John Mark Gubatan, MD

All Publications

• Immunogenicity of Therapeutic Antibodies Used for Inflammatory Bowel Disease: Treatment and Clinical Considerations. Drugs Nielsen, O. H., Hammerhøj, A., Ainsworth, M. A., Gubatan, J., D'Haens, G. 2024

  Abstract

  The introduction of tumor necrosis factor inhibitors has led to a paradigm shift in the management of inflammatory bowel disease (IBD). The subsequent introduction of both anti-integrins and cytokine blockers has since expanded the biologic armamentarium. However, immunogenicity, defined as the production of anti-drug antibodies (ADAs) to the prescribed biopharmaceutical, means a significant fraction of patients exposed to biologic agents will experience a secondary loss of response to one or more of the drugs. In clinical settings, immunogenicity may be caused by several factors, both patient related (e.g., underlying chronic disease, systemic immune burden, including previous biologic therapy failure, and [epi]genetic background) and treatment related (e.g., dose and administration regimens, drug physical structure, photostability, temperature, and agitation). Here, we outline these elements in detail to enhance biopharmaceutical delivery and therapy for patients with IBD. Moreover, concurrent immunomodulator medication may reduce the risks of ADA generation, especially when using the chimeric drug infliximab. Summarizing the latest developments and knowledge in the field, this review aims to provide strategies to prevent ADA production and information on managing non-responsiveness or loss of response to biologics. Better understanding of the molecular mechanisms underlying the formation of ADAs and the critical factors influencing the immunogenicity of biopharmaceuticals may lead to improved health outcomes in the IBD community that may benefit both the individual patient and society through lower healthcare expenses.

  View details for DOI 10.1007/s40265-024-02115-3

  View details for PubMedID 39532820

  View details for PubMedCentralID 9342949

• Immune effector cell-associated enterocolitis following chimeric antigen receptor T-cell therapy in multiple myeloma. Blood cancer journal Fortuna, G. G., Banerjee, R., Savid-Frontera, C., Song, J., Morán-Segura, C. M., Nguyen, J. V., Lekakis, L., Fernandez-Pol, S., Samraj, A. N., Naresh, K. N., Vazquez-Martinez, M., Baz, R. C., Spiegel, J. Y., Mikkilineni, L., Gubatan, J. M., Sidana, S., de Menezes Silva Corraes, A., Kalariya, N. M., Patel, K. K., Shim, K. G., Fonseca, R., Ferreri, C., Voorhees, P. M., Richard, S., Valdes, C. R., Wolf, J. L., Cowan, A. J., Sborov, D. W., Locke, F. L., Lin, Y., Wang, Y., Hansen, D. K. 2024; 14 (1): 180

  Abstract

  We report 14 cases of immune effector cell (IEC)-associated enterocolitis following chimeric antigen receptor T-cell (CAR-T) therapy in multiple myeloma, with a 1.2% incidence overall (0.2% for idecabtagene vicleucel and 2.2% for ciltacabtagene autoleucel). Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 92.5 days (range: 22-210 days) after CAR-T therapy and a median of 85 days after cytokine release syndrome resolution. Gut biopsies uniformly demonstrated inflammation, including intra-epithelial lymphocytosis and villous blunting. In one case where CAR-specific immunofluorescence stains were available, CAR T-cell presence was confirmed within the lamina propria. Systemic corticosteroids were initiated in 10 patients (71%) a median of 25.5 days following symptom onset, with symptom improvement in 40%. Subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. Five patients (36%) have died from bowel perforation or treatment-emergent sepsis. In conclusion, IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy typically beginning 1-3 months after infusion. Thorough diagnostic workup is essential, including evaluation for potential T-cell malignancies. The early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.

  View details for DOI 10.1038/s41408-024-01167-8

  View details for PubMedID 39414769

  View details for PubMedCentralID 8873238

• Artificial intelligence and machine learning technologies in ulcerative colitis. Therapeutic advances in gastroenterology Kulkarni, C., Liu, D., Fardeen, T., Dickson, E. R., Jang, H., Sinha, S. R., Gubatan, J. 2024; 17: 17562848241272001

  Abstract

  Interest in artificial intelligence (AI) applications for ulcerative colitis (UC) has grown tremendously in recent years. In the past 5 years, there have been over 80 studies focused on machine learning (ML) tools to address a wide range of clinical problems in UC, including diagnosis, prognosis, identification of new UC biomarkers, monitoring of disease activity, and prediction of complications. AI classifiers such as random forest, support vector machines, neural networks, and logistic regression models have been used to model UC clinical outcomes using molecular (transcriptomic) and clinical (electronic health record and laboratory) datasets with relatively high performance (accuracy, sensitivity, and specificity). Application of ML algorithms such as computer vision, guided image filtering, and convolutional neural networks have also been utilized to analyze large and high-dimensional imaging datasets such as endoscopic, histologic, and radiological images for UC diagnosis and prediction of complications (post-surgical complications, colorectal cancer). Incorporation of these ML tools to guide and optimize UC clinical practice is promising but will require large, high-quality validation studies that overcome the risk of bias as well as consider cost-effectiveness compared to standard of care.

  View details for DOI 10.1177/17562848241272001

  View details for PubMedID 39247718

  View details for PubMedCentralID PMC11378191

• Network meta-analysis: Comparative onset of early effect of biologics and small molecules in moderately to severely active luminal Crohn's disease. Alimentary pharmacology & therapeutics Attauabi, M., Steenholdt, C., Poulsen, A., Gubatan, J., Burisch, J., Haagen Nielsen, O., Seidelin, J. B. 2024

  Abstract

  Rapidity of effect of advanced therapies for patients with Crohn's disease (CD) can be an essential decision parameter; however, comparative evaluation is lacking. We aimed to compare early response for advanced CD therapies in a network meta-analysis (NMA).We searched systematically MEDLINE, Embase, and CENTRAL up to 19 February 2024, for randomised controlled trials. The co-primary outcomes were induction of clinical remission (Crohn's Disease Activity Index (CDAI) ≤150) and clinical response (≥100-point reduction in CDAI) within the first 6 weeks of treatment. We incorporated any assessment within this time point in a Bayesian random-effects NMA following PRISMA-NMA guidance (PROSPERO ID: CRD42022368509).Twenty-five studies, comprising 7414 patients, were included. Infliximab combined with azathioprine or monotherapy ranked highest for induction of clinical remission within 6 weeks and was significantly superior to certolizumab, ustekinumab, guselkumab, vedolizumab, and upadacitinib. However, superiority over risankizumab 600 mg and adalimumab 160/80 mg was non-significant. Accordingly, infliximab in combination with azathioprine and guselkumab 600 mg ranked highest in the corresponding analysis of clinical response with no statistical significance demonstrated. Among bio-exposed patients, none of whom received infliximab, upadacitinib, and risankizumab induced the highest clinical responses. On the other hand, vedolizumab, certolizumab, and ustekinumab ranked lowest across the analyses.We found infliximab to be ranked highest and superior to all other agents but risankizumab and adalimumab, demonstrating the highest probability of early induction of remission. Upadacitinib and risankizumab induced the highest clinical responses in bio-exposed patients. However, infliximab was not investigated in this population.

  View details for DOI 10.1111/apt.18110

  View details for PubMedID 38863153

• Influence of vitamin D receptor signaling and vitamin D on colonic epithelial cell fate decisions in ulcerative colitis. Journal of Crohn's & colitis Kellermann, L., Hansen, S. L., Maciag, G., Granau, A. M., Johansen, J. V., Teves, J. M., Bressan, R. B., Pedersen, M. T., Soendergaard, C., Baattrup, A. M., Hammerhøj, A., Riis, L. B., Gubatan, J., Jensen, K. B., Nielsen, O. H. 2024

  Abstract

  Epidemiological studies have shown that subnormal levels of vitamin D (25(OH)D) are associated with a more aggravated clinical course of ulcerative colitis (UC). Despite an increased focus on the therapeutic importance of vitamin D and vitamin D receptor (VDR) signaling, the mechanisms underlying the effects of the vitamin D-VDR axis on UC remain elusive. Therefore, we aimed to investigate whether exposure to active vitamin D (1,25(OH)2D3)/VDR signaling in human organoids could influence the maintenance of the colonic epithelium.Intestinal VDR expression was studied by immunohistochemistry, RNA expression arrays, and single-cell RNA sequencing of colonic biopsy specimens obtained from patients with UC and healthy individuals. To characterize the functional and transcriptional effects of 1,25(OH)2D3, we used patient-derived colonic organoids. The dependency of VDR was assessed by knocking out the receptor with CRISPR/Cas9.Our results suggest that 1,25(OH)2D3/VDR stimulation supports differentiation of the colonic epithelium and that impaired 1,25(OH)2D3/VDR signaling thereby may compromise the structure of the intestinal epithelial barrier, leading to flares of UC. Furthermore, a transcriptional response to VDR activity was observed primarily in fully differentiated cells at the top of the colonic crypt, and this response was reduced during flares of UC.We identified an important role of vitamin D signaling in supporting differentiated cell states in the human colonic epithelium, and thereby maintenance of the intestinal barrier integrity. This makes the vitamin D-VDR signaling axis an interesting target for therapeutic efforts to achieve and maintain remission in patients with UC.

