Monogenic Inflammatory Bowel Disease Research Articles

A224 CHARACTERIZATION OF VERY-EARLY-ONSET INFLAMMATORY BOWEL DISEASE IN CHILDREN ampersand:003C6 YEARS OF AGE: A SINGLE CENTER EXPERIENCE

Abstract Background Very-early-onset inflammatory bowel disease (VEO-IBD), diagnosed before the age of six years old, presents a distinct subtype of pediatric inflammatory bowel disease (IBD). This chronic inflammatory condition is believed to result from an abnormal immune response triggered by environmental factors including the gut microbiota, in genetically susceptible individuals. Aims This study aims to analyze the clinical characteristics and management of VEO-IBD patients in a tertiary medical center, evaluating disease presentation, localization and treatment strategies. Methods A retrospective descriptive study was conducted of 28 VEO-IBD patients diagnosed between January 2001 and January 2019 at our institution. Data was abstracted including patient demographics, clinical features, laboratory and histological parameters, treatment, and disease classification based on the revised Porto Criteria. Results Among the 28 patients, Crohn’s disease (CD) was the predominant diagnosis (89%) with predominantly colonic involvement. Thiry-two percent of patients had isolated colitis whereas the upper gastrointestinal (UGI) tract was involved in 57% of the cohort, approximately one third had involvement of the small bowel. The most common presenting symptoms were rectal bleeding and diarrhea, both occurred in 65% of the patients. Patients were followed for a mean duration of 115 months. Despite prior assumptions of its severity, VEO-IBD patients in this cohort responded well to conventional treatments in which 64% were induced with steroid therapy, 25% received biologics and 35% received immunomodulators. Surgical interventions were relatively infrequent. Only 2 patients out the 28 VEO-IBD patients underwent surgery for refractory colitis, one of them in the 1st 2 years of life. There were limited genetic testing results which made it difficult to know our incidence of monogenic IBD. However, only 5 of our patients had full genetic workup done in other centers for research purposes with 1 patient being diagnosed with monogenic IBD consistent IPEX syndrome. Conclusions This study highlights the unique clinical profile of VEO-IBD, with CD being the prevalent diagnosis in this age group in our population. Our cohort did not have a more severe phenotype, emphasizing that there is significant variation within this group Understanding the predictors of response is needed in individual patients with VEO-IBD is vital for tailored management and improved outcomes in this young population. Funding Agencies None

Catalyzing change: Implementing standardised reporting in monogenic inflammatory bowel disease research.

Catalyzing change: Implementing standardised reporting in monogenic inflammatory bowel disease research.

P186 Comparative Analysis of Clinical Phenotypes and Pathogenic Features between Late-Onset and Infantile-Onset Monogenic Inflammatory Bowel Disease

Abstract Background Previous research on monogenic IBD (m-IBD) has mainly focused on very-early-onset IBD (VEO-IBD) and Montreal classification A1 type IBD patients. In non-A1 type (age > 16y) late-onset IBD patients, some individuals also exhibit IBD manifestations due to monogenic mutations. Here we systematically review the literature, using infantile-onset monogenic IBD patients as a control, to explore the genetic characteristics, clinical presentations, and treatment strategies of late-onset monogenic IBD. Methods Based on the onset age of IBD, m-IBD was categorized into infantile-onset (IO, <2 years) and late-onset (LO, >16 years as non-A1 type based on Montreal classification) groups. A systematic review was conducted to analyze the gastrointestinal (GI) clinical features of detailed cases published from January 1990 to June 2023 and to summarize the correlation between genetic pathogenesis and onset ages. Results 512 m-IBD cases (398 IO and 114 LO) associated with 87 genes were included. Of these genes, 25 out of 87 genes were found to cause both IO and LO conditions. Crohn’s disease (CD) was the predominant type of IBD, account for 42.2% of IO and 44.7% of LO cases. Difficult-to-treat IBD patients showed similar rates (17.4% for IO and 13.0% for LO). However, infantile-onset cases were predominantly associated with complex perianal disease (13.5%), while late-onset cases were linked to postoperative recurrence following surgical resections (10.6%). Anti-inflammatory medicine and biologics were the main strategies, but in infantile-onset (IO) cases, immunosuppressants (57.9%), parenteral nutrition (26.8%), gastroenterostomy (20.2%), and HSCT (24.6%) were more frequently utilized compared to late-onset (LO) cases, where intestinal resection (37.8%) was more prevalent. Homozygosity was the predominant zygosity type (39.9% in IO and 39.3% in LO), while heterozygosity was more prevalent in LO cases (28.9%) compared to IO cases (13.3%) (p<0.05). Most of the genes associated with median onset ages of IBD before 2 years were causative genes for primary immunodeficiency (PID), whereas significantly lower rate of PID genes mutation was found in LO cases (26/27, 96.3% vs. 6/11, 54.5%, p= 0.005). Conclusion m-IBD patients predominantly present with CD, ulceration and atypical pathology, colon involvement, and difficult to treat regardless of onset ages, but vary in terms of family history, GI symptoms, location of the lesion, polyps and villous atrophy, type of complications, treatment options, and type of Difficult-to- treat IBD.

