Immune Dysregulation Research Articles

Profile of immunological biomarkers in Behcet’s syndrome: a large-scale single-center real-world study

Behcet's syndrome (BS) is a vasculitis characterized by immune dysregulation. Biomarkers are valuable for assessing clinically atypical pathogenesis. We aimed to investigate the distribution of different biomarkers and their effects on the clinical features of patients with BS in a large-scale, real-world study. This is a retrospective, single-center study. In total, 502 patients diagnosed with BS were enrolled in this study. We analyzed the clinical features of this cohort and divided patients’ symptoms into six categories, including mucocutaneous, articular, neurological, gastrointestinal, vascular, and ocular involvements. HLA-B51 cells, autoantibodies, and subsets of immune cells from the patients were tested. Pearson’s correlation, Wilcoxon rank sum test and multivariate logistic regression were used for data analysis. Various autoantibodies were detected in the serum of 40.8% of patients with BS. The positivity rate of anti-endothelial cell antibodies (AECA) was the highest among autoantibodies and was found in 23.5% (118/502) of patients with BS. The positivity rate of HLA-B51 in patients with BS was 27.1%. Tumor necrosis factor (TNF)-α, IL-2, and IL-4 producing CD4+ T cells were positively correlated with the gastrointestinal BS. Increased IL-4+CD4+ T cell was a risk factor for gastrointestinal BS (P = 0.006, Overall rate [OR] = 2.491, 95% Confidence interval [CI]: [1.317, 5.100]). Various autoantibodies can be detected in patients with BS. HLA-B51 and AECA are the most common biomarkers. Increased IL-4+ CD4+ T cell was a risk factor for gastrointestinal involvement in BS.

Endometriosis and aspirin: a systematic review.

Endometriosis is delineated as a benign yet steroid-dependent disorder characterized by the ectopic presence of endometrial glandular and stromal cells outside the uterine cavity, affecting estimated 10%-15% of women of reproductive age, 20%-50% of all women with infertility and costing a great economic burden per-patient. Endometriosis exerts pervasive influence on multiple facets of female reproductive physiology. Given its characterization as a chronic inflammatory disorder, escalated levels of pro-inflammatory cytokines were unequivocally recognized as well-established characteristics of endometriosis, which might attribute to mechanisms like retrograde menstruation, progesterone receptor resistance, and immune dysregulation. Therapeutic utilization of non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin, analgesic agent for reducing pain, inflammation, and fever, could be holding promise in augmenting reproductive outcomes of endometriosis women. Therefore, the objective of this comprehensive review is to elucidate the intricate interplay between endometriosis and aspirin, both within the context of infertility and beyond. We meticulously explore potential pharmacological agents targeting endometriosis, which may concurrently optimize the efficacy of reproductive interventions, while also delving into the underlying mechanistic pathways linking endometriosis with inflammatory processes. We conducted a comprehensive search in the data available in PubMed and the Web of Science using the terms 'endometriosis' and 'aspirin'. Then analyzed the identified articles based on established inclusion and exclusion criteria independently by three reviewers. The survey of the chosen terms revealed 72 articles, only 10 of which were considered for review. Based on the research available currently, it is not substantial enough to address the conclusion that aspirin shall be an effective therapeutic choice for endometriosis, further studies are needed to elucidate the efficacy, safety profile, and optimal dosing regimens of aspirin in the context of endometriosis treatment.

A rare case of late-onset immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome confused with IgA vasculitis nephropathy.

A 3-year-old boy initially presented with purpura-like rashes and nephrotic syndrome, suspected to be IgA vasculitis nephritis (IgAVN). The suggestion of kidney biopsy was rejected. Although the patient responded well to glucocorticoids, they later developed recurrent proteinuria, refractory diarrhea, and subsequent metabolic acidosis. Kidney biopsy showed membranous nephropathy with positive semaphorin 3B expression, indicative of other kidney diseases rather than IgAVN. Although his kidney responded well to glucocorticoid combined with cyclosporine A treatment regimen, enteropathy and severe food allergy still progressed afterwards as evidenced by villous atrophy on gastrointestinal endoscopy examination. Whole exome sequencing identified a heterozygous missense variant in exon 11 of FOXP3: c.1121T > G, confirming the diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. The case expanded the phenotypic spectrum of IPEX syndrome, suggesting high phenotypic heterogeneity despite similar genotypes. It also put emphasis on the significance of kidney biopsy to differentiate IgA vasculitis nephropathy from other immune disorders.