  View details for DOI 10.1093/ecco-jcc/jjae074

  View details for PubMedID 38747639

• Differential expression of small bowel TGFβ1 and TGFβ3 characterizes intestinal strictures in patients with fibrostenotic Crohn's disease. Histochemistry and cell biology Levitte, S., Khan, I., Iyahen, V., Ziai, J., Gubatan, J., Sheng, R., Glickstein, S. B., Sun, T., Park, K. T., McBride, J., Keir, M. 2024

  Abstract

  Small bowel strictures remain a debilitating consequence of Crohn's disease and contribute to poor outcomes for patients. Recently, TGFβ has been identified as an important driver of intestinal fibrosis. We studied the localization of TGFβ isoforms in ileal strictures of patients with Crohn's disease using in situ hybridization to understand TGFβ's role in stricture formation. The mucosa of strictures was characterized by higher TGFβ1 while the stricture submucosa showed higher TGFβ3 compared to normal ileum from patients without Crohn's disease (p = 0.02 and p = 0.044, respectively). We correlated these findings with single-cell transcriptomics which demonstrated that TGFβ3 transcripts overall are very rare, which may partially explain why its role in intestinal fibrosis has remained unclear to date. There were no significant differences in fibroblast or B cell TGFβ1 and/or TGFβ3 expression in inflamed vs. noninflamed ileum. We discuss the implications of these findings for therapeutic development strategies to treat patients with fibrostenotic Crohn's disease.

  View details for DOI 10.1007/s00418-024-02290-0

  View details for PubMedID 38705911

  View details for PubMedCentralID 10476777

• Some Drugs Have Two Faces: Paradoxical Colitis in a Patient with Psoriatic Arthritis Previously Treated with Etanercept and IL-17 Inhibitors. Digestive diseases and sciences Huynh, S., Achalu, S., Berry, R., Lin, J., Wang, C. X., Gubatan, J., Cheng, A. G. 2024

  Abstract

  Tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) inhibitors are among the most potent treatments for inflammatory arthropathies including rheumatoid arthritis, psoriasis, and spondyloarthropathies. The availability of these biologic agents have revolutionized the management of these conditions and improved patient outcomes. Though generally safe, these biologics may contribute to the induction or exacerbation of colitis. This paradoxical colitis has been observed in patients on TNF-α inhibitor etanercept and IL-17 inhibitors (secukinumab and ixekizumab). We report a case of a 46-year-old female with psoriasis and psoriatic arthritis who presented with gastrointestinal symptoms after treatment with etanercept and IL-17 inhibitors. She was later diagnosed with paradoxical indeterminate colitis that was masked and treated by subsequent biologics given for her RA and psoriatic arthritis. In this report, we will discuss the importance of considering paradoxical colitis in the differential diagnosis for patients even several years after TNF-α/IL-17 inhibitor initiation and explain why careful consideration must be made when initiating these colitis-inducing agents to treat patients with inflammatory disorders.

  View details for DOI 10.1007/s10620-024-08380-2

  View details for PubMedID 38502378

  View details for PubMedCentralID 3886036

• Gut Microbiome and Disorders of the Gastrointestinal Tract. Microorganisms Hammerhøj, A., Gubatan, J. M., Nielsen, O. H. 2024; 12 (3)

  Abstract

  The protective intestinal epithelial barrier is constantly exposed to more than 100 trillion commensal microorganisms (bacteria, archaea, viruses, and fungi), i [...].

  View details for DOI 10.3390/microorganisms12030576

  View details for PubMedID 38543627

• Updates on the management of inflammatory bowel disease from periconception to pregnancy and lactation. Lancet (London, England) Nielsen, O. H., Gubatan, J. M., Kolho, K. L., Streett, S. E., Maxwell, C. 2024

  Abstract

  Inflammatory bowel disease (IBD) affects reproductive planning due to psychological effects and mechanical problems related to surgery. Children of people with IBD have an increased risk of about 10% if one parent has IBD and up to 33% if both parents have IBD. The fertility of people with IBD is similar to the general population, but fertility might be reduced in individuals with active IBD, ileal pouch-anal anastomosis, or perianal Crohn's disease. Flaring disease during pregnancy increases complications, such as preterm birth. Thus, disease management with appropriate medications can optimise outcomes. As most medications have minimal fetal risks, people with IBD should be informed about the risks of stopping medications and the importance of maintaining remission. A period of disease remission is advisable before pregnancy and could reduce the risks for both the pregnant person and the fetus. Flexible endoscopy, intestinal ultrasound, and gadolinium-free magnetic resonance enterography are safe during pregnancy. We provide state-of-the-art knowledge on the basis of the latest evidence to ensure successful pregnancy outcomes in controlled IBD.

  View details for DOI 10.1016/S0140-6736(24)00052-7

  View details for PubMedID 38458222

• Kinase Signaling in Colitis-Associated Colon Cancer and Inflammatory Bowel Disease. Biomolecules Temby, M., Boye, T. L., Hoang, J., Nielsen, O. H., Gubatan, J. 2023; 13 (11)

  Abstract

  Colorectal cancer is a known complication of chronic inflammation of the colon ("colitis-associated colon cancer"). Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract. Patients with IBD are at increased risk of colon cancer compared to the general population. Kinase signaling pathways play critical roles in both the inflammation and regulating cellular processes such as proliferation and survival that contribute to cancer development. Here we review the interplay of kinase signaling pathways (mitogen-activated protein kinases, cyclin-dependent kinases, autophagy-activated kinases, JAK-STAT, and other kinases) and their effects on colitis-associated colon cancer. We also discuss the role of JAK-STAT signaling in the pathogenesis of IBD and the therapeutic landscape of JAK inhibitors for the treatment of IBD.

  View details for DOI 10.3390/biom13111620

  View details for PubMedID 38002302

  View details for PubMedCentralID PMC10669043

• Effectiveness of Non-Budesonide Therapies in Management of Microscopic Colitis: A Systematic Review and Meta-analysis. Drugs Rehde, A., Hendel, S. K., Juhl, C. B., Gubatan, J., Nielsen, O. H. 2023

  Abstract

  Budesonide is accepted as first-choice therapy for microscopic colitis (MC); however, symptoms often recur and some patients may be dependent, intolerant, or even fail budesonide. We performed a systematic review and meta-analysis to determine the effectiveness of non-budesonide therapies (thiopurines, bismuth subsalicylate [BSS], bile acid sequestrants [BAS], loperamide and biologics) for MC suggested by international guidelines.We searched the CENTRAL, MEDLINE, and EMBASE databases from their inception to 18 April 2023 for the above-mentioned therapeutics in MC. We pooled the response and remission rates by medication using a random-effects model.Twenty-five studies comprising 1475 patients were included in the meta-analysis. Treatment with BSS showed the highest response rate of 75% (95% confidence interval [CI] 0.65-0.83; I2 = 70.12%), with 50% achieving remission of symptoms (95% CI 0.35-0.65; I2 = 71.06%). Treatment with tumor necrosis factor (TNF) inhibitors (infliximab and adalimumab) demonstrated a response rate of 73% (95% CI 0.63-0.83; I2 = 0.00%), with a remission rate of 44% (95% CI 0.32-0.56; I2 = 0.00%). The response rate for those treated with vedolizumab was similar; 73% responded to treatment (95% CI 0.57-0.87; I2 = 35.93%), with a remission rate of 56% (95% CI 0.36-0.75; I2 = 46.30%). Loperamide was associated with response and remission rates of 62% (95% CI 0.43-0.80; I2 = 92.99%) and 14% (95% CI 0.07-0.25), respectively, whereas BAS use was associated with response and remission rates of 60% (95% CI 0.51-0.68; I2 = 61.65%) and 29% (95% CI 0.12-0.55), respectively. Finally, the outcomes for thiopurine use were 49% (95% CI 0.27-0.71; I2 = 81.45%) and 38% (95% CI 0.23-0.54; I2 = 50.05%), respectively DISCUSSION: The present systematic review and meta-analysis provides rates of effectiveness of non-budesonide therapies for MC based on available data in the field. Studies in the meta-analysis showed a large amount of heterogeneity due to the variability in assessing the clinical effects of intervention between the studies caused by differences in the definitions of response or remission rates between the studies included. This may likely result in overestimating the benefit of a treatment. Furthermore, the number of participants and drug dosages varied, and only a few studies applied disease-specific activity indices. Only one randomized controlled trial (RCT) was identified. All other 24 included studies were either case series or (retrospective) cohort studies, which complicated efforts to perform further sensitivity analyses to adjust for potential confounders and risk of bias. In addition, the overall evidence on the effect of these treatment options was judged as low, mostly due to comparability bias and the observational nature of the available studies, which limited statistically robust comparisons of rates of effectiveness of the different non-budesonide agents ranked against each other. However, our observational findings may inform clinicians regarding the most rational selection of non-budesonide therapies to patients with MC.PROSPERO protocol #CRD42020218649.