Precision medicine in monogenic inflammatory bowel disease: proposed mIBD REPORT standards.

Owing to advances in genomics that enable differentiation of molecular aetiologies, patients with monogenic inflammatory bowel disease (mIBD) potentially have access to genotype-guided precision medicine. In this Expert Recommendation, we review the therapeutic research landscape of mIBD, the reported response to therapies, the medication-related risks and systematic bias in reporting. The mIBD field is characterized by the absence of randomized controlled trials and is dominated by retrospective observational data based on case series and case reports. More than 25 off-label therapeutics (including small-molecule inhibitors and biologics) as well as cellular therapies (including haematopoietic stem cell transplantation and gene therapy) have been reported. Heterogeneous reporting of outcomes impedes the generation of robust therapeutic evidence as the basis for clinical decision making in mIBD. We discuss therapeutic goals in mIBD and recommend standardized reporting (mIBD REPORT (monogenic Inflammatory Bowel Disease Report Extended Phenotype and Outcome of Treatments)standards) to stratify patients according to a genetic diagnosis and phenotype, to assess treatment effects and to record safety signals. Implementation of these pragmatic standards should help clinicians toassess the therapy responses of individual patients in clinical practice and improve comparability between observational retrospective studies and controlled prospective trials, supporting future meta-analysis.

Approach to a Child with Chronic Diarrhea.

Chronic diarrhea in children is challenging both with regards to etiological diagnosis and for management. Etiology and pathophysiological mechanisms vary widely from neonates to adolescents. Congenital or genetic causes are more frequent in neonates, while infections, allergy and immune-mediated mechanisms are more frequent in childhood. A thorough history and proper physical examination are required to decide for further diagnostic evaluation. The approach to a child with chronic diarrhea should be age specific and based predominantly on the pathophysiological mechanism involved. The nature of the stool like watery, bloody or fatty (steatorrhea) can suggest the probable etiology and organ system involved. After routine tests, evaluation with specific serological tests, imaging, endoscopy (gastroscopy/colonoscopy), histopathology of intestinal mucosa, breath tests or radionuclide imaging may be required to make a definitive diagnosis. Genetic evaluation is important in congenital diarrheas, monogenic inflammatory bowel disease (IBD) and immunodeficiency disorders. Management is aimed at stabilization, nutritional support and etiology specific treatment. Specific therapy can be as simple as exclusion of specific nutrient or as complicated as small bowel transplant. Evaluation and management require expertise and thus patients need to be referred in a timely fashion. This will minimise morbidity including nutritional consequences and improve outcome.

Attenuated Expression of SLCO2A1 Caused by DNA Methylation in Pediatric Inflammatory Bowel Disease.

SLCO2A1 encodes a prostaglandin (PG) transporter, and autosomal recessive pathogenic variants of this gene cause chronic enteropathy associated with SLCO2A1. It is unclear whether a heterozygous pathogenic variant of SLCO2A1 has a role in the pathogenesis of other types of inflammatory bowel disease (IBD). In this study, we investigated the possible involvement of a local epigenetic alteration in SLCO2A1 in patients with a heterozygous pathogenic variant. We conducted whole-exome sequencing of samples from 2 sisters with suspected monogenic IBD. In addition, we performed bisulfite sequencing using DNA extracted from their small and large intestine samples to explore epigenetic alterations. A heterozygous splicing site variant, SLCO2A1:c.940 + 1G > A, was detected in both patients. To explore the possible involvement of epigenetic alterations, we analyzed protein and messenger RNA expression of SLCO2A1, and observed attenuated SLCO2A1 expression in the inflamed lesions of these patients compared with that in the control individuals. Furthermore, bisulfite sequencing indicated dense methylation in the promoter region of SLCO2A1 only in the inflamed lesions of both patients. The urinary PG metabolite levels in these patients were comparable to those in patients with chronic enteropathy associated with SLCO2A1 and higher than those in the control individuals. We found considerably higher levels of the metabolites in patient 1, who showed more severe symptoms than patient 2. Local DNA methylation attenuated SLCO2A1 expression, which may evoke local inflammation of the mucosa by the unincorporated PG. These findings may improve our understanding of the epigenetic mechanisms underlying IBD development.

