Specific bacterial co-abundance groups are associated with inflammatory status in patients with ulcerative colitis.

BACKGROUND AND AIMS: While there is increasing interest in microbiome-directed therapies for patients with ulcerative colitis (UC), the identification of microbial targets remains elusive, underlining the need for novel approaches. METHODS: Utilizing metagenomic data from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease, available via the IBD Plexus Program of the Crohn's & Colitis Foundation, we used a tree-based dichotomous approach to assemble distinct clusters of species-level bacterial co-abundance groups (CAGs). We evaluated the abundance of bacterial CAGs and fungal taxa during remission (n=166) and activity (n=46). We examined if the bacterial CAGs identified in our cohorts were conserved in 2 healthy cohorts and in a Korean UC cohort. RESULTS: CAG3 and CAG8, dominated by bacteria from family Lachnospiraceae, were associated with remission. Low CAG8 and elevated Candida genus were predictive of active UC. Constituents from CAG8 were influential hub species of the remission-associated microbial UC network, including Ruminococcus gnavus, Erysipelatoclostridium ramosum, Blautia and Dorea species. These hub species interactions were preserved in 2 healthy cohorts and were partially recapitulated in a Korean UC cohort. CAG8 abundance correlated with the secondary bile acid production pathway. Bacterial CAGs did not correlate with Candida, however Bifidobacterium adolescentis and Alistipes putredinis were negatively associated with Candida. CONCLUSIONS: Lachnospiriceae-dominated bacterial CAGs were associated with remission in UC, with key bacterial interactions within the CAG also observed in 2 healthy cohorts and a Korean UC cohort. Bacterial CAG-based analyses may help to inform the design of candidate consortia for microbiome-based therapeutics.

Microbial butyrate capacity is reduced in inflamed mucosa in patients with ulcerative colitis.

Reduced butyrate-production capacity has been reported in fecal microbial communities in patients with active ulcerative colitis. However, the butyrate-production capacity of the mucosal microbiome from active vs quiescent mucosa in ulcerative colitis has been unexplored. We sought to determine the diversity and relative abundance of mucosal bacterial and fungal communities from endoscopically active vs quiescent mucosa in patients with UC, and aimed to predict contributions of mucosal microbial communities to butyrate synthesis. Systematic, segmental right- and left-sided biopsies were obtained from endoscopically active (n = 13) or quiescent (n = 17) colonic mucosa, among 15 patients with pan-colonic ulcerative colitis. Dietary fiber intake of patients was performed using the validated five-item FiberScreen questionnaire. Amplicon sequencing of mucosal bacteria and fungi was performed. The diversity and relative abundance of mucosal bacterial and fungal taxa were quantified, and predicted contributions to butyrate synthesis were ascertained. Bacterial alpha and beta diversity were similar between active vs quiescent mucosa. Butyrogenic taxa were significantly increased in quiescence, including Butyricimonas, Subdoligranulum, and Alistipes. Predicted butyrate kinase activity was significantly and concomitantly increased in quiescent mucosa. Fiber intake was positively correlated with butyrogenic microbes. Compared to mucosal bacterial prevalence, mucosal fungi were detected in low prevalence. Butyrogenic microbes are relatively increased in quiescent mucosa in ulcerative colitis, and may be related to increased fiber intake during quiescence. Manipulation of the mucosal microbiome towards butyrate-producing bacteria may be associated with endoscopic quiescence.

Colorectal Neoplasia in Asian Americans Undergoing First Time Asymptomatic Average-risk Screening Colonoscopies.

GOALS: We identified the prevalence and subtype of colorectal neoplasia removed during index screening colonoscopies in a large Asian American population. BACKGROUND: Asian Americans are the fastest growing demographic group in the United States yet there is a paucity of data on the characteristics of colorectal neoplasia found in this cohort. STUDY: Cross-sectional study of 2208 index colonoscopies performed on average-risk Asian and White patients at a large, tertiary academic center. Patients were identified via diagnostic or procedure codes between 2015 and 2020, with retrospective classification of polyp histopathology. Univariate and multivariate analysis were performed to identify risk factors associated with colorectal neoplasia. RESULTS: A total of 2208 patients were identified, of which 1085 were Asian. When adjusted for age and sex, Asians were as likely as Whites to have any type of colorectal neoplasia [44.2% vs. 43.5%, odds ratio (OR)=0.93, (CI: 0.78-1.11)]. On multivariate analysis, Asians were less likely to have sessile serrated polyps (5.5% vs. 9.9%, OR=0.53, 95% CI: 0.38-0.73) and more likely to have tubular adenomas in the left colon (22.6% vs. 18.0%, OR=1.33, 95% CI: 1.08-1.64) compared with Whites. CONCLUSIONS: Quality measures, such as sessile serrated polyp detection rates, may need to take into account demographic factors such as race. The prevalence of colorectal neoplasia among Asian Americans is substantial and warrants efforts to promote optimal uptake of colorectal cancer screening tests.