Current development of Fc gamma receptors (FcγRs) in diagnostics: a review.

The ability of the immune system to fight against pathogens relies on the intricate collaboration between antibodies and Fc gamma receptors (FcγRs). These receptors are a group of transmembrane glycoprotein molecules, which can specifically detect and bind to the Fc portion of immunoglobulin G (IgG) molecules. They are distributed on a diverse array of immune cells, forming a strong defence system to eliminate invading threats. FcγRs have gained increasing attention as potential biomarkers for various diseases in recent years due to their ability to reflect immune dysregulation and disease pathogenesis. Increasing lines of evidence have shed new light on the remarkable association of FcγRs polymorphisms with the susceptibility of autoimmune diseases such as systemic lupus erythematosus (SLE) and lupus nephritis. Several studies have also reported the application of FcγR as a novel biomarker for the diagnosis of infection and cancer. Due to the surge in interest and concern regarding the potential of FcγRs as promising diagnostic biomarkers, this review, thereby, serves to provide a comprehensive overview of the structural characteristics, functional roles, and expression patterns of FcγRs, with a particular focus on their evolving role as diagnostic and prognostic biomarkers.

Role of Dysregulated Immune Biomarkers in Hepatocellular Carcinoma Metastasis: A Systematic Meta-Analysis Review

The liver plays a crucial role in immune system regulation, but dysregulation of immunological networks contributes to chronic liver diseases like hepatocellular carcinoma. This malignant tumor is the third leading cause of cancer death. An imbalanced immune system, characterized by alterations in immune cell count, cytokine levels, and inhibitory receptors, can impact metastasis by suppressing the immune system's ability to fight cancer cells. This study aims to investigate the potential biomarkers playing a crucial role in immune dysregulation resulting in hepatocellular carcinoma metastasis. A comprehensive and systematic literature review was conducted using both free words and search terms. The data extraction was then performed by a thorough literature screening. Next, the meta-analysis was performed using the metabin function of the meta library in R to evaluate the patient cases reporting metastasis in the event group. A total of 1,008 cases were considered, with 357 as events and 651 as nonevents. The results of the meta-analysis demonstrated the significant role of biomarkers in immune dysregulation causing metastasis (risk ratio = 0.54, 95% confidence interval: 0.4972, 0.6048, I 2 = 92.4%, p < 0.01). In addition to the immune dysregulation explored in this study, the impact of tumor size on hepatocellular carcinoma progression and metastasis is a crucial consideration. A notable difference of 41 more cases was reported for larger tumor sizes. The study integrates immune dysregulation biomarkers and tumor size factors influencing hepatocellular carcinoma metastasis, offering valuable insights for future research and therapeutic interventions for improved clinical outcomes.

Metabolic and Immune System Dysregulation: Unraveling the Connections between Alzheimer's Disease, Diabetes, Inflammatory Bowel Diseases, and Rheumatoid Arthritis.

Alzheimer's disease (AD), diabetes mellitus (DM), inflammatory bowel diseases (IBD), and rheumatoid arthritis (RA) are chronic conditions affecting millions globally. Despite differing clinical symptoms, these diseases share pathophysiological mechanisms involving metabolic and immune system dysregulation. This paper examines the intricate connections between these disorders, focusing on shared pathways such as insulin resistance, lipid metabolism dysregulation, oxidative stress, and chronic inflammation. An important aspect is the role of amyloid-beta plaques and tau protein tangles, which are hallmark features of AD. These protein aggregates are influenced by metabolic dysfunction and inflammatory processes similar to those seen in DM, RA, and IBD. This manuscript explores how amyloid and tau pathologies may be exacerbated by shared metabolic and immune dysfunction. Additionally, this work discusses the gut-brain axis and the influence of gut microbiota in mediating disease interactions. Understanding these commonalities opens new avenues for multi-targeted therapeutic approaches that address the root causes rather than merely the symptoms of these conditions. This integrative perspective could lead to more effective interventions and improved patient outcomes, emphasizing the importance of a unified approach in managing these interconnected diseases.

Chronic Lymphocytic Leukemia: Immune Dysregulation and Management: A Case Report

Chronic Lymphocytic Leukemia: Immune Dysregulation and Management: A Case Report

From immune dysregulation to organ dysfunction: understanding the enigma of Sepsis.

