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BackgroundInflammatory bowel diseases (IBDs) are characterised by dysbiosis and a leaky gut. The NADPH oxidase dual oxidase 2 (DUOX2) is upregulated in patients with IBD, yet its role in driving the disease remains unclear.ObjectiveWe interrogated the functional consequences of epithelial DUOX2 activity for the host and microbiome.DesignDUOX2 function was studied in mice with epithelial-specific DUOX2 overactivation (vTLR4), inactivation (vTLR4 DUOXA IEC-KO) and wild-type controls. We assessed the effect of dysbiosis on DUOX2 signalling and intestinal permeability (FITC-dextran, serum zonulin, bacterial translocation) with germ-free (GF) mice engrafted with IBD or healthy microbiota. RNA sequencing of colonic mucosa and microbiota and faecal metabolomics were used to characterise the host–microbe interface. Mechanistic studies were conducted in mouse colonoids, IBD biopsies and patient serum samples.ResultsDUOX2 activity increased permeability and bacterial translocation and induced subclinical inflammation in vTLR4 mice. GF vTLR4 mice had increased DUOX2 activity and permeability but no subclinical inflammation. In patients with IBD, DUOX2 expression was positively associated with plasma zonulin levels and negatively associated with ZO-1 expression. Engraftment of GF mice with IBD stool increased DUOX2 activity and triggered low-grade inflammation and permeability defects in mice. DUOX2 activity functionally altered the microbiome, reduced butyrate metabolism and promoted proinflammatory and pro-oncogenic bacterial metabolites. Butyrate and histone deacetylase (HDAC) inhibitors blocked DUOX2 activation and reversed its effects.ConclusionsElevated DUOX2 signalling contributes to epithelial barrier dysfunction, microbiome alterations and subclinical inflammation. Butyrate and HDAC inhibitors reversed these effects, indicating that DUOX2 may be a therapeutic target in IBD.

BACKGROUND:Patients with inflammatory bowel disease (IBD) have higher rates of psychiatric comorbidity which can impact adherence to treatment plans, medical response, and overall quality of life. Integrated behavioral management within an IBD-specific medical home (MH) shows promise in improving clinical outcomes. Effective behavioral interventions may differ depending on source of symptoms (active vs inactive disease). Study aims are to: 1) characterize behavioral complexity in adults with moderate to severe IBD symptoms at the time of enrollment in the IBD MH; and 2) evaluate the relationship between use of behavioral services and medical and behavioral self-reported measures over a 6-month period.METHODS:The sample consisted of adults with moderate to severe IBD symptoms, enrolled in the IBD MH from 2018 to 2019 with at least two office visits over a 6-month period. Clinical data from the electronic health records were included. Patient-reported depression (PHQ9), generalized anxiety disorder 7 (GAD-7), quality of life (QoL; SIBDQ), and IBD severity (HBI/UCAI) were recorded at baseline and subsequent office visits. These scores were used to calculate the IBD Biopsychosocial Complexity Grid, a tool which organizes this health information into biological, psychological, and nutritional domains and serves as the basis for algorithm-driven treatment planning within the IBD MH. Psychiatric diagnoses and patient engagement in behavioral services within the IBD MH were recorded.RESULTS:62 IBD patients with high baseline IBD symptoms were examined. All but one of these patients had at least one psychiatric diagnosis and 13 had ≥3 psychiatric diagnoses. All but 2 patients engaged in at least one encounter with behavioral providers within the MH. Approximately half (n = 30) of the 62 patients had active inflammation noted on colonoscopy at baseline. Of these 30 patients, 47% (n = 14) had significant improvement of their IBD inflammation, symptoms, and behavioral outcomes over the 6-month period. While 53% (n = 16) of patients with persistent active inflammation, also showed significant improvement in IBD symptoms and behavioral scores. All 30 patients engaged with behavioral providers. Another 30 patients had no active inflammation noted at their first and second visits yet reported high levels of IBD symptoms. These patients with more functional GI symptoms had more comorbid psychiatric diagnoses and even though they utilized behavioral services, showed less improvement in depression/anxiety scores compared to those with high baseline IBD inflammation. IBD patients with high baseline and continued active inflammation noted on colonoscopy all utilized behavioral health services at high rates and had improvement in PHQ9, GAD7, SIBDQ, and HBI/UCAI scores. None of the sample had a surgical intervention during the study period.CONCLUSION(S):IBD patients with moderate-severe reported symptoms had significant psychiatric comorbidity and utilized behavioral health providers in the IBD MH at equally high rates, regardless of symptom source (active inflammation or functional symptoms). Patients with active inflammation showed improvement in psychosocial functioning despite no disease improvement, suggesting that an integrated approach benefits patients with active disease even when disease markers do not improve. Patients with functional symptoms had more psychiatric complexity, and distress persisted despite behavioral interventions, suggesting patients with functional symptoms may benefit from different and possibly more intensive psychosocial care.