  View details for DOI 10.1007/s40265-023-01914-4

  View details for PubMedID 37358712

  View details for PubMedCentralID 9342949

• Gut microbiome-based therapeutics in inflammatory bowel disease CLINICAL AND TRANSLATIONAL DISCOVERY Hu, K. A., Gubatan, J. 2023; 3 (2)

  View details for DOI 10.1002/ctd2.182

  View details for Web of Science ID 001224381800008

• Selective JAK1 inhibitors for the treatment of inflammatory bowel disease. Pharmacology & therapeutics Nielsen, O. H., Boye, T. L., Gubatan, J., Chakravarti, D., Jaquith, J. B., LaCasse, E. C. 2023: 108402

  Abstract

  Janus kinase (JAK) inhibitors, also known as jakinibs, are third-generation oral small molecules that have expanded the therapeutic options for the management of chronic inflammatory diseases, including inflammatory bowel disease (IBD). Tofacitinib, a pan-JAK inhibitor, has spearheaded the new JAK class for IBD treatment. Unfortunately, serious adverse effects, including cardiovascular complications such as pulmonary embolism and venous thromboembolism or even death from any cause, have been reported for tofacitinib. However, it is anticipated that next-generation selective JAK inhibitors may limit the development of serious adverse events, leading to a safer treatment course with these novel targeted therapies. Nevertheless, although this drug class was recently introduced, following the launch of second-generation biologics in the late 1990s, it is breaking new ground and has been shown to efficiently modulate complex cytokine-driven inflammation in both preclinical models and human studies. Herein, we review the clinical opportunities for targeting JAK1 signaling in the pathophysiology of IBD, the biology and chemistry underpinning these target-selective compounds, and their mechanisms of actions. We also discuss the potential for these inhibitors in efforts to balance their benefits and harms.

  View details for DOI 10.1016/j.pharmthera.2023.108402

  View details for PubMedID 37004800

• Small bowel adenocarcinoma in neoterminal ileum in setting of stricturing Crohn's disease: A case report and review of literature. World journal of clinical cases Karthikeyan, S., Shen, J., Keyashian, K., Gubatan, J. 2023; 11 (9): 2021-2028

  Abstract

  Small bowel adenocarcinomas (SBA) are rare malignancies with exceedingly low survival rates, with different presentation in Crohn's disease (CD). CD-induced SBA poses diagnostic challenges given overlapping presentation with stricturing CD and lack of diagnostics for early detection. Moreover, guidance is lacking on the impact of recently approved therapeutics in CD on SBA management. Here, we aim to highlight the future of CD-induced SBA management and discuss the potential merit of balloon enteroscopy and genetic testing for earlier detection.We report the case of a 60-year-old female with longstanding Crohn's ileitis, presenting with acute obstructive symptoms attributed to stricturing phenotype. Her obstructive symptoms were refractory to intravenous (IV) steroids, with further investigation via computed tomography enterography not providing additional diagnostic yield. Ultimately, surgical resection revealed SBA in the neoterminal ileum, with oncologic therapy plan created. However, this therapy plan could not be initiated due to continued obstructive symptoms attributed to active CD. Ultimately, infused biologic therapy was initiated, but her obstructive symptoms continued to remain dependent on IV corticosteroids. Review of diagnostics by a multidisciplinary care team suggested metastatic disease in the peritoneum, lending to a shift in the goals of care to comfort.With the diagnostic and therapeutic challenges of concurrent SBA and CD, multidisciplinary care and algorithmic management can optimize outcomes.

  View details for DOI 10.12998/wjcc.v11.i9.2021

  View details for PubMedID 36998944

  View details for PubMedCentralID PMC10044945

• Case Series of Precision Delivery of Methylprednisolone in Pediatric Inflammatory Bowel Disease: Feasibility, Clinical Outcomes, and Identification of a Vasculitic Transcriptional Program. Journal of clinical medicine Levitte, S., Yarani, R., Ganguly, A., Martin, L., Gubatan, J., Nadel, H. R., Franc, B., Gugig, R., Syed, A., Goyal, A., Park, K. T., Thakor, A. S. 2023; 12 (6)

  Abstract

  Systemic steroid exposure, while useful for the treatment of acute flares in inflammatory bowel disease (IBD), is associated with an array of side effects that are particularly significant in children. Technical advancements have enabled locoregional intraarterial steroid delivery directly into specific segments of the gastrointestinal tract, thereby maximizing tissue concentration while limiting systemic exposure. We investigated the feasibility of intraarterial steroid administration into the bowel in a cohort of nine pediatric patients who had IBD. This treatment approach provided symptom relief in all patients, with sustained relief (>2 weeks) in seven out of nine; no serious adverse effects occurred in any patient. In addition, we identified patterns of vascular morphologic changes indicative of a vasculopathy within the mesenteric circulation of inflamed segments of the bowel in pediatric patients with Crohn's disease, which correlated with disease activity. An analysis of publicly available transcriptomic studies identified vasculitis-associated molecular pathways activated in the endothelial cells of patients with active Crohn's disease, suggesting a possible shared transcriptional program between vasculitis and IBD. Intraarterial corticosteroid treatment is safe and has the potential to be widely accepted as a locoregional approach for therapy delivery directly into the bowel; however, this approach still warrants further consideration as a short-term "bridge" between therapy transitions for symptomatic IBD patients with refractory disease, as part of a broader steroid-minimizing treatment strategy.

  View details for DOI 10.3390/jcm12062386

  View details for PubMedID 36983386

• Editorial: treat-to-target in ulcerative colitis clinical management-a small price to pay? Alimentary pharmacology & therapeutics Barber, G. E., Gubatan, J. 2023; 57 (5): 569-570

  View details for DOI 10.1111/apt.17298

  View details for PubMedID 36786463

• Comparative onset of effect of biologics and small molecules in moderate-to-severe ulcerative colitis: a systematic review and network meta-analysis. EClinicalMedicine Attauabi, M., Dahl, E. K., Burisch, J., Gubatan, J., Nielsen, O. H., Seidelin, J. B. 2023; 57: 101866

  Abstract

  Onset of effect of advanced therapies is an important parameter due to symptom load and risk of disease complications in moderate-to-severe ulcerative colitis (UC), but comparative data are lacking. Therefore, we aimed to assess the comparative onset of efficacy of biological therapies and small molecules for this patient population.In this systematic review and network meta-analysis, we searched MEDLINE, Embase, and Cochrane Central Register of Controlled Trials from inception to 24 August 2022, for randomised controlled trials or open-label studies assessing the efficacy of biologics or small molecule drugs within the first six weeks of treatment in adults with UC. The co-primary outcomes were the induction of clinical response and clinical remission at week 2. Network meta-analyses was conducted under the Bayesian framework. This study is registered with PROSPERO: CRD42021250236.The systematic literature search identified 20,406 citations, of which 25 studies comprising 11,074 patients fulfilled the eligibility criteria. Upadacitinib ranked highest for induction of clinical response and clinical remission at week 2 and was significantly superior to all agents but tofacitinib, which ranked second highest. Although the rankings remained consistent, no differences between upadacitinib and biological therapies were demonstrated in the sensitivity analyses of partial Mayo clinic score response or resolution of rectal bleeding at week 2. Tumor necrosis factor-α (TNF) inhibitors were significantly superior to vedolizumab and ustekinumab for patient-reported outcome-2 (PRO-2) remission at week 2 in bio-naïve patients. Filgotinib 100 mg, ustekinumab, and ozanimod ranked lowest across all endpoints.In this network meta-analysis, we found upadacitinib to be significantly superior to all agents but tofacitinib for the induction of clinical response and clinical remission two weeks after treatment initiation. In contrast, ustekinumab and ozanimod ranked lowest. Our findings help to establish the evidence regarding the onset of efficacy of advanced therapies.None.

  View details for DOI 10.1016/j.eclinm.2023.101866

  View details for PubMedID 36864986

  View details for PubMedCentralID PMC9971510

• Dietary Exposures and Interventions in Inflammatory Bowel Disease: Current Evidence and Emerging Concepts. Nutrients Gubatan, J., Kulkarni, C. V., Talamantes, S. M., Temby, M., Fardeen, T., Sinha, S. R. 2023; 15 (3)

  Abstract

  Diet is intimately linked to the gastrointestinal (GI) tract and has potent effects on intestinal immune homeostasis. Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the GI tract. The therapeutic implications of diet in patients with IBD have received significant attention in recent years. In this review, we provide a contemporary and comprehensive overview of dietary exposures and interventions in IBD. Epidemiological studies suggest that ultra-processed foods, food additives, and emulsifiers are associated with a higher incidence of IBD. Exclusion and elimination diets are associated with improved symptoms in patients with IBD, but no effects on objective markers of inflammation. Specific dietary interventions (e.g., Mediterranean, specific carbohydrate, high fiber, ketogenic, anti-inflammatory diets) have been shown to reduce symptoms, improve inflammatory biomarkers, and quality of life metrics to varying degrees, but these studies are limited by study design, underpowering, heterogeneity, and confounding. To date, there is no robust evidence that any dietary intervention alone may replace standard therapies in patients with IBD. However, diet may play an adjunct role to induce or maintain clinical remission with standard IBD therapies. The results of novel dietary trials in IBD such as personalized fiber, intermittent fasting, and time-restricted diets are eagerly awaited.