Pharmacologic Management of Monogenic and Very Early Onset Inflammatory Bowel Diseases.

Inflammatory bowel disease (IBD) is treated with a variety of immunomodulating and immunosuppressive therapies; however, for the majority of cases, these therapies are not targeted for specific disease phenotypes. Monogenic IBD with causative genetic defect is the exception and represents a disease cohort where precision therapeutics can be applied. With the advent of rapid genetic sequencing platforms, these monogenic immunodeficiencies that cause inflammatory bowel disease are increasingly being identified. This subpopulation of IBD called very early onset inflammatory bowel disease (VEO-IBD) is defined by an age of onset of less than six years of age. Twenty percent of VEO-IBDs have an identifiable monogenic defect. The culprit genes are often involved in pro-inflammatory immune pathways, which represent potential avenues for targeted pharmacologic treatments. This review will provide an overview of the current state of disease-specific targeted therapies, as well as empiric treatment for undifferentiated causes of VEO-IBD.

Vertebral Compression Fractures in Very Early Onset Inflammatory Bowel Disease.

Patients with VEOIBD receiving care at a single tertiary center were prospectively enrolled in a longitudinal data repository. Retrospective chart review was performed to identify clinical characteristics and comorbidities. Those with clinically apparent vertebral compression fractures subsequently underwent an additional chart review focused on bone health. Three out of 216 (1.4%) patients with VEOIBD had symptomatic vertebral compression fractures. Of the 3 patients with vertebral compression fractures, all had Crohn's disease, 2 had monogenic inflammatory bowel disease, and all reported back pain. One patient notably had a normal dual-energy X-ray absorptiometry, highlighting a potential limitation of dual-energy X-ray absorptiometry to identify increased skeletal fragility in this population. Risk factors for suboptimal bone health included chronic inflammation secondary to poorly controlled inflammatory bowel disease, substantial glucocorticoid exposure, chronic use of other medications associated with suboptimal bone health including proton pump inhibitors and granulocyte colony-stimulating factor, and solid organ transplant. Patients treated with bisphosphonates had improved clinical outcomes, with resolution of back pain and increased bone mineral density. Vertebral compression fracture should be considered in the differential diagnosis of patients with VEOIBD and back pain, especially in those with other risk factors for suboptimal bone health. Treatment of compression fractures with bisphosphonates resulted in resolution of back pain and improved bone density.

P302 Precision medicine for a case with monogenic inflammatory bowel disease

Abstract Background Here we report the case of a 33-year-old patient suffering from recurring infections since childhood, and Crohn’s disease (CD)-like inflammation in the ileum and colon for 5 years. The patient was transferred to our hospital due to severe pneumonia with Pseudomonas aeruginosa and Mycobacterium chimaera infection, recurrent fever, bronchiectasis, cachexia (BMI 12.9) and severe gastrointestinal symptoms (diarrhoea with blood 15 times per day). Colonoscopy revealed a peculiar inflammatory pattern in the ileum and the colon without healthy sections and deep punched lesions which did not fit to a diagnosis of CD. Methods Exome sequencing was performed and pathogenic variants identified by in silico prediction. Peripheral blood mononuclear cells (PBMCs) were isolated and Signal Transducer And Activator Of Transcription 1 (STAT1) activation was assessed by immunoblot after treatment with JAK-inhibitors. STAT1 activation was quantified in leukocytes of whole blood samples by flow cytometry. Mucosal sections were used to quantify STAT1 activation within mucosal cells by multicolour immunofluorescence. Two healthy individuals served as controls. Results Exome sequencing revealed a pathogenic mutation (c.1256C>G) in the STAT1 gene, which was predicted to cause a gain-of-function. STAT1 is part of the JAK/STAT1 pathway which is induced by different stimuli and orchestrates proliferation and responses of immune cells as a transcription factor. Isolated PBMCs from the patient exhibited increased STAT1 activation, and in whole blood samples increased levels were particularly observed in Monocytes and T-helper cells. In mucosal sections activated STAT1 was especially expressed in immune cells but also epithelial cells. Stimulation of PBMCs with Upadacitinib or Tofacitinib and partially with Filgotinib decreased STAT1 levels. We initiated treatment with Tofacitinib due to the in vitro results and its approval to treat ulcerative colitis. After two weeks, clinical symptoms improved drastically and endoscopy performed after 3 month indicated full remission, which was paralleled by a normalisation of STAT1 in PBMCs. Conclusion We present a case with a rare form of Inflammatory bowel disease (IBD) caused by a gain-of-function mutation affecting the STAT1 gene. IBD-like symptoms are unusual for STAT1 mutations, which usually present as immunodeficiency, and this specific mutation was only identified twice before and listed in data bases without describing the clinical phenotype. Our results and approach demonstrate how delineating the specific pathomechanism of a case with IBD enables targeted and precision treatment, a currently intensively investigated concept which might be implemented into clinical routine to treat IBD in the future.

