with the oral administration of the same amount of drug in solution form. We suggest that the nanoparticle-assembled coacervate provides a promising drug delivery platform for management and treatment of numerous gastrointestinal diseases where controlled drug release with extended residence time is desired. The development of a drug delivery system capable of prolonged retention in the gastrointestinal tract remains a clinical challenge. Here the authors present a bio-adhesive liquid coacervate coating on the intestinal tract that acts as a flowable drug carrier, mediates the sustained release of diverse drugs, and potentially enhances therapeutic efficacy against gastrointestinal diseases.

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer 1 – 3 . However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ , TRAF3IP2 , ZC3H12A , PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ- mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz -mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer. In patients with ulcerative colitis, chronic inflammation can lead to remodelling of the colorectal epithelium through positive selection of clones with mutations in genes related to IL-17 signalling, which, however, might be negatively selected during colitis-associated carcinogenesis.

Colonic antigen-experienced lymphocytes such as tissue-resident memory CD8 + T cells can respond rapidly to repeated antigen exposure. However, their cellular phenotypes and the mechanisms by which they drive immune regulation and inflammation remain unclear. Here we compiled an unbiased atlas of human colonic CD8 + T cells in health and ulcerative colitis (UC) using single-cell transcriptomics with T-cell receptor repertoire analysis and mass cytometry. We reveal extensive heterogeneity in CD8 + T-cell composition, including expanded effector and post-effector terminally differentiated CD8 + T cells. While UC-associated CD8 + effector T cells can trigger tissue destruction and produce tumor necrosis factor (TNF)-α, post-effector cells acquire innate signatures to adopt regulatory functions that may mitigate excessive inflammation. Thus, we identify colonic CD8 + T-cell phenotypes in health and UC, define their clonal relationships and characterize terminally differentiated dysfunctional UC CD8 + T cells expressing IL-26, which attenuate acute colitis in a humanized IL-26 transgenic mouse model. Multimodal single-cell profiling reveals heterogeneity of colonic CD8 + T cells in patients with ulcerative colitis, including expansion of a chronically activated IL-26-expressing subpopulation with innate-like features.

The pathogenesis of ulcerative colitis (UC), a major type of inflammatory bowel disease, remains unknown. No model exists that adequately recapitulates the complexity of clinical UC. Here, we take advantage of induced pluripotent stem cells (iPSCs) to develop an induced human UC-derived organoid (iHUCO) model and compared it with the induced human normal organoid model (iHNO). Notably, iHUCOs recapitulated histological and functional features of primary colitic tissues, including the absence of acidic mucus secretion and aberrant adherens junctions in the epithelial barrier both in vitro and in vivo. We demonstrate that the CXCL8/CXCR1 axis was overexpressed in iHUCO but not in iHNO. As proof-of-principle, we show that inhibition of CXCL8 receptor by the small-molecule non-competitive inhibitor repertaxin attenuated the progression of UC phenotypes in vitro and in vivo. This patient-derived organoid model, containing both epithelial and stromal compartments, will generate new insights into the underlying pathogenesis of UC while offering opportunities to tailor interventions to the individual patient. Although ulcerative colitis (UC) is a major type of inflammatory bowel disease, attempts to model it fully have fallen short. Here the authors use patient-derived iPS cells to develop a UC organoid model that recapitulates disease histological and functional features, and confirm the role of CXCL8/CXCR1 in pathogenesis.

Excessive accumulation of reactive oxygen and nitrogen species (RONS) and dysbiosis of intestinal microbiota are pivotal symptoms for inflammatory bowel disease (IBD) and its associated complications, such as intestinal fibrosis. This research introduces a probiotic inulin hydrogel loaded with polypyrrole (PPy) nanozymes and antifibrotic drug pirfenidone (PFD) (PPy/PFD@Inulin gel) designed for the concurrent amelioration of IBD and its fibrotic complication. Upon oral administration, the inulin gel matrix could extend the gastrointestinal residence time of PPy nanozymes and PFD, facilitating the efficient reduction of pro-inflammatory cytokine levels and enhancement of the intestinal epithelial barrier repair as well as the suppression of intestinal fibrosis through sustained RONS scavenging, modulation of gut microbiota and attenuation of the TGF-β/Smad signaling pathway to inhibit fibroblast proliferation. Notably, the PPy/PFD@Inulin gel demonstrated significant prophylactic and therapeutic efficacy in acute and chronic colitis as well as intestinal fibrosis induced by dextran sodium sulfate (DSS) in mouse models. Thus, the engineered ternary PPy/PFD@Inulin gel offered a pioneered paradigm for simultaneous reversal of IBD and its associated complications, such as intestinal fibrosis, in a single therapeutic regimen. Because of its complex pathophysiology, the management of inflammatory bowel disease as well as its fibrotic complication has become a global challenge. Here, the authors show a probiotic inulin hydrogel loaded with polypyrrole (PPy) nanozymes and antifibrotic drug pirfenidone (PFD) (PPy/PFD@Inulin gel) designed for the concurrent amelioration of IBD and its fibrotic complication.