  View details for DOI 10.3390/nu15030579

  View details for PubMedID 36771288

• Subcutaneous Sweet Syndrome Successfully Treated With Ustekinumab in a Patient With Ulcerative Colitis. ACG case reports journal Hu, K. A., Shen, J., Rieger, K., Wei, M. T., Gubatan, J. 2022; 9 (11): e00881

  Abstract

  Ustekinumab, an inhibitor of the interleukin-12/23 pathway, received Food and Drug Administration (FDA) approval in 2019 for induction and maintenance therapy in patients with moderate-to-severe ulcerative colitis (UC). Data regarding the efficacy of ustekinumab in the treatment of extraintestinal manifestations of UC are unclear. Sweet syndrome, an acute febrile neutrophilic dermatosis, is a cutaneous manifestation of inflammatory bowel disease that parallels disease activity. In this study, we present the first case of subcutaneous Sweet syndrome with sterile osteomyelitis in a patient with UC successfully treated with ustekinumab.

  View details for DOI 10.14309/crj.0000000000000881

  View details for PubMedID 36447766

  View details for PubMedCentralID PMC9699508

• Immune checkpoint inhibitor-mediated colitis is associated with cancer overall survival. World journal of gastroenterology Weingarden, A. R., Gubatan, J., Singh, S., Balabanis, T. C., Patel, A., Sharma, A., Habtezion, A. 2022; 28 (39): 5750-5763

  Abstract

  Immune checkpoint inhibitor-mediated colitis (IMC) is a common adverse event following immune checkpoint inhibitor (ICI) therapy for cancer. IMC has been associated with improved overall survival (OS) and progression-free survival (PFS), but data are limited to a single site and predominantly for melanoma patients.To determine the association of IMC with OS and PFS and identify clinical predictors of IMC.We performed a retrospective case-control study including 64 ICI users who developed IMC matched according to age, sex, ICI class, and malignancy to a cohort of ICI users without IMC, from May 2011 to May 2020. Using univariate and multivariate logistic regression, we determined association of presence of IMC on OS, PFS, and clinical predictors of IMC. Kaplan-Meier curves were generated to compare OS and PFS between ICI users with and without IMC.IMC was significantly associated with a higher OS (mean 24.3 mo vs 17.7 mo, P = 0.05) but not PFS (mean 13.7 mo vs 11.9 mo, P = 0.524). IMC was significantly associated with OS greater than 12 mo [Odds ratio (OR) 2.81, 95% confidence interval (CI) 1.17-6.77]. Vitamin D supplementation was significantly associated with increased risk of IMC (OR 2.48, 95%CI 1.01-6.07).IMC was significantly associated with OS greater than 12 mo. In contrast to prior work, we found that vitamin D use may be a risk factor for IMC.

  View details for DOI 10.3748/wjg.v28.i39.5750

  View details for PubMedID 36338892

  View details for PubMedCentralID PMC9627421

• De Novo Diagnosis of Lymphocytic Colitis After SARS-CoV-2 Vaccination. ACG case reports journal Lee, P., Wei, M. T., Gubatan, J., Forgó, E., Berry, G. J., Verma, R., Friedland, S. 2022; 9 (9): e00849

  Abstract

  SARS-CoV-2 mRNA vaccines are safe and effective for most patients. Gastrointestinal complications reported after vaccination have included gastroparesis and inflammatory bowel disease flares. In this study, we present a unique case of lymphocytic colitis that occurred in a healthy middle-aged man after Moderna SARS-CoV-2 mRNA vaccination. This reveals an unexpected complication of a mRNA vaccine that presented as worsening diarrhea after vaccination in a dose-dependent pattern. Caregivers should be aware of lymphocytic colitis as a possible complication of the Moderna vaccine and monitor those patients closely for symptom resolution.

  View details for DOI 10.14309/crj.0000000000000849

  View details for PubMedID 36134123

  View details for PubMedCentralID PMC9485468

• The Tumor Immune Microenvironment in Pancreatic Ductal Adenocarcinoma: Neither Hot nor Cold. Cancers Rubin, S. J., Sojwal, R. S., Gubatan, J., Rogalla, S. 2022; 14 (17)

  Abstract

  Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic tumor and is associated with poor prognosis and treatment response. The tumor microenvironment (TME) is recognized as an important factor in metastatic progression across cancers. Despite extensive study of the TME in PDAC, the cellular and molecular signaling networks remain poorly understood, largely due to the tremendous heterogeneity across tumors. While earlier work characterized PDAC as an immunologically privileged tumor poorly recognized by the immune system, recent studies revealed the important and nuanced roles of immune cells in the pathogenesis of PDAC. Distinct lymphoid, myeloid, and stromal cell types in the TME exert opposing influences on PDAC tumor trajectory, suggesting a more complex organization than the classical "hot" versus "cold" tumor distinction. We review the pro- and antitumor immune processes found in PDAC and briefly discuss their leverage for the development of novel therapeutic approaches in the field.

  View details for DOI 10.3390/cancers14174236

  View details for PubMedID 36077772

• Paternal Medications in Inflammatory Bowel Disease and Male Fertility and Reproductive Outcomes: A Systematic Review and Meta-Analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Gubatan, J., Barber, G. E., Nielsen, O. H., Juhl, C. B., Maxwell, C., Eisenberg, M. L., Streett, S. E. 2022

  Abstract

  Studies evaluating reproductive outcomes among male patients with inflammatory bowel disease (IBD) are limited. We evaluated use of IBD medications and association with semen parameters, a proxy of male fertility, and adverse pregnancy outcomes [early pregnancy loss (EPL), preterm birth (PB), congenital malformations (CM)].We searched Medline, Embase, Scopus, and Web of Science (PROSPERO CRD42020197098) from inception to April 2022 for studies reporting semen parameters and adverse pregnancy outcomes among male patients exposed to biologics, thiopurine, or methotrexate. Standardized mean difference, prevalence, and odds ratios of outcomes were pooled and analysed using a random effects model.Ten studies reporting semen parameters (268 IBD patients) and 16 studies reporting adverse pregnancy outcomes (over 25,000 IBD patients) were included. Biologic, thiopurine, or methotrexate use were not associated with decreased sperm count, motility, or abnormal morphology compared to non-exposed patients. The prevalence of adverse pregnancy outcomes with paternal biologic (5%), thiopurine (6%), or methotrexate (6%) exposure was comparable to non-exposed patients (5%). Biologic use was not associated with risk of EPL (OR 1.26, I2= 0%, P=0.12), PB (OR 1.10, I2= 0%, P=0.17), or CM (OR 1.03, I2=0%, P=0.69). Thiopurine use was not associated with risk of EPL (OR 1.31, I2= 19%, P=0.17), PB (OR 1.05, I2= 0%, P=0.20), or CM (OR 1.07, I2=7%, P=0.34). Methotrexate use was not associated with risk of PB (OR 1.06, I2= 0%, P=0.62) or CM (OR 1.03, I2=0%, P=0.81).Biologic, thiopurine, or methotrexate use among male patients with IBD are not associated with impairments in fertility or with increased odds of adverse pregnancy outcomes.Biologic therapy, congenital malformations, early pregnancy loss, father, inflammatory bowel disease, male, pregnancy outcomes, preterm birth, reproductive health.

  View details for DOI 10.1016/j.cgh.2022.07.008

  View details for PubMedID 35870769

• Gut Microbiome in Inflammatory Bowel Disease: Role in Pathogenesis, Dietary Modulation, and Colitis-Associated Colon Cancer. Microorganisms Gubatan, J., Boye, T. L., Temby, M., Sojwal, R. S., Holman, D. R., Sinha, S. R., Rogalla, S. R., Nielsen, O. H. 2022; 10 (7)

  Abstract

  The gut microbiome has increasingly been recognized as a critical and central factor in inflammatory bowel disease (IBD). Here, we review specific microorganisms that have been suggested to play a role in the pathogenesis of IBD and the current state of fecal microbial transplants as a therapeutic strategy in IBD. We discuss specific nutritional and dietary interventions in IBD and their effects on gut microbiota composition. Finally, we examine the role and mechanisms of the gut microbiome in mediating colitis-associated colon cancer.