Sepsis is a syndrome precipitated by immune dysregulation in response to infection, and represents a pivotal factor in global mortality attributed to diseases. The recent consensus delineates sepsis as a perilous state of organ dysfunction arising from the host's maladaptive reaction to infection. It masks the complexity and breadth of the immune mechanisms involved in sepsis, which is characterized by simultaneous hyperinflammation and immunosuppression. Sepsis is highly correlated with the dysregulation of immune response, which is mainly mediated by various immune cells and their interactions. This syndrome can lead to a plethora of complications, encompassing systemic inflammatory response, metabolic disturbances, infectious shock, MODS, and DIC. Furthermore, more research studies have been conducted on sepsis in the past few years. The pathological characteristics of sepsis have been improved or treated by targeting signaling pathways like NF-B, JAK-STAT, PI3K-Akt, and p38-MAPK. Combined drug therapy is better than single drug therapy for sepsis. This article will review the latest progress in the pathogenesis and treatment of sepsis.

Molecular characterization analysis of PANoptosis-related genes in colorectal cancer based on bioinformatic analysis.

Colorectal cancer (CRC) ranks as the third most prevalent cancer globally and stands as the second principal contributor to cancer-related fatalities. Recently, emerging research has emphasized the role of pan apoptosis (PANoptosis) in tumor development and anti-tumor therapy. In the course of this investigation, we meticulously identified and conducted a correlation analysis between differentially expressed genes associated with PANoptosis in CRC (CPAN_DEGs) and the proportion of immune cells. Subsequently, we formulated a prognostic score based on the CPAN_DEGs. Further our analysis revealed a noteworthy reduction in UNC5D mRNA expression within HCT116, HT29 and SW480 cells, as validated by qRT-PCR assay. Furthermore, scrutinizing the TCGA database unveiled a distinctive trend wherein individuals with the low UNC5D expression exhibited significantly reduced overall survival compared to their counterparts with the high UNC5D levels. The drug susceptibility analysis of UNC5D was further performed, which showed that UNC5D was corassociated with the sensitivity of CRC to 6-Thioguanine. The outcomes of our investigation underscore the mechanisms by which PANoptosis influences immune dysregulation as well as prognostic outcome in CRC.

Reassessing the Risk of Severe Parvovirus B19 Infection in the Immunocompetent Population: A Call for Vigilance in the Wake of Resurgence.

Despite Parvovirus B19 (B19V) generally causing mild or asymptomatic infections, and only certain high-risk groups such as hematological or immunocompromised patients and pregnant women tending to develop complications, several factors challenge the assumption of a "benign" clinical course in immunocompetent adults and adolescents. A significant proportion of the population may harbor undiagnosed health conditions or genetic predispositions that could render them more susceptible to severe B19V complications. These could include mild hematological disorders, immune dysregulation not resulting in overt immunodeficiency, or underlying cardiac conditions. Concurrent infections with other pathogens, even seemingly minor ones, could synergistically increase the severity of B19V infection, leading to more pronounced clinical manifestations. While not definitively proven, the possibility of emerging B19V strains with increased virulence or altered tissue tropism cannot be entirely discounted. Additionally, the period of pandemic-related restrictions likely led to reduced B19V circulation, potentially resulting in a cohort of young adults with limited natural immunity, making them more vulnerable to infection. Potential clinical consequences include atypical and severe presentations, even in individuals without known risk factors. The traditional focus on B19V primarily as a pediatric concern might lead to underdiagnosis or delayed diagnosis in adults, potentially hindering timely intervention and management. A surge in B19V-related complications, even if individually mild, could collectively strain healthcare resources, particularly in settings with limited capacity or pre-existing pressures. Possible recommendations are to heighten clinical awareness with a high index of suspicion for B19V infection in adults and adolescents presenting with compatible symptoms, even in the absence of classic risk factors. Additionally, expanding testing criteria and enhancing public health surveillance efforts would be prudent.

Premature aging effects on COVID-19 pathogenesis: new insights from mouse models

Aging is identified as a significant risk factor for severe coronavirus disease-2019 (COVID-19), often resulting in profound lung damage and mortality. Yet, the biological relationship between aging, aging-related comorbidities, and COVID-19 remains incompletely understood. This study aimed to elucidate the age-related COVID19 pathogenesis using an Hutchinson-Gilford progeria syndrome (HGPS) mouse model, a premature aging disease model, with humanized ACE2 receptors. Pathological features were compared between young, aged, and HGPS hACE2 mice following SARS-CoV-2 challenge. We demonstrated that young mice display robust interferon response and antiviral activity, whereas this response is attenuated in aged mice. Viral infection in aged mice results in severe respiratory tract hemorrhage, likely contributing a higher mortality rate. In contrast, HGPS hACE2 mice exhibit milder disease manifestations characterized by minor immune cell infiltration and dysregulation of multiple metabolic processes. Comprehensive transcriptome analysis revealed both shared and unique gene expression dynamics among different mouse groups. Collectively, our studies evaluated the impact of SARS-CoV-2 infection on progeroid syndromes using a HGPS hACE2 mouse model, which holds promise as a useful tool for investigating COVID-19 pathogenesis in individuals with premature aging.