Predictors and Etiologies of Clinical Relapse Among Patients With Ulcerative Colitis in Deep Remission.

GOAL: The objective of this study was to evaluate for potential predictors and etiologies of clinical relapse among patients with ulcerative colitis in deep remission. BACKGROUND: Patients displaying deep (endoscopic and histologic) remission have a decreased cumulative risk of relapse in ulcerative colitis of <10% per year, but predictors and etiologies of relapse in this population are poorly understood. MATERIALS AND METHODS: We performed a retrospective cohort study utilizing electronic medical records at Tufts Medical Center to identify patients in deep remission, classified as having both endoscopic remission (Mayo Endoscopic Score of 0 or 1) and histologic remission (Simplified Geboes Score 0.2). We evaluated the cumulative risk of clinical relapse following attainment of deep remission and examined predictors and etiologies of relapse. RESULTS: Among 139 patients with ulcerative colitis in deep remission, the cumulative risk of relapse was <10% and <20% at 1 and 2 years. Patients with complete normalization of mucosa (Geboes=0) and normalization of C-reactive protein (<7.48 mg/dL) at the time of remission were associated with a lower risk of relapse. Discontinuation of therapy was the most commonly identified etiology of relapse. CONCLUSIONS: Patients in deep remission have a 1-year risk of clinical relapse of <10%, with those demonstrating a non-normalized mucosa or elevated C-reactive protein predictive of persistent relapse risk. Discontinuation of therapy or minor histologic changes may drive relapse among those in deep remission.

Efficacy and Safety of Hyperbaric Oxygen Therapy in Fistulizing Crohn's Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Hyperbaric oxygen therapy (HBOT) delivers 100% oxygen in a pressurized chamber, increasing tissue oxygen levels and regulating inflammatory pathways. Mounting evidence suggests that HBOT may be effective for inflammatory bowel disease. Our systematic review and meta-analysis aimed to quantify the efficacy and safety of HBOT in fistulizing Crohn's disease (CD). METHODS: A systematic review was conducted using the EMBASE, Web of Science, Pubmed, and Cochrane Library databases according to the "Preferred Reporting Items for Systematic Reviews and Meta-analyses" criteria. Study bias was assessed using the Cochrane Handbook guidelines. RESULTS: Sixteen studies with 164 patients were included in the analysis. For all fistula subtypes, the pooled overall clinical response was 87% (95% CI: 0.70-0.95, I2 = 0) and the pooled clinical remission was 59% (95% CI: 0.35-0.80, I2 = 0). The overall clinical response was 89%, 84%, and 29% for perianal, enterocutaneous, and rectovaginal fistulas, respectively. On meta-regression, hours in the chamber and the number of HBOT sessions were not found to correlate with clinical response. The pooled number of adverse events was low at 51.7 per 10,000 HBOT sessions for all fistula types (95% CI: 16.8-159.3, I2 = 0). The risk of bias was observed across all studies. CONCLUSION: HBOT is a safe and potentially effective treatment option for fistulizing CD. Randomized control trials are needed to substantiate the benefit of HBOT in fistulizing CD.

Dynamics of the Gut Mycobiome in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Intestinal fungi have been implicated in the pathogenesis of ulcerative colitis (UC). However, it remains unclear if fungal composition is altered during active versus quiescent disease. METHODS: We analyzed clinical and metagenomic data from the Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease (SPARC IBD), available via the IBD Plexus Program of the Crohn's & Colitis Foundation. We evaluated the fungal composition of fecal samples from 421 patients with UC during clinical activity and remission. Within a longitudinal subcohort (n = 52), we assessed for dynamic taxonomic changes across alterations in clinical activity over time. We examined if fungal amplicon sequence variants and fungal-bacterial relationships were altered during activity versus remission. Finally, we classified activity in UC using a supervised machine learning random forest model trained on fungal abundance data. RESULTS: During clinical activity, the relative abundance of genus Candida was increased 3.5-fold (P-adj < 1 × 10-4) compared with during remission. Patients with longitudinal reductions in clinical activity demonstrated parallel reductions in Candida relative abundance (P < .05). Candida relative abundance correlated with Parabacteroides diastonis, Faecalibacterium prausnitzii, and Bacteroides dorei relative abundance (P < .05) during remission; however, these correlations were disrupted during activity. Fungal abundance data successfully classified patients with active or quiescent UC (area under the curve ∼0.80), with Candida relative abundance critical to the success of the model. CONCLUSIONS: Clinical activity in UC is associated with an increased relative abundance of Candida, cross-sectionally and dynamically over time. The role of fecal Candida as a target for therapeutics in UC should be evaluated.