  View details for DOI 10.3390/microorganisms10071371

  View details for PubMedID 35889090

• p38γ and p38δ as biomarkers in the interplay of colon cancer and inflammatory bowel diseases. Cancer communications (London, England) Fajardo, P., Taskova, M., Martín-Serrano, M. A., Hansen, J., Slott, S., Jakobsen, A. K., Wibom, M. L., Salegi, B., Muñoz, A., Barbachano, A., Sharma, A., Gubatan, J. M., Habtezion, A., Sanz-Ezquerro, J. J., Astakhova, K., Cuenda, A. 2022

  View details for DOI 10.1002/cac2.12331

  View details for PubMedID 35796643

• Rates and Predictors of Long-term Clinical Outcomes in Patients With Perianal Crohn's Disease on Biologic Therapy. Journal of clinical gastroenterology Gubatan, J., Frost, S., Levitte, S., Keyashian, K. 2022

  Abstract

  Perianal Crohn's disease (pCD) represents an aggressive phenotype with limited studies on long-term outcomes. We evaluated 5-year outcomes of these patients on biologic therapies.We performed a retrospective analysis of patients with pCD at a tertiary medical center. We used Kaplan-Meier curves to estimate rates and multivariate logistic regression to identify predictors of long-term outcomes.We included 311 patients with pCD of which 168 patients were started on biologics [138 anti-tumor necrosis factor (TNF) α, 14 vedolizumab, 16 ustekinumab] at the time of diagnosis. Anti-TNF use at the time of diagnosis was associated with decreased rates of perianal abscess recurrence [hazard ratio (HR)=0.48, 95% confidence interval (CI): 0.32-0.74], whereas ustekinumab use was associated with increased rates of perianal fistula closure (HR=3.58, 95% CI: 1.04-12.35) and decreased rates of perianal abscess recurrence (HR=0.20, 95% CI: 0.07-0.56) at follow-up. Among patients who failed their first anti-TNF, switching to another anti-TNF was associated with decreased rates of colectomy (HR=0.20, 95% CI: 0.04-0.90) and permanent diversion (HR=0.16, 95% CI: 0.03-0.94) compared with ustekinumab, whereas vedolizumab use was associated with decreased perianal fistula closure (HR=0.22, 95% CI: 0.05-0.96) compared with ustekinumab. Predictors of colectomy included colonic disease (odds ratio=2.71, 95% CI: 1.36-5.38) and anal stenosis (odds ratio=4.44, 95% CI: 1.59-12.43).Type of biologic use at the time of pCD diagnosis or after first anti-TNF failure may be associated with long-term outcomes in patients with pCD.

  View details for DOI 10.1097/MCG.0000000000001729

  View details for PubMedID 35703262

• INTEGRATION OF SPATIAL MULTI-OMIC IMAGING WITH MASS CYTOMETRY IDENTIFIES RARE CELL SUBSETS IN ULCERATIVE COLITIS Holman, D., Rogalla, S., Gubatan, J., Rubin, S. J., Ferenc, M. W B SAUNDERS CO-ELSEVIER INC. 2022: S516-S517

  View details for Web of Science ID 000826446202059

• SINGLE-CELL IMMUNE PROFILING AND REPERTOIRE ANALYSIS OF CONVALESCENT PATIENTS WITH INFLAMMATORY BOWEL DISEASE AND SARS-COV-2 ANTIBODY RESPONSE Gubatan, J., Singh, G., Balabanis, T., Patel, A., Sharma, A., Ji, A. R., Rogalla, S., Sinha, S. R., Davis, M. M., Habtezion, A. W B SAUNDERS CO-ELSEVIER INC. 2022: S277-S278

  View details for Web of Science ID 000826446201069

• ANTI-TNF BIOLOGICS AND 5-YEAR RISK OF EXTRAINTESTINAL MANIFESTATIONS OF INFLAMMATORY BOWEL DISEASE: A PROPENSITY-MATCHED NATIONAL DATABASE COHORT ANALYSIS Gubatan, J., Kuswanto, W., Gombar, S., Peach, S. E., Limsui, D., Sinha, S. R., Keyashian, K. W B SAUNDERS CO-ELSEVIER INC. 2022: S184-S185

  View details for Web of Science ID 000826446200442

• Selective tyrosine kinase 2 inhibitors in inflammatory bowel disease. Trends in pharmacological sciences Nielsen, O. H., Boye, T. L., Chakravarti, D., Gubatan, J. 2022

  Abstract

  Recent significant advances have been made in the treatment of chronic inflammatory diseases with initiation of the era of biologics. However, an unmet medical need still exists for novel targeted therapies. Compared with biologics, Janus kinase inhibitors (JAKis) are a new drug class of orally administered small molecules that have been shown to efficiently modulate complex cytokine-driven inflammation in preclinical models and human studies. Unfortunately, serious adverse effects have been reported with the first introduced pan-JAKi, tofacitinib. Here, we review tyrosine kinase 2 (TYK2) signaling in the pathophysiology of inflammatory bowel disease (IBD), examine mechanisms of action of selective TYK2 inhibitors (TYK2is), and discuss the potential for these inhibitors in efforts to balance benefits and harms.

  View details for DOI 10.1016/j.tips.2022.02.008

  View details for PubMedID 35277286

• Disease exacerbation is common in inflammatory bowel disease patients treated with immune checkpoint inhibitors for malignancy. World journal of clinical cases Rubin, S. J., Balabanis, T., Gubatan, J., Habtezion, A. 2022; 10 (6): 1787-1794

  Abstract

  Colitis is a known potential toxicity of immune checkpoint inhibitors (ICIs). Studies evaluating the risk of disease exacerbation following ICI treatment in patients with pre-existing inflammatory bowel disease (IBD) are limited.To assess the clinical characteristics of IBD patients treated with ICIs and determine prevalence of subsequent IBD exacerbations.We conducted a retrospective cohort study of all patients in the Stanford Research Repository database with pre-existing IBD who were exposed to ICIs.The prevalence of IBD exacerbation following ICI was 36.8% amongst 19 patients meeting inclusion criteria. Patients with exacerbations had more gastrointestinal-related hospitalizations (4 of 7) than patients without exacerbations (0 of 12; P = 0.0090).The prevalence of IBD exacerbations following ICI was higher than reported rates of ICI-induced colitis and diarrhea in the general population and was associated with hospitalization.

  View details for DOI 10.12998/wjcc.v10.i6.1787

  View details for PubMedID 35317167

  View details for PubMedCentralID PMC8891792

• Antimicrobial peptides and the gut microbiome in inflammatory bowel disease. World journal of gastroenterology Gubatan, J., Holman, D. R., Puntasecca, C. J., Polevoi, D., Rubin, S. J., Rogalla, S. 2021; 27 (43): 7402-7422

  Abstract

  Antimicrobial peptides (AMP) are highly diverse and dynamic molecules that are expressed by specific intestinal epithelial cells, Paneth cells, as well as immune cells in the gastrointestinal (GI) tract. They play critical roles in maintaining tolerance to gut microbiota and protecting against enteric infections. Given that disruptions in tolerance to commensal microbiota and loss of barrier function play major roles in the pathogenesis of inflammatory bowel disease (IBD) and converge on the function of AMP, the significance of AMP as potential biomarkers and novel therapeutic targets in IBD have been increasingly recognized in recent years. In this frontier article, we discuss the function and mechanisms of AMP in the GI tract, examine the interaction of AMP with the gut microbiome, explore the role of AMP in the pathogenesis of IBD, and review translational applications of AMP in patients with IBD.

  View details for DOI 10.3748/wjg.v27.i43.7402

  View details for PubMedID 34887639

  View details for PubMedCentralID PMC8613745

• Immune Checkpoint Inhibitor-Mediated Colitis Is Associated With Improved Cancer Overall Survival Weingarden, A. R., Gubatan, J., Balabanis, T., Patel, A., Singh, S., Habtezion, A. LIPPINCOTT WILLIAMS & WILKINS. 2021: S1381

  View details for Web of Science ID 000717526105475

• Biologic Therapy in Patients With Perianal Crohn's Disease and Association With Long-Term Rates of Surgical and Clinical Outcomes Gubatan, J., Frost, S., Levitte, S., Keyashian, K. LIPPINCOTT WILLIAMS & WILKINS. 2021: S354

  View details for Web of Science ID 000717526101241

• Paternal Biologic and Thiopurine Exposure in Inflammatory Bowel Disease and Association With Adverse Pregnancy Outcomes and Semen Parameters: A Systematic Review and Meta-Analysis Gubatan, J., Barber, G., Nielsen, O., Juhl, C., Maxwell, C., Eisenberg, M., Streett, S. LIPPINCOTT WILLIAMS & WILKINS. 2021: S353

  View details for Web of Science ID 000717526101240

• Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives. Clinical and experimental gastroenterology Gubatan, J., Keyashian, K., Rubin, S. J., Wang, J., Buckman, C. A., Sinha, S. 2021; 14: 333-342

  Abstract

  Leukocyte trafficking to the gastrointestinal tract is recognized to play a role in the pathogenesis of inflammatory bowel disease (IBD). Integrins are expressed on immune cells and interact with cell adhesion molecules (CAM) to mediate leukocyte trafficking. Blockade of the gut-tropic integrin α4β7 and its subunits has been exploited as a therapeutic target in IBD. Natalizumab (anti-α4) is approved for moderate to severe Crohn's disease (CD), but its use is limited due to potential risk of progressive multifocal leukoencephalopathy. Vedolizumab (anti-α4β7) is approved for the treatment of ulcerative colitis (UC) and CD. It is the most widely used anti-integrin therapy in IBD and has been shown to be effective in both induction and maintenance therapy, with a favorable safety profile. Several models incorporating clinical, genetic, immune, gut microbial, and vitamin D markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. Large phase 3 clinical trials evaluating efficacy of etrolizumab in the induction and maintenance of patients with IBD are underway. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).