Tofacitinib Citrate Coordination-Based Dual-Responsive/Scavenge Nanoplatform Toward Regulate Colonic Inflammatory Microenvironment for Relieving Colitis.

Ulcerative colitis is an inflammation of the colon characterized by immune dysregulation and intestinal inflammation. Developing safe oral nanomedicines that suppress intestinal inflammation, while modulating colonic inflammatory microenvironment by scavenging reactive oxygen species (ROS) and hydrogen sulfide (H2S) is crucial for the effective treatment of colitis. Here, the tofacitinib citrate and copper coordination-based nanoparticle (TF-Cu nanoparticle, T-C) to dual-scavenge ROS and H2S by coordination competition is synthesized. Moreover, the coordination of T-C using computer simulation is explored. To enhance the acid stability and inflammatory targeting of T-C, it is encapsulated with hyaluronic acid-modified chitosan, along with a calcium pectinate coating (T-C@HP). Owing to the dual pH/pectinase-responsive characteristics of T-C@HP, the nanoplatform can target inflamed colonic lesions, inhibiting phosphorylated Janus kinase 1. Furthermore, T-C@HP scavenges ROS and H2S, as well as increases NADPH levels, which is investigated by combining biosensor (HyPer7 and iNap1/c) and chemical probes. T-C@HP also alleviates colitis by regulating the colonic inflammatory microenvironment through multiple processes, including the modulation of apoptosis, macrophage polarization, tight junction, mucus layer, and intestinal flora. Complemented by satisfactory anti-inflammatory and biosafety results, this nanoplatform represents a promising, effective, and safe treatment option for colitis patients.

Hepatic Gα13 ablation shifts region-specific colonic inflammatory status by modulating the bile acid synthetic pathway in mice

Inflammatory bowel disease is defined by inflammation and immune dysregulation. This study investigated the effects of Gα13 liver-specific knockout (LKO) on proximal and distal colons of dextran sodium sulfate (DSS)-induced mice in conjunction with a high-fat diet (HFD). HFD improved body weight gain and disease activity index scores. Gα13LKO exerted no improvement. In the proximal colon, HFD augmented the DSS effect on Il6, which was not observed in Gα13LKO mice. In the distal colon, HFD plus DSS oppositely fortified an increase in Tnfa and Cxcl10 mRNA in Gα13LKO but not WT. Il6 levels remained unchanged. Bioinformatic approaches using Gα13LKO livers displayed bile acid and cholesterol metabolism-related gene sets. Cholic acid and chenodeoxycholic acid levels were increased in the liver of mice treated with DSS, which was reversed by Gα13LKO. Notably, mice treated with DSS showed a reduction in hepatic ABCB11, CYP7B1, CYP7A1, and CYP8B1, which was reversed by Gα13LKO. Overall, feeding HFD augments the effect of DSS on Il6 in the proximal colon of WT, but not Gα13LKO mice, and enhances DSS effect on Tnfa and Cxcl10 in the distal colon of Gα13LKO mice, suggesting site-specific changes in the inflammatory cytokines, potentially resulting from changes in BA synthesis and excretion.

Immunophenotyping and Therapeutic Insights from Chronic Mucocutaneous Candidiasis Cases with STAT1 Gain-of-Function Mutations.

Heterozygous STAT1 Gain-of-Function (GOF) mutations are the most common cause of chronic mucocutaneous candidiasis (CMC) among Inborn Errors of Immunity. Clinically, these mutations manifest as a broad spectrum of immune dysregulation, including autoimmune diseases, vascular disorders, and malignancies. The pathogenic mechanisms of immune dysregulation and its impact on immune cells are not yet fully understood. In treatment, JAK inhibitors have shown therapeutic effectiveness in some patients. We analyzed clinical presentations, cellular phenotypes, and functional impacts in five Taiwanese patients with STAT1 GOF. We identified two novel GOF mutations in 5 patients from 2 Taiwanese families, presenting with symptoms of CMC, late-onset rosacea, and autoimmunity. The enhanced phosphorylation and delayed dephosphorylation were displayed by the patients' cells. There are alterations in both innate and adaptive immune cells, including expansion of CD38+HLADR +CD8+ T cells, a skewed activated Tfh cells toward Th1, reduction of memory, marginal zone and anergic B cells, all main functional dendritic cell lineages, and a reduction in classical monocyte. Baricitinib showed therapeutic effectiveness without side effects. Our study provides the first comprehensive clinical and molecular characteristics in STAT1 GOF patient in Taiwan and highlights the dysregulated T and B cells subsets which may hinge the autoimmunity in STAT1 GOF patients. It also demonstrated the therapeutic safety and efficacy of baricitinib in pediatric patient. Further research is needed to delineate how the aberrant STAT1 signaling lead to the changes in cellular populations as well as to better link to the clinical manifestations of the disease.