Abstract Background Inflammatory bowel disease (IBD) is associated with alterations of the innate and adaptive immune systems. Monocytes respond to inflammation and infection, yet the relationship between monocytosis and IBD severity is not fully understood. We aimed to characterize the prevalence of monocytosis in IBD and the association between monocytosis and disease severity and IBD-related health care utilization. Methods We used a multiyear, prospectively collected natural history registry to compare patients with IBD with monocytosis to those without monocytosis, among all patients and by disease type. Results A total of 1290 patients with IBD (64.1% with Crohn disease; 35.9% with ulcerative colitis) were included (mean age 46.4 years; 52.6% female). Monocytosis was found in 399 (30.9%) of patients with IBD (29.3% with Crohn disease; 33.9% with ulcerative colitis). Monocytosis was significantly associated with abnormal C-reactive protein level and erythrocyte sedimentation rate, anemia, worse quality of life, active disease, and increased exposure to biologics (all P < 0.001). Compared with patients without monocytosis, patients with monocytosis had a 3-fold increase in annual financial health care charges (median: $127,013 vs. $32,925, P < 0.001) and an increased likelihood of hospitalization (adjusted odds ratio [AOR], 4.5; P < 0.001), IBD-related surgery (AOR, 1.9; P = 0.002), and emergency department (ED) use (AOR, 2.8; P < 0.001). Patients with monocytosis had a shorter time to surgery, hospitalization, and ED visit after stratifying by disease activity (all P < 0.05). Conclusions Patients with IBD with monocytosis, regardless of disease type, are at increased risk for worse clinical outcomes, hospitalization, surgery, and ED use. Peripheral monocytosis may represent a routinely available biomarker of a distinct subgroup with severe disease.

Mutations in RAS occur in 30–50% of metastatic colorectal carcinomas (mCRCs) and correlate with resistance to anti-EGFR therapy. Consequently, mCRC biomarker guidelines state RAS mutational testing should be performed when considering EGFR inhibitor treatment. However, a small subset of mCRCs are reported to harbor RAS amplification. In order to elucidate the clinicopathologic features and anti-EGFR treatment response associated with RAS amplification, we retrospectively reviewed a large cohort of mCRC patients that underwent targeted next-generation sequencing and copy number analysis for KRAS, NRAS, HRAS, BRAF, and PIK3CA. Molecular testing was performed on 1286 consecutive mCRC from 1271 patients as part of routine clinical care, and results were correlated with clinicopathologic findings, mismatch repair (MMR) status and follow-up. RAS amplification was detected in 22 (2%) mCRCs and included: KRAS, NRAS, and HRAS for 15, 5, and 2 cases, respectively (6–21 gene copies). Patients with a KRAS-amplified mCRC were more likely to report a history of inflammatory bowel disease (p < 0.001). In contrast, mutations in KRAS were associated with older patient age, right-sided colonic origin, low-grade differentiation, mucinous histology, and MMR proficiency (p ≤ 0.017). Four patients with a KRAS-amplified mCRC and no concomitant RAS/BRAF/PIK3CA mutations received EGFR inhibitor-based therapy, and none demonstrated a clinicoradiographic response. The therapeutic impact of RAS amplification was further evaluated using a separate, multi-institutional cohort of 23 patients. Eight of 23 patients with KRAS-amplified mCRC received anti-EGFR therapy and all 8 patients exhibited disease progression on treatment. Although the number of KRAS-amplified mCRCs is limited, our data suggest the clinicopathologic features associated with mCRC harboring a KRAS amplification are distinct from those associated with a KRAS mutation. However, both alterations seem to confer EGFR inhibitor resistance and, therefore, RAS testing to include copy number analyses may be of consideration in the treatment of mCRC.