Rising Inpatient Utilization and Costs of Cannabis Hyperemesis Syndrome Hospitalizations in Massachusetts After Cannabis Legalization.

GOALS: We described the demographics, inpatient utilization, and cost of services among patients hospitalized for putative cannabinoid hyperemesis syndrome (CHS) predating and postdating cannabis legalization in Massachusetts. BACKGROUND: As the recreational use of cannabis has been widely legalized nationally, the resulting shifts in clinical presentation, health care utilization, and estimated costs of CHS hospitalizations remain unclear in the postlegalization era. STUDY: We performed a retrospective cohort study among patients admitted to a large urban hospital between 2012 and 2021, before and after the date of cannabis legalization in Massachusetts (Dec 15, 2016). We examined the demographic and clinical characteristics of patients admitted for putative CHS, the utilization of hospital services, and estimated inpatient costs pre and postlegalization. RESULTS: We identified a significant increase in putative CHS hospitalizations pre and post-cannabis legalization in Massachusetts (0.1% vs 0.02% of total admissions per time period, P < 0.05). Across 72 CHS hospitalizations, patient demographics were similar pre and postlegalization. Hospital resource utilization increased postlegalization, with increased length of stay (3 d vs 1 d, P < 0.005), and need for antiemetics ( P < 0.05). Multivariate linear regression confirmed that postlegalization admissions were independently associated with increased length of stay ( Β = 5.35, P < 0.05). The mean cost of hospitalization was significantly higher postlegalization ($18,714 vs $7460, P < 0.0005), even after adjusting for medical inflation ($18,714 vs $8520, P < 0.001) with intravenous fluid administration and endoscopy costs increased ( P < 0.05). On multivariate linear regression, hospitalization for putative CHS during postlegalization predicted increased costs ( Β = 10,131.25, P < 0.05). CONCLUSIONS: In the postlegalization era of cannabis in Massachusetts, we found increased putative CHS hospitalizations, with a concomitant increased length of hospital stay and total cost per hospitalization. As cannabis use increases, the recognition and costs of its deleterious effects are necessary to incorporate into future clinical practice strategies and health policy.

Defective Induction of IL-27-Mediated Immunoregulation by Myeloid DCs in Multiple Sclerosis.

The purpose of this study was to examine whether myeloid dendritic cells (mDCs) from patients with multiple sclerosis (MS) and healthy controls (HCs) become similarly tolerogenic when exposed to IL-27 as this may represent a potential mechanism of autoimmune dysregulation. Our study focused on natural mDCs that were isolated from HCs and MS patient peripheral blood mononuclear cells (PBMCs). After a 24-h treatment with IL-27 ± lipopolysaccharide (LPS), the mDCs were either harvested to identify IL-27-regulated gene expression or co-cultured with naive T-cells to measure how the treated DC affected T-cell proliferation and cytokine secretion. mDCs isolated from HCs but not untreated MS patients became functionally tolerogenic after IL-27 treatment. Although IL-27 induced both HC and untreated MS mDCs to produce similar amounts of IL-10, the tolerogenic HC mDCs expressed PD-L2, IDO1, and SOCS1, while the non-tolerogenic untreated MS mDCs expressed IDO1 and IL-6R. Cytokine and RNA analyses identified two signature blocks: the first identified genes associated with mDC tolerizing responses to IL-27, while the second was associated with the presence of MS. In contrast to mDCs from untreated MS patients, mDCs from HCs and IFNb-treated MS patients became tolerogenic in response to IL-27. The genes differentially expressed in the different donor IL-27-treated mDCs may contain targets that regulate mDC tolerogenic responses.

Alterations in the Fungal Microbiome in Ulcerative Colitis.