Modulation of Metabolomic Profile in Sepsis According to the State of Immune Activation.

To investigate the metabolomic profiles associated with different immune activation states in sepsis patients. Subgroup analysis of the PROVIDE (a Personalized Randomized trial of Validation and restoration of Immune Dysfunction in severe infections and Sepsis) prospective clinical study. Results of the PROVIDE study showed that patients with sepsis may be classified into three states of immune activation: 1) macrophage-activation-like syndrome (MALS) characterized by hyperinflammation, sepsis-induced immunoparalysis, and 3) unclassified or intermediate patients without severe immune dysregulation. Two hundred ten patients from 14 clinical sites in Greece meeting the Sepsis-3 definitions with lung infection, acute cholangitis, or primary bacteremia. During our comparison, we did not perform any intervention. Untargeted metabolomics analysis was performed on plasma samples from 210 patients (a total of 1394 products). Differential abundance analysis identified 221 significantly different metabolites across the immune states. Metabolites were enriched in pathways related to ubiquinone biosynthesis, tyrosine metabolism, and tryptophan metabolism when comparing MALS to immunoparalysis and unclassified patients. When comparing MALS to unclassified, 312 significantly different metabolites were found, and pathway analysis indicated enrichment in multiple pathways. Comparing immunoparalysis to unclassified patients revealed only two differentially regulated metabolites. Findings suggest distinct metabolic dysregulation patterns associated with different immune dysfunctions in sepsis: the strongest metabolic dysregulation is associated with MALS.

Identification and multimodal characterization of a specialized epithelial cell type associated with Crohn’s disease

Crohn’s disease (CD) is a complex chronic inflammatory disorder with both gastrointestinal and extra-intestinal manifestations associated immune dysregulation. Analyzing 202,359 cells from 170 specimens across 83 patients, we identify a distinct epithelial cell type in both terminal ileum and ascending colon (hereon as ‘LND’) with high expression of LCN2, NOS2, and DUOX2 and genes related to antimicrobial response and immunoregulation. LND cells, confirmed by in-situ RNA and protein imaging, are rare in non-IBD controls but expand in active CD, and actively interact with immune cells and specifically express IBD/CD susceptibility genes, suggesting a possible function in CD immunopathogenesis. Furthermore, we discover early and late LND subpopulations with different origins and developmental potential. A higher ratio of late-to-early LND cells correlates with better response to anti-TNF treatment. Our findings thus suggest a potential pathogenic role for LND cells in both Crohn’s ileitis and colitis.

Allogeneic Hematopoietic Stem Cell Transplantation in Immunodeficiency—Centromeric Instability—Facial Dysmorphism (ICF) Syndrome: an EBMT/ESID Inborn Errors Working Party Study

Immunodeficiency–Centromeric instability–Facial dysmorphism (ICF) syndrome is an inborn error of immunity characterized by progressive immune dysfunction and multi-organ disease usually treated with antimicrobial prophylaxis and immunoglobulin substitution. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment, but data on outcome are scarce. We provide a detailed description of disease characteristics and HSCT outcome in an international cohort of ICF syndrome patients. Eighteen patients (including all four genotypes) were enrolled. Main HSCT indications were infections (83%), enteropathy/failure to thrive (56%), immune dysregulation (22%) and myelodysplasia/haematological malignancy (17%). Two patients underwent pre-emptive HSCT after early diagnosis. Patients were transplanted between 2003–2021, at median age 4.3 years (range 0.5–19), after myeloablative or reduced-intensity conditioning, from matched sibling or matched family donors, matched unrelated or mismatched donors in 39%, 50% and 12% of cases respectively. Overall survival was 83% (all deaths occurred within the first 5 months post-HSCT; mean follow-up 54 months (range 1–185)). Acute GvHD occurred in 35% of patients, severe (grade III) in two (12%), while none developed chronic GvHD. At latest follow-up (median 2.2 years (range 0.1–14)), complete donor chimerism was achieved in 15/17 surviving patients. All survivors demonstrated normalized T and B cell numbers. Immunoglobulin substitution independence was achieved in all but two patients. All survivors recovered from pre-transplant infections, enteropathy/failure to thrive and immune dysregulation. All three patients transplanted at young age (≤ 3 years), after early diagnosis, survived. The favourable clinical and immunological HSCT outcome in this cohort of patients supports the timely use of this curative treatment in ICF syndrome.