Hematopoietic cell transplantation for monogenic inflammatory bowel disease

The pathogenesis of inflammatory bowel disease (IBD) may include immune dysregulation. About 20% of inborn errors of immunity (IEIs) are related to IBD, and more than 60 IEIs are known to present IBD. Monogenic IBDs include those that are refractory to traditional treatment and can be cured by allogeneic hematopoietic cell transplantation (HCT), making early diagnosis and treatment essential. In this report, we present a series of monogenic IBDs that are relatively frequently found in Japan, such as interleukin (IL)-10/IL-10 receptor deficiency, chronic granulomatous disease, XIAP deficiency, immunodysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, NEMO deficiency, and A20 haploinsufficiency and will describe the features of each IEI and the indications for HCT.

Mucosal immune systems of pediatric inflammatory bowel disease: A review.

Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract in chronic or recurrent remission phase and is classified as Crohn's disease (CD) and ulcerative colitis (UC). IBD is a multifactorial disease that results from genetic and environmental factors, immunological disorders, and gut microbiota dysregulation called dysbiosis. Recently, the number of patients with IBD in Japan has been increasing. This review describes studies of T cells, such as type 1 helper T (Th1) and type 1 cytotoxic T (Tc1) cells, and cytokines, such as IL-17 and IL-21, as representatives of mucosal immunity in IBD. Th1 cells and Tc1 cells are involved in Peyer's patches of CD. IL-12 significantly reduced the production of IL-17 but significantly increased in that of IFN-γ, and IL-21 reduced IL-17 production. It also describes genetic analysis studies on the cause of very early-onset IBD (VEO-IBD). Furthermore, 11.6% of patients with VEO-IBD presented with monogenic IBD in Japan. Genetic analysis for patients with VEO-IBD and suspected monogenic IBD was investigated. XIAP and heterozygous SLCO2A1 were detected owing to the result of functional confirmation, and several candidate genes were detected. Cytokine analysis and genetic analysis studies have revealed several pathophysiologies of IBD. Clinical and basic studies on mucosal immunity as well as immunological and genetic analyses are currently ongoing and are anticipated to provide an elaborate understanding of the pathophysiology of IBD.

Monogenic inflammatory bowel disease with STXBP2 mutations is not resolved by hematopoietic stem cell transplantation but can be alleviated via immunosuppressive drug therapy

STXBP2, encoding syntaxin-binding protein 2, is involved in intracellular organelle trafficking and is associated with familial hemophagocytic lymphohistiocytosis type 5. Although STXBP2 mutations reportedly cause monogenic inflammatory bowel disease, the clinical course and underlying pathogenic mechanisms remain unclear. We identified a novel mutation in STXBP2 [c.1197delC, p.Ala400fs] in a boy with congenital intractable diarrhea and hemophagocytic lymphohistiocytosis (HLH). HLH was treated with intravenous prednisolone, cyclosporine, and dexamethasone palmitate. Hematopoietic stem cell transplantation (HSCT) along with prophylaxis for graft-versus-host-disease was performed at 5 months of age. Additionally, colonoscopies done before and after HSCT showed mild colitis with cryptitis. The patient showed elevated fecal calprotectin levels and persistent diarrhea even after HSCT and required partial parenteral nutrition. While anti-inflammatory treatment reduced diarrhea, it was not completely normalized even after HSCT, suggesting that the pathogenesis of inflammatory bowel disease associated with STXBP2 mutations involves both hyperinflammation and functional epithelial barrier defects.