BACKGROUND: Although gut fungi have been implicated in the immunopathogenesis of inflammatory bowel disease, the fungal microbiome has not been deeply explored across endohistologic activity and treatment exposure in ulcerative colitis. METHODS: We analyzed data from the SPARC IBD (Study of a Prospective Adult Research Cohort with Inflammatory Bowel Disease) registry. We evaluated the fungal composition of fecal samples from 98 patients with ulcerative colitis across endoscopic activity (n = 43), endohistologic activity (n = 41), and biologic exposure (n = 82). Across all subgroups, we assessed fungal diversity and differential abundance of taxonomic groups. RESULTS: We identified 500 unique fungal amplicon sequence variants across the cohort of 82 patients, dominated by phylum Ascomycota. Compared with endoscopic remission, patients with endoscopic activity had increased Saccharomyces (log2 fold change = 4.54; adjusted P < 5 × 10-5) and increased Candida (log2 fold change = 2.56; adjusted P < .03). After adjusting for age, sex, and biologic exposure among patients with endoscopic activity, Saccharomyces (log2 fold change = 7.76; adjusted P < 1 × 10-15) and Candida (log2 fold change = 7.28; adjusted P< 1 × 10-8) remained enriched during endoscopic activity compared with quiescence. CONCLUSIONS: Endoscopic inflammation in ulcerative colitis is associated with an expansion of Saccharomyces and Candida compared with remission. The role of these fungal taxa as potential biomarkers and targets for personalized approaches to therapeutics in ulcerative colitis should be evaluated.

Gut fungi have been implicated in the pathogenesis of ulcerative colitis. In this retrospective study utilizing deep sequencing of the fecal fungal microbiome, Saccharomyces and Candida were increased during endoscopic inflammation and Penicillium was increased during endoscopic remission.

Ozanimod-Associated Iatrogenic Kaposi Sarcoma in a Patient With Ulcerative Colitis.

Ozanimod is an oral sphingosine-1-phosphate receptor modulator. Although it can be an effective drug for the induction and maintenance of remission in patients with moderately to severely active ulcerative colitis, there have been a few reported cases of various malignancies after exposure to this small molecule. We describe a unique case of biopsy-proven Kaposi sarcoma of the skin and colon in a patient with biologic-resistant ulcerative colitis after treatment with ozanimod for 2 months. Given the potential risk of malignancy associated with this agent, physicians should be aware of this rare adverse event.

Comparative Safety of Biologic Agents in Patients With Inflammatory Bowel Disease With Active or Recent Malignancy: A Multi-Center Cohort Study.

BACKGROUND & AIMS: Safety of biologic agents is a key consideration in patients with inflammatory bowel disease (IBD) and active or recent cancer. We compared the safety of tumor necrosis factor (TNF)-α antagonists vs non-TNF biologics in patients with IBD with active or recent cancer. METHODS: We conducted a multicenter retrospective cohort study of patients with IBD and either active cancer (cohort A) or recent prior cancer (within ≤5 years; cohort B) who were treated with TNFα antagonists or non-TNF biologics after their cancer diagnosis. Primary outcomes were progression-free survival (cohort A) or recurrence-free survival (cohort B). Safety was compared using inverse probability of treatment weighting with propensity scores. RESULTS: In cohort A, of 125 patients (483.8 person-years of follow-up evaluation) with active cancer (age, 54 ± 15 y, 75% solid-organ malignancy), 10 of 55 (incidence rate [IR] per 100 py, 4.4) and 9 of 40 (IR, 10.4) patients treated with TNFα antagonists and non-TNF biologics had cancer progression, respectively. There was no difference in the risk of progression-free survival between TNFα antagonists vs non-TNF biologics (hazard ratio, 0.76; 95% CI, 0.25-2.30). In cohort B, of 170 patients (513 person-years of follow-up evaluation) with recent prior cancer (age, 53 ± 15 y, 84% solid-organ malignancy; duration of remission, 19 ± 19 mo), 8 of 78 (IR, 3.4) and 5 of 66 (IR 3.7) patients treated with TNFα antagonists and non-TNF biologics had cancer recurrence, respectively. The risk of recurrence-free survival was similar between both groups (hazard ratio, 0.94; 95% CI, 0.24-3.77). CONCLUSIONS: In patients with IBD with active or recent cancer, TNFα antagonists and non-TNF biologics have comparable safety. The choice of biologic should be dictated by IBD disease severity in collaboration with an oncologist.

Natural History of New-onset Inflammatory Bowel Disease Among Patients With Multiple Sclerosis.

Patients with MS and IBD were as likely to have stricturing, fistulizing, and extensive IBD as IBD controls. Although MS-IBD patients were less likely to initiate anti-TNF therapy, they did not have worsened risk of progression to surgery on follow-up.

Spatial Evolution of Histologic and Endoscopic Healing in the Left and Right Colon in Patients With Ulcerative Colitis.