Clinicopathologic Insights and Molecular Oncogenesis: Understanding Epstein-Barr Virus-Induced B-cell Lymphoproliferations.

Epstein-Barr virus (EBV) is a highly prevalent virus among adults worldwide. In an immunocompetent individual, EBV infection generally results in lifelong latency of the virus and no sequelae. However, in the setting of immune dysfunction, EBV can induce the development of autoimmune disorders, hyperplastic proliferations, and cancers, including lymphoma. Here, we explore the pathogenic and oncogenic role of EBV in Burkitt lymphoma, diffuse large B-cell lymphoma, Hodgkin lymphoma, plasmablastic lymphoma, lymphomatoid granulomatosis, and post-transplant lymphoproliferative disorders and lymphoproliferative disorders associated with immune deficiency and dysregulation. In addition to describing general mechanisms of EBV-associated oncogenesis, we also discuss EBV-associated oncogenesis in the context of each disorder, as well as their microscopic, phenotypic, and clinical presentations.

The role of dendritic cells in the instruction of helper T cells in the allergic march.

Allergy is a complex array of diseases influenced by innate and adaptive immunity, genetic polymorphisms, and environmental triggers. Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by barrier defects and immune dysregulation, sometimes leading to asthma and food allergies because of the atopic march. During atopic skin inflammation, Langerhans cells and dendritic cells (DCs) in the skin capture and deliver allergen information to local lymph nodes. DCs are essential immune sensors coordinating immune reactions by capturing and presenting antigens to T cells. In the context of allergic responses, DCs play a crucial role in instructing two types of helper T cells - type 2 helper T (Th2) cells and follicular helper T (TFH) cells - in allergic responses and IgE antibody responses. In skin sensitization, the differentiation and function of Th2 cells and TFH cells are influenced by skin-derived factors, including epithelial cytokines, chemokines, and signaling pathways to modify the function of migratory DCs and conventional DCs. In this review, we aim to understand the specific mechanisms involving DCs in allergic responses to provide insights into the pathogenesis of allergic diseases and potential therapeutic strategies.

Regulation of Bacteroides acidifaciens by the aryl hydrocarbon receptor in IL-22-producing immune cells has sex-dependent consequential impact on colitis.

Colitis is an inflammatory bowel disease (IBD) characterized by immune cell dysregulation and alterations in the gut microbiome. In our previous report, we showed a natural product in cruciferous vegetables and ligand of the aryl hydrocarbon receptor (AhR), indole-3-carbinol (I3C), was able to reduce colitis-induced disease severity and microbial dysbiosis in an interleukin-22 (IL-22) dependent manner. In the current study, we performed single-cell RNA sequencing (scRNAseq) from colonocytes during colitis induction and supplementation with I3C and show how this treatment alters expression of genes involved in IL-22 signaling. To further define the role of IL-22 signaling in I3C-mediated protection during colitis and disease-associated microbial dysbiosis, we generated mice with AhR deficiency in RAR-related orphan receptor c (Rorc)-expressing cells (AhR ΔRorc ) which depletes this receptor in immune cells involved in production of IL-22. Colitis was induced in wildtype (WT), AhR ΔRorc , and littermate (LM) mice with or without I3C treatment. Results showed AhR ΔRorc mice lost the efficacy effects of I3C treatment which correlated with a loss of ability to increase IL-22 by innate lymphoid type 3 (ILC3s), not T helper 22 (Th22) cells. 16S rRNA microbiome profiling studies showed AhR ΔRorc mice were unable to regulate disease-associated increases in Bacteroides, which differed between males and females. Lastly, inoculation with a specific disease-associated Bacteroides species, Bacteroides acidifaciens (B. acidifaciens), was shown to exacerbate colitis in females, but not males. Collectively, this report highlights the cell and sex-specific role of AhR in regulating microbes that can impact colitis disease.