Pathogenic Interleukin-10 Receptor Alpha Variants in Humans — Balancing Natural Selection and Clinical Implications

Balancing natural selection is a process by which genetic variants arise in populations that are beneficial to heterozygous carriers, but pathogenic when homozygous. We systematically investigated the prevalence, structural, and functional consequences of pathogenic IL10RA variants that are associated with monogenic inflammatory bowel disease. We identify 36 non-synonymous and non-sense variants in the IL10RA gene. Since the majority of these IL10RA variants have not been functionally characterized, we performed a systematic screening of their impact on STAT3 phosphorylation upon IL-10 stimulation. Based on the geographic accumulation of confirmed pathogenic IL10RA variants in East Asia and in Northeast China, the distribution of infectious disorders worldwide, and the functional evidence of IL-10 signaling in the pathogenesis, we identify Schistosoma japonicum infection as plausible selection pressure driving variation in IL10RA. Consistent with this is a partially augmented IL-10 response in peripheral blood mononuclear cells from heterozygous variant carriers. A parasite-driven heterozygote advantage through reduced IL-10 signaling has implications for health care utilization in regions with high allele frequencies and potentially indicates pathogen eradication strategies that target IL-10 signaling.Graphical abstract

Understanding inborn errors of immunity: A lens into the pathophysiology of monogenic inflammatory bowel disease.

Inflammatory bowel diseases (IBD) are chronic inflammatory conditions of the gastrointestinal tract, including Crohn’s disease, ulcerative colitis and inflammatory bowel disease-undefined (IBD-U). IBD are understood to be multifactorial, involving genetic, immune, microbial and environmental factors. Advances in next generation sequencing facilitated the growing identification of over 80 monogenic causes of IBD, many of which overlap with Inborn errors of immunity (IEI); Approximately a third of currently identified IEI result in gastrointestinal manifestations, many of which are inflammatory in nature, such as IBD. Indeed, the gastrointestinal tract represents an opportune system to study IEI as it consists of the largest mass of lymphoid tissue in the body and employs a thin layer of intestinal epithelial cells as the critical barrier between the intestinal lumen and the host. In this mini-review, a selection of pertinent IEI resulting in monogenic IBD is described involving disorders in the intestinal epithelial barrier, phagocytosis, T and B cell defects, as well as those impairing central and peripheral tolerance. The contribution of disrupted gut-microbiota-host interactions in disturbing intestinal homeostasis among patients with intestinal disease is also discussed. The molecular mechanisms driving pathogenesis are reviewed along with the personalized therapeutic interventions and investigational avenues this growing knowledge has enabled.

Monogenic inflammatory bowel disease-genetic variants, functional mechanisms and personalised medicine in clinical practice.

Over 100 genes are associated with monogenic forms of inflammatory bowel disease(IBD). These genes affect the epithelial barrier function, innate and adaptive immunity in the intestine, and immune tolerance. We provide an overview of newly discovered monogenic IBD genes and illustrate how a recently proposed taxonomy model can integrate phenotypes and shared pathways. We discuss how functional understanding of genetic disorders and clinical genomics supports personalised medicine for patients with monogenic IBD.

Very-Early Onset Chronic Active Colitis with Heterozygous Variants in LRBA1 and CARD11, a Case of “Immune TOR-Opathies”

Background A small subset of cases of inflammatory bowel disease (IBD) occurs as a result of single gene defects, and typically occurs in young or very young pediatric patients, referred to as “monogenic very-early onset IBD (VEO-IBD)”. The gene variants leading to monogenic VEO-IBD are often associated with primary immunodeficiency syndromes. Case report A six year-old girl presented to our gastroenterology clinic with LRBA deficiency with a heterozygous mutation at c.1399 A > G, p Met467Val, histopathologic chronic active colitis without granulomas and clinical chronic colitis. Her gastrointestinal symptoms began at age 5 with bloody diarrhea, abdominal pain and weight loss. Whole exome sequencing revealed a CARD11 heterozygous de novo mutation (c.220 + 1G > A). She was in clinical remission on only abatacept. Discussion We present a case of monogenic VEO-IBD associated with two heterozygous variants in LRBA1 and CARD11, both considered as key players in the newly proposed “immune TOR-opathies”.

Linking Genetic Diagnosis to Therapeutic Approach in Very Early Onset Inflammatory Bowel Disease: Pharmacologic Considerations.