  View details for DOI 10.2147/CEG.S293272

  View details for PubMedID 34466013

  View details for PubMedCentralID PMC8402953

• COVID-19 PANDEMIC INCREASED HEALTHCARE UTILIZATION AMONG PATIENTS WITH FUNCTIONAL GASTROINTESTINAL DISORDERS Gubatan, J., Zikos, T., Wu, J., Spear, E., Gottfried, A. C., Becker, L. S., Habtezion, A., Nashatian, L. W B SAUNDERS CO-ELSEVIER INC. 2021: S28-S29

  View details for Web of Science ID 000649085000065

• IMMUNOMODULATORY EFFECTS OF NON-INVASIVE VAGAL NERVE STIMULATION THERAPY IN IDIOPATHIC GASTROPARESIS Gottfried, A. C., Namkoong, H., Adler, E. P., Gubatan, J., Lei, C., Fernandez-Becker, N., Clarke, J. O., Nguyen, L. B., Habtezion, A. W B SAUNDERS CO-ELSEVIER INC. 2021: S102-S103

  View details for Web of Science ID 000649085000239

• Dual targeting of lymphocyte homing and retention through α4β7 and αEβ7 inhibition in inflammatory bowel disease. Cell reports. Medicine Dai, B., Hackney, J. A., Ichikawa, R., Nguyen, A., Elstrott, J., Orozco, L. D., Sun, K. H., Modrusan, Z., Gogineni, A., Scherl, A., Gubatan, J., Habtezion, A., Deswal, M., Somsouk, M., Faubion, W. A., Chai, A., Sharafali, Z., Hassanali, A., Oh, Y. S., Tole, S., McBride, J., Keir, M. E., Yi, T. 2021; 2 (8): 100381

  Abstract

  Anti-integrins are therapeutically effective for inflammatory bowel disease, yet the relative contribution of α4β7 and αEβ7 to gut lymphocyte trafficking is not fully elucidated. Here, we evaluate the effect of α4β7 and αEβ7 blockade using a combination of murine models of gut trafficking and longitudinal gene expression analysis in etrolizumab-treated patients with Crohn's disease (CD). Dual blockade of α4β7 and αEβ7 reduces CD8+ T cell accumulation in the gut to a greater extent than blockade of either integrin alone. Anti-αEβ7 reduces epithelial:T cell interactions and promotes egress of activated T cells from the mucosa into lymphatics. Inflammatory gene expression is greater in human intestinal αEβ7+ T cells. Etrolizumab-treated patients with CD display a treatment-specific reduction in inflammatory and cytotoxic intraepithelial lymphocytes (IEL) genes. Concurrent blockade of α4β7 and αEβ7 promotes reduction of cytotoxic IELs and inflammatory T cells in the gut mucosa through a stepwise inhibition of intestinal tissue entry and retention.

  View details for DOI 10.1016/j.xcrm.2021.100381

  View details for PubMedID 34467254

  View details for PubMedCentralID PMC8385326

• Vitamin D is Associated with α4β7+ Immunophenotypes and Predicts Vedolizumab Therapy Failure in Patients with Inflammatory Bowel Disease. Journal of Crohn's & colitis Gubatan, J., Rubin, S. J., Bai, L., Haileselassie, Y., Levitte, S., Balabanis, T., Patel, A., Sharma, A., Sinha, S. R., Habtezion, A. 2021

  Abstract

  Vitamin D downregulates the in vitro expression of the gut-tropic integrin α4β7 on immune cells. The clinical relevance of this finding in patients with inflammatory bowel disease (IBD) is unclear. We tested the hypothesis that vitamin D is associated with α4β7 immunophenotypes and risk of vedolizumab (anti- α4β7) failure in IBD.We performed single-cell immunophenotyping of peripheral and intestinal immune cells using mass cytometry (CyTOF) in vedolizumab-naïve patients with IBD (N=48). We analyzed whole-genome mucosal gene expression (GSE73661) from GEMINI I and GEMINI long-term safety (LTS) to determine the association between vitamin D receptor (VDR) and integrin alpha-4 (ITGA4) and beta-7 (ITGB7) genes. We estimated the odds of vedolizumab failure with low pre-treatment vitamin D in a combined retrospective and prospective IBD cohort (N= 252) with logistic regression.Immunophenotyping revealed that higher 25(OH)D was associated with decreased α4β7+ peripheral blood mononuclear cells (R = -0.400, P < 0.01) and α4β7+ intestinal leukocytes (R = -0.538, P= 0.03). Serum 25(OH)D was inversely associated with α4β7+ peripheral B cells and natural killer (NK) cells and α4β7+ intestinal B cells, NK cells, monocytes, and macrophages. Mucosal expression of VDR was inversely associated with ITGA4 and ITGB7 expression. In multivariate analysis, 25(OH)D < 25 ng/mL was associated with increased vedolizumab primary non-response during induction (OR 26.10, 95% CI 14.30-48.90, P<0.001) and failure at 1-year follow-up (OR 6.10, 95% CI 3.06-12.17, P<0.001).Low serum 25(OH)D is associated with α4β7+ immunophenotypes and predicts future vedolizumab failure in patients with IBD.

  View details for DOI 10.1093/ecco-jcc/jjab114

  View details for PubMedID 34180967

• Artificial intelligence applications in inflammatory bowel disease: Emerging technologies and future directions. World journal of gastroenterology Gubatan, J. n., Levitte, S. n., Patel, A. n., Balabanis, T. n., Wei, M. T., Sinha, S. R. 2021; 27 (17): 1920-1935

  Abstract

  Inflammatory bowel disease (IBD) is a complex and multifaceted disorder of the gastrointestinal tract that is increasing in incidence worldwide and associated with significant morbidity. The rapid accumulation of large datasets from electronic health records, high-definition multi-omics (including genomics, proteomics, transcriptomics, and metagenomics), and imaging modalities (endoscopy and endomicroscopy) have provided powerful tools to unravel novel mechanistic insights and help address unmet clinical needs in IBD. Although the application of artificial intelligence (AI) methods has facilitated the analysis, integration, and interpretation of large datasets in IBD, significant heterogeneity in AI methods, datasets, and clinical outcomes and the need for unbiased prospective validations studies are current barriers to incorporation of AI into clinical practice. The purpose of this review is to summarize the most recent advances in the application of AI and machine learning technologies in the diagnosis and risk prediction, assessment of disease severity, and prediction of clinical outcomes in patients with IBD.

  View details for DOI 10.3748/wjg.v27.i17.1920

  View details for PubMedID 34007130

  View details for PubMedCentralID PMC8108036

• Gastrointestinal symptoms and healthcare utilization have increased among patients with functional gastrointestinal and motility disorders during the COVID-19 pandemic. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society Gubatan, J., Zikos, T., Spear Bishop, E., Wu, J., Gottfried, A., Becker, L., Habtezion, A., Neshatian, L. 2021: e14243

  Abstract

  The coronavirus disease 2019 (COVID-19) pandemic has led to unprecedented disruptions in healthcare. Functional gastrointestinal and motility disorders (FGIMD) are associated with significant healthcare utilization. The clinical implications of these healthcare disruptions due to the COVID-19 pandemic on clinical outcomes in patients with FGIMD are unclear.We performed a retrospective study of patients with three common FGIMD (irritable bowel syndrome [IBS], gastroparesis, functional dyspepsia [FD]) tested for SARS-CoV-2 to describe alterations in gastrointestinal symptoms, medication use, and healthcare utilization during and before the pandemic and factors associated with COVID-19.The prevalence of COVID-19 during the pandemic (03/2020-09/2020) was 3.20% (83/2592) among patients with FGIMD, 3.62% in IBS (57/1574), 3.07% in gastroparesis (23/749), and 2.44% in FD (29/1187) at our institution. Patients with FGIMD had increased abdominal pain, nausea/vomiting, diarrhea, constipation, and weight loss (p < 0.001) along with increased proton pump inhibitor, H2 blocker, and opioid use (p < 0.0001). Both inpatient hospitalizations and outpatient visits (p < 0.0001) and number of diagnostic tests including cross-sectional imaging (p = 0.002), and upper and lower endoscopies (p < 0.0001) were significantly higher during the pandemic as compared to 6 months prior. Diarrhea-predominant IBS was positively (OR 2.37, 95% CI 1.34-4.19, p = 0.003) associated with COVID-19, whereas functional dyspepsia was negatively (OR 0.46, 95% CI 0.27-0.79, p = 0.004) associated.Patients with common functional gastrointestinal and motility disorders have reported more gastrointestinal symptoms during the COVID-19 pandemic with concurrent increased medication use and healthcare utilization.

  View details for DOI 10.1111/nmo.14243

  View details for PubMedID 34378840

• Immune checkpoint inhibitor-mediated colitis in gastrointestinal malignancies and inflammatory bowel disease. World journal of gastrointestinal oncology Weingarden, A. R., Rubin, S. J., Gubatan, J. 2021; 13 (8): 772-798

  Abstract

  Immune checkpoint inhibitors (ICI) have markedly changed the landscape of cancer therapy. By re-invigorating the immune system against tumors, ICI provide novel therapeutic options for a broad variety of malignancies, including many gastrointestinal (GI) cancers. However, these therapies can also induce autoimmune-like side effects in healthy tissue across the body. One of the most common of these side effects is ICI-mediated colitis and diarrhea (IMC). Here, we review the incidence and risk of IMC in ICI therapy, with a focus on what is known regarding IMC in patients with GI malignancies. We also discuss data available on the use of ICI and risk of IMC in patients with pre-existing inflammatory bowel disease, as these patients may have increased risk of IMC due to their underlying intestinal pathology.