BACKGROUND AND AIMS: Despite increasing interest in histologic remission as a treatment target in ulcerative colitis (UC), the accuracy of histologic findings in left colon in detecting pancolonic histologic remission is unknown. METHODS: In a retrospective cohort study of patients with endoscopically active pancolitis undergoing treat-to-target interventions, we evaluated the diagnostic accuracy of left-sided (distal to splenic flexure) histologic and endoscopic findings on colonoscopy for detecting histologic and endoscopic healing elsewhere in the colon. RESULTS: Of 86 patients with moderate to severely active pancolitis who underwent 2 consecutive colonoscopies during treat-to-target interventions, 38% and 51% achieved histologic and endoscopic remission, respectively. Substantial agreement (kappa, 0.67; 95% confidence interval (CI), 0.51-0.83) was observed in histologic findings between left and right colon on follow-up colonoscopy. Histologic, and endoscopic, findings in left colon showed excellent accuracy in detecting pancolonic histologic remission (area under the curve (AUC), 0.96 [95% CI, 0.93-1.0]; misclassification rate, 5.9%), histologic normalization (AUC, 1.0, 0%), endoscopic improvement (AUC, 0.95 [0.96-1.0], 3.5%) and endoscopic remission (AUC, 0.98 [0.96-1.00], 5.8%), respectively. CONCLUSIONS: In patients with active pancolitis undergoing treat-to-target interventions, histologic and endoscopic findings in the left colon on colonoscopy have excellent accuracy for detecting pancolonic histologic remission, histologic normalization, endoscopic improvement, and endoscopic remission. Flexible sigmoidoscopy may suffice for monitoring histologic and endoscopic activity in patients with pancolitis.

Histologic Remission Is Associated With Lower Risk of Treatment Failure in Patients With Crohn Disease in Endoscopic Remission.

BACKGROUND: Although achieving histologic remission in ulcerative colitis is established, the incremental benefit of achieving histologic remission in patients with Crohn disease (CD) treated to a target of endoscopic remission is unclear. We evaluated the risk of treatment failure in patients with CD in clinical and endoscopic remission by histologic activity status. METHODS: In a single-center retrospective cohort study, we identified adults with active CD who achieved clinical and endoscopic remission through treatment optimization. We evaluated the risk of treatment failure (composite of clinical flare requiring treatment modification, hospitalization, and/or surgery) in patients who achieved histologic remission vs persistent histologic activity through Cox proportional hazard analysis. RESULTS: Of 470 patients with active CD, 260 (55%) achieved clinical and endoscopic remission with treatment optimization; 215 patients with histology were included (median age, 33 years; 46% males). Overall, 132 patients (61%) achieved histologic remission. No baseline demographic, disease, or treatment factor was associated with achieving histologic remission. Over a 2-year follow-up, patients with CD in clinical and endoscopic remission who achieved histologic remission experienced a 43% lower risk of treatment failure (1-year cumulative risk: 12.9% vs 18.2%; adjusted hazard ratio, 0.57 [95% confidence interval, 0.35-0.94]) as compared with persistent histologic activity. CONCLUSIONS: Approximately 61% of patients with active CD who achieved clinical and endoscopic remission with treatment optimization simultaneously achieved histologic remission, which was associated with a lower risk of treatment failure. Whether histologic remission should be a treatment target in CD requires evaluation in randomized trials.

Risk of Relapse in Patients With Ulcerative Colitis With Persistent Endoscopic Healing: A Durable Treatment Endpoint.

BACKGROUND: Deep remission in patients with UC has relied on initial achievement of biochemical, endoscopic, and/or histological remission. We evaluated persistent symptomatic remission and endoscopic healing (EH: Mayo endoscopy score [MES] 0 or 1) on consecutive endoscopic examinations as a durable treatment endpoint. METHODS: In a retrospective cohort study, we estimated and compared cumulative risk of clinical relapse in patients with persistent EH, with and without persistent histological remission and depth of EH, among adults with active UC treated-to-target of symptomatic remission and EH who achieved and maintained symptomatic remission and EH over two serial endoscopic assessments. We also explored risk of relapse in patients with persistent EH whose therapy was de-escalated. RESULTS: Of 270 patients who initially achieved EH with treatment-to-target, 89 maintained symptomatic remission and EH on follow-up endoscopy [interval between EH1 and EH2, 16 months]. On follow-up after EH2 [median, 19 months], 1-year cumulative risk of relapse in patients with persistent EH was 11.5%, and with persistent histological remission was 9.5%. Seventeen patients with persistent EH, who underwent de-escalation of therapy, did not have an increased risk of relapse as compared with patients who continued index therapy [5.3% vs 14%, p = 0.16]. CONCLUSIONS: Patients with active UC treated-to-target of clinical remission, who achieve and maintain symptomatic remission and EH over consecutive endoscopies, have a low risk of relapse, particularly in a subset of patients who simultaneously achieve histological remission. Persistent EH should be examined as a treatment endpoint suggestive of deep remission.