Very early onset inflammatory bowel disease (VEO-IBD) is diagnosed in children <6 years of age, and in rare cases may be due to an identifiable monogenic cause. Recent advances in genetic testing have allowed for more accurate diagnosis, with as many as 100 genes now known to be associated with monogenic inflammatory bowel disease. These genes are involved in many immune pathways and thus may represent potential avenues for targeted precision medicine with pharmacologic treatments aimed at these. This review describes the broad classifications of monogenic disorders known to cause VEO-IBD, as well as empiric and disease-specific medical therapies. These include immune-modulating or immunosuppressant medications, nutritional therapy, surgery, and hematopoietic stem cell transplantation. We aim to provide an overview of the current state of targeted therapy for VEO-IBD.

Histopathological Features of Monogenic Inflammatory Bowel Disease: Subanalysis of Systematic Review

Histopathological Features of Monogenic Inflammatory Bowel Disease: Subanalysis of Systematic Review

A Machine Learning Approach to Identifying Causal Monogenic Variants in Inflammatory Bowel Disease

<h3>Background and Aims</h3> Diagnosis of monogenic disease is increasingly important for patient care and personalizing therapy. However, the current process is nonstandardized, expensive, and time consuming. There is currently no accepted strategy to help identify disease-causing variants in monogenic inflammatory bowel disease (IBD). The aim of the study is to develop a prioritization strategy for monogenic IBD variant discovery through detailed analysis of a whole-exome sequencing (WES) data set. <h3>Methods</h3> All consenting pediatric patients with IBD presenting to our tertiary care hospital during the study period were enrolled and underwent WES (n = 1005). Available family members also underwent WES. Variants were analyzed en masse using the GEMINI framework and were further annotated using data from dbNSFP, Combined Annotation Dependent Depletion, and gnomAD. Known disease-causing variants (n = 36) were used as positive controls. Machine learning algorithms were optimized and then compared to assist with identifying monogenic IBD case characteristics. <h3>Results</h3> Initial gene-level analysis identified 11 genes not previously linked to IBD that could potentially harbor IBD-causing variants. Machine learning algorithms identified 4 primary variant characteristics (Combined Annotation Dependent Depletion score, dbNSFP score, relationship with a known immunodeficiency gene, and alternate allele frequency), and optimal threshold values for each were determined to assist with identifying monogenic IBD variants. Based on these characteristics, an automated variant prioritization pipeline was then created that filters and prioritizes variants from >100,000 variants per patient down to a mean of 15. This pipeline is available online for all to use. <h3>Conclusion</h3> Leveraging a large WES data set, we demonstrate a statistically rigorous strategy for prioritization of variants for monogenic IBD diagnosis.

An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease

Monogenic forms of inflammatory bowel disease (IBD) illustrate the essential roles of individual genes in pathways and networks safeguarding immune tolerance and gut homeostasis. To build a taxonomy model, we assessed 165 disorders. Genes were prioritized based on penetrance of IBD and disease phenotypes were integrated with multi-omics datasets. Monogenic IBD genes were classified by (1) overlapping syndromic features, (2) response to hematopoietic stem cell transplantation, (3) bulk RNA-sequencing of 32 tissues, (4) single-cell RNA-sequencing of >50 cell subsets from the intestine of healthy individuals and patients with IBD (pediatric and adult), and (5) proteomes of 43 immune subsets. The model was validated by addition of newly identified monogenic IBD defects. As a proof-of-concept, we explore the intersection between immunometabolism and antimicrobial activity for a group of disorders (G6PC3/SLC37A4). Our quantitative integrated taxonomy defines the cellular landscape of monogenic IBD gene expression across 102 genes with high and moderate penetrance (81 in the model set and 21 genes in the validation set). We illustrate distinct cellular networks, highlight expression profiles across understudied cell types (e.g., CD8+ T cells, neutrophils, epithelial subsets, and endothelial cells) and define genotype-phenotype associations (perianal disease and defective antimicrobial activity). We illustrate processes and pathways shared across cellular compartments and phenotypic groups and highlight cellular immunometabolism with mammalian target of rapamycin activation as one of the converging pathways. There is an overlap of genes and enriched cell-specific expression between monogenic and polygenic IBD. Our taxonomy integrates genetic, clinical and multi-omic data; providing a basis for genomic diagnostics and testable hypotheses for disease functions and treatment responses.