  View details for DOI 10.4251/wjgo.v13.i8.772

  View details for PubMedID 34457186

  View details for PubMedCentralID PMC8371513

• Gastric Mucosal Immune Profiling and Dysregulation in Idiopathic Gastroparesis. Clinical and translational gastroenterology Gottfried-Blackmore, A. n., Namkoong, H. n., Adler, E. n., Martin, B. n., Gubatan, J. n., Fernandez-Becker, N. n., Clarke, J. O., Idoyaga, J. n., Nguyen, L. n., Habtezion, A. n. 2021; 12 (5): e00349

  Abstract

  It is unclear how immune perturbations may influence the pathogenesis of idiopathic gastroparesis, a prevalent functional disorder of the stomach which lacks animal models. Several studies have noted altered immune characteristics in the deep gastric muscle layer associated with gastroparesis, but data are lacking for the mucosal layer, which is endoscopically accessible. We hypothesized that immune dysregulation is present in the gastroduodenal mucosa in idiopathic gastroparesis and that specific immune profiles are associated with gastroparesis clinical parameters.In this cross-sectional prospective case-control study, routine endoscopic biopsies were used for comprehensive immune profiling by flow cytometry, multicytokine array, and gene expression in 3 segments of the stomach and the duodenal bulb. Associations of immune endpoints with clinical parameters of gastroparesis were also explored.The gastric mucosa displayed large regional variation of distinct immune profiles. Furthermore, several-fold increases in innate and adaptive immune cells were found in gastroparesis. Various immune cell types showed positive correlations with duration of disease, proton pump inhibitor dosing, and delayed gastric emptying.This initial observational study showed immune compartmentalization of the human stomach mucosa and significant immune dysregulation at the level of leukocyte infiltration in idiopathic gastroparesis patients that extends to the duodenum. Select immune cells, such as macrophages, may correlate with clinicopathological traits of gastroparesis. This work supports further mucosal studies to advance our understanding of gastroparesis pathophysiology.

  View details for DOI 10.14309/ctg.0000000000000349

  View details for PubMedID 33979305

• Reply to Letter to the Editor: What is the incidence of COVID-19 in patients with IBD in western countries? Gastroenterology Gubatan, J. n., Sinha, S. R., Habtezion, A. n. 2021

  View details for DOI 10.1053/j.gastro.2021.01.014

  View details for PubMedID 33453234

• Cathelicidin Mediates a Protective Role of Vitamin D in Ulcerative Colitis and Human Colonic Epithelial Cells. Inflammatory bowel diseases Gubatan, J. n., Mehigan, G. A., Villegas, F. n., Mitsuhashi, S. n., Longhi, M. S., Malvar, G. n., Csizmadia, E. n., Robson, S. n., Moss, A. C. 2020

  Abstract

  Vitamin D plays a protective role in ulcerative colitis (UC) patients through unclear mechanisms. Cathelicidin is an antimicrobial peptide induced by 1,25(OH)D2. Our goal was to evaluate the link between cathelicidin and vitamin D-associated clinical outcomes in UC patients, explore vitamin D induction of cathelicidin in human colon cells, and evaluate the effects of intrarectal human cathelicidin on a murine model of colitis.Serum and colonic cathelicidin levels were measured in UC patients and correlated with clinical and histologic outcomes. Human colon cells were treated with 1,25(OH)2D and production of cathelicidin and cytokines were quantified. Antimicrobial activity against Escherichia coli from cell culture supernatants was measured. Mice were treated with intrarectal cathelicidin, and its effects on DSS colitis and intestinal microbiota were evaluated.In UC patients, serum 25(OH)D positively correlated with serum and colonic cathelicidin. Higher serum cathelicidin is associated with decreased risk of histologic inflammation and clinical relapse but not independent of 25(OH)D or baseline inflammation. The 1,25(OH)2D treatment of colon cells induced cathelicidin and IL-10, repressed TNF-α, and suppressed Escherichia coli growth. This antimicrobial effect was attenuated with siRNA-cathelicidin transfection. Intrarectal cathelicidin reduced the severity of DSS colitis but did not mitigate the impact of colitis on microbial composition.Cathelicidin plays a protective role in 25(OH)D-associated UC histologic outcomes and murine colitis. Cathelicidin is induced by vitamin D in human colonic epithelial cells and promotes antimicrobial activity against E. coli. Our study provides insights into the vitamin D-cathelicidin pathway as a potential therapeutic target.

  View details for DOI 10.1093/ibd/izz330

  View details for PubMedID 31955203

• Mucosal vitamin D signaling in inflammatory bowel disease. Autoimmunity reviews Kellermann, L. n., Jensen, K. B., Bergenheim, F. n., Gubatan, J. n., Chou, N. D., Moss, A. n., Nielsen, O. H. 2020: 102672

  Abstract

  Epidemiological studies have identified vitamin D (25(OH)D) deficiency to be highly prevalent among patients with inflammatory bowel disease (IBD), and low serum levels correlate with a higher disease activity and a more complicated disease course. The link to IBD pathogenesis has been subject of investigations, primarily due to the distinct immunological functions of vitamin D signaling, including anti-inflammatory and anti-fibrotic actions. Vitamin D is a pleiotropic hormone that executes its actions on cells through the vitamin D receptor (VDR). A leaky gut, i.e. an insufficient intestinal epithelial barrier, is thought to be central for the pathogenesis of IBD, and emerging data support the concept that vitamin D/VDR signaling in intestinal epithelial cells (IECs) has an important role in controlling barrier integrity. Here we review the latest evidence on how vitamin D promotes the interplay between IECs, the gut microbiome, and immune cells and thereby regulate the intestinal immune response. On the cellular level, vitamin D signaling regulates tight junctional complexes, apoptosis, and autophagy, leading to increased epithelial barrier integrity, and promotes expression of antimicrobial peptides as part of its immunomodulating functions. Further, intestinal VDR expression is inversely correlated with the severity of inflammation in patients with IBD, which might compromise the positive effects of vitamin D signaling in patients with flaring disease. Efforts to reveal the role of vitamin D in the pathophysiology of IBD will pave the road for the invention of more rational treatment strategies of this debilitating disease in the future.

  View details for DOI 10.1016/j.autrev.2020.102672

  View details for PubMedID 32942038

• Are Proton Pump Inhibitors Contributing to SARS-COV-2 Infection? The American journal of gastroenterology Tarlow, B. n., Gubatan, J. n., Khan, M. A., Cholankeril, G. n. 2020

  View details for DOI 10.14309/ajg.0000000000000933

  View details for PubMedID 32925197

• Biologics for Inflammatory Bowel Disease and their Safety in Pregnancy: A Systematic Review and Meta-analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association Nielsen, O. H., Gubatan, J. M., Juhl, C. B., Streett, S. E., Maxwell, C. n. 2020

  Abstract

  Biologics are routinely used in pregnant women with inflammatory bowel disease (IBD) but large-scale data reporting adverse pregnancy outcomes among biologic users are lacking. We sought to estimate the prevalence of adverse pregnancy outcomes in women with IBD on biologic therapies.We searched major databases from inception to June 2020 for studies estimating the prevalence of adverse pregnancy outcomes in IBD when using biologics (anti-TNF, anti-integrins, and anti-cytokines). Prevalence and relative risk (RR) were pooled using a random effects model.Forty-eight studies were included in the meta-analysis comprising 6963 patients. Biologic therapy in IBD pregnancies was associated with a pooled prevalence of 8% (95% CI 6-10%, I2= 87.4%) for early pregnancy loss, 9% (95% CI 7-11%, I2=89.9%) preterm birth, 0% (95% CI 0-0%, I2=0%) still birth, 8% (95% CI 5-10%, I2=87.0%) low birth weight, and 1% (95% CI 1-2%, I2=78.3%) congenital malformations. These rates are comparable to those published in the general population. In subgroup analyses of a small number of studies, the prevalence of early pregnancy loss and preterm birth were higher in vedolizumab versus anti-TNF users. Meta-regression did not reveal an association of disease activity or concomitant thiopurine on adverse outcomes. Continued TNF inhibitor use during the third trimester was not associated with risk of preterm birth (RR 1.41, 95% CI 0.77-2.60, I2=0%), low birth weight (RR 1.32, 95% CI 0.80-2.18, I2=0%), or congenital malformations (RR 1.28, 95% 0.47-3.49, I2=0%).Adverse pregnancy outcomes among pregnant IBD women with biologic use are comparable with that of the general population. PROSPERO protocol #CRD42019135721.

  View details for DOI 10.1016/j.cgh.2020.09.021

  View details for PubMedID 32931960

• Biologics During Pregnancy in Women With Inflammatory Bowel Disease and Risk of Infantile Infections: A Systematic Review and Meta-Analysis. The American journal of gastroenterology Gubatan, J. n., Nielsen, O. H., Levitte, S. n., Juhl, C. B., Maxwell, C. n., Streett, S. E., Habtezion, A. n. 2020

  Abstract

  Biologics, such as tumor necrosis factor inhibitors, anti-integrins and anticytokines, are therapies for inflammatory bowel disease (IBD) that may increase the risk of infection. Most biologics undergo placental transfer during pregnancy and persist at detectable concentrations in exposed infants. Whether this is associated with an increased risk of infantile infections is controversial. We performed a systematic review and meta-analysis evaluating the risk of infantile infections after in utero exposure to biologics used to treat IBD.We searched PubMed, Embase, Scopus, Web of Science, and CENTRAL from inception to June 2020 to evaluate the association of biologic therapy during pregnancy in women with IBD and risk of infantile infections. Odds ratios of outcomes were pooled and analyzed using a random effects model.Nine studies met the inclusion criteria comprising 8,013 women with IBD (5,212 Crohn's disease, 2,801 ulcerative colitis) who gave birth to 8,490 infants. Biologic use during pregnancy was not associated with an increased risk of all infantile infections (odds ratio [OR] 0.91, 95% confidence interval [CI] 0.73-1.14, I = 30%). In a subgroup analysis for the type of infection, biologic use was associated with increased infantile upper respiratory infections (OR 1.57, 95% CI 1.02-2.40, I = 4%). Biologic use during pregnancy was not associated with infantile antibiotic use (OR 0.91, 95% CI 0.73-1.14, I = 30%) or infection-related hospitalizations (OR 1.33, 95% CI 0.95-1.86, I = 26%).Biologics use during pregnancy in women with IBD is not associated with the overall risk of infantile infections or serious infections requiring antibiotics or hospitalizations but is associated with an increased risk of upper respiratory infections.

  View details for DOI 10.14309/ajg.0000000000000910

  View details for PubMedID 33110017

• SARS-CoV-2 Testing, Prevalence, and Predictors of COVID-19 in Patients with Inflammatory Bowel Disease in Northern California. Gastroenterology Gubatan, J. n., Levitte, S. n., Balabanis, T. n., Patel, A. n., Sharma, A. n., Habtezion, A. n. 2020

  View details for DOI 10.1053/j.gastro.2020.05.009

  View details for PubMedID 32387541

• Gastric Leiomyosarcoma Unmasked by Bleeding From a Percutaneous Endoscopic Gastrostomy Tube. ACG case reports journal Gubatan, J. n., Shah, N. n. 2020; 7 (1): e00301

  Abstract

  Gastrointestinal bleeding from percutaneous endoscopic gastrostomy tubes and malignancy are uncommon. Gastric leiomyosarcomas are rare and differentiated from other gastric tumors with histology and immunohistochemical staining. We present a case of upper gastrointestinal bleeding from a percutaneous endoscopic gastrostomy tube manifesting as a gastric leiomyosarcoma in a 50-year-old man with a medical history of Wilms tumor. We reviewed the epidemiology, diagnosis, and management of gastric leiomyosarcomas. We also explored the risk factors and potential mechanisms in the pathogenesis of gastric leiomyosarcoma in our patient.

  View details for DOI 10.14309/crj.0000000000000301

  View details for PubMedID 32309495

  View details for PubMedCentralID PMC7145162

• Prevalence, risk factors and clinical outcomes of COVID-19 in patients with a history of pancreatitis in Northern California. Gut Gubatan, J. n., Levitte, S. n., Patel, A. n., Balabanis, T. n., Sharma, A. n., Jones, E. n., Lee, B. n., Manohar, M. n., Swaminathan, G. n., Park, W. n., Habtezion, A. n. 2020

  View details for DOI 10.1136/gutjnl-2020-321772

  View details for PubMedID 32493828

• Novel use of endoscopic morcellator to clear large obscuring clot in patient with upper-GI bleed. VideoGIE : an official video journal of the American Society for Gastrointestinal Endoscopy Gubatan, J. n., Kwo, P. n., Hwang, J. H. 2020; 5 (2): 58–60

  View details for DOI 10.1016/j.vgie.2019.10.006

  View details for PubMedID 32051910

  View details for PubMedCentralID PMC7003128

• Managing vitamin D deficiency in inflammatory bowel disease. Frontline gastroenterology Nielsen, O. H., Hansen, T. I., Gubatan, J. M., Jensen, K. B., Rejnmark, L. n. 2019; 10 (4): 394–400

  Abstract

  Management of inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is generally cumbersome for patients and is a massive health-economic burden. In recent years, the immunomodulating effects of vitamin D have gained a huge interest in its possible pathogenic influence on the pathophysiology of IBD. Vitamin D deficiency is frequent among patients with IBD. Several clinical studies have pointed to a critical role for vitamin D in ameliorating disease outcomes. Although causation versus correlation unfortunately remains an overwhelming issue in the illusive chicken versus egg debate regarding vitamin D and IBD, here we summarise the latest knowledge of the immunological effects of vitamin D in IBD and recommend from available evidence that physicians regularly monitor serum 25(OH)D levels in patients with IBD. Moreover, we propose an algorithm for optimising vitamin D status in patients with IBD in clinical practice. Awaiting well-powered controlled clinical trials, we consider vitamin D supplementation to be an affordable and widely accessible therapeutic strategy to ameliorate IBD clinical outcomes.

  View details for DOI 10.1136/flgastro-2018-101055

  View details for PubMedID 31656565

  View details for PubMedCentralID PMC6788352

• Systematic review with meta-analysis: association of vitamin D status with clinical outcomes in adult patients with inflammatory bowel disease. Alimentary pharmacology & therapeutics Gubatan, J. n., Chou, N. D., Nielsen, O. H., Moss, A. C. 2019

  Abstract

  Vitamin D deficiency is highly prevalent among patients with IBD, however, data on its association with clinical outcomes are conflicting.To perform a systematic review and meta-analysis to explore the association of low vitamin D status with clinical outcomes in patients with IBD.We searched PubMed, Embase, Scopus and Web of Science from inception to February 2018 for observational studies evaluating the association of low 25(OH)D status on IBD disease activity, mucosal inflammation, clinical relapse and quality of life. Odds ratios (ORs) were pooled and analysed using a random effects model.Twenty-seven studies were eligible for inclusion comprising 8316 IBD patients (3115 ulcerative colitis, 5201 Crohn's disease). Among IBD patients, low 25(OH)D status was associated with increased odds of disease activity (OR 1.53, 95% CI 1.32-1.77, I2  = 0%), mucosal inflammation (OR 1.25, 95% CI 1.06-1.47, I2  = 0%), low quality of life (QOL) scores (OR 1.30, 95% CI 1.06-1.60, I2  = 0%) and future clinical relapse (OR 1.23, 95% CI 1.03-1.47, I2  = 0%). In subgroup analysis, low vitamin D status was associated with Crohn's disease activity (OR 1.66, 95% CI 1.36-2.03, I2  = 0%), mucosal inflammation (OR 1.39, 95% CI 1.03-1.85, I2  = 0%), clinical relapse (OR 1.35, 95% CI 1.14-1.59, I2  = 0%), and low QOL scores (OR 1.25, 95% CI 1.04-1.50, I2  = 0%) and ulcerative colitis disease activity (OR 1.47, 95% CI 1.03-2.09, I2  = 0%) and clinical relapse (OR 1.20, 95% 1.01-1.43, I2  = 0%).Low 25(OH)D status is a biomarker for disease activity and predictor of poor clinical outcomes in IBD patients.

  View details for DOI 10.1111/apt.15506

  View details for PubMedID 31647134

• Double Threat: Interplay of Celiac Disease with Inflammatory Bowel Disease. Digestive diseases and sciences Gubatan, J. n., Triadafilopoulos, G. n., Fernandez-Becker, N. Q. 2019

  View details for DOI 10.1007/s10620-019-05994-9

  View details for PubMedID 31828460

• Higher serum vitamin D levels are associated with protective serum cytokine profiles in patients with ulcerative colitis. Cytokine Gubatan, J. n., Mitsuhashi, S. n., Longhi, M. S., Zenlea, T. n., Rosenberg, L. n., Robson, S. n., Moss, A. C. 2018; 103: 38–45

  Abstract

  Vitamin D has immune modulating effects on cytokines. Serum vitamin D levels are associated with the risk of relapse in patients with ulcerative colitis (UC), through unknown mechanisms. We tested the hypothesis that this beneficial role of vitamin D on UC is mediated through anti-inflammatory serum cytokine profiles.Serum samples from a prospective cohort of seventy UC patients in clinical remission were collected and baseline histological and endoscopic scores were recorded at enrollment. Clinical relapse events were recorded over the 12-month follow-up period. Serum vitamin D and cytokines levels (IL-6, IL-8, IL-17A, TNF-α, IFN-γ, IL-4, IL-10) were quantified using ELISA. Linear regression was used to determine correlation between vitamin D and cytokine profiles. Logistic regression models were used to determine the association between serum cytokine profiles and baseline histologic mucosal healing and clinical relapse.Higher serum vitamin D levels positively correlated with higher ratios of IL-4 + IL-10/IL-17A + TNF-α (r = 0.37, P < .01), and IL-4 + IL-10/IL-6 + TNF-α (r = 0.32, P < .01). In multivariate analysis, IL-4 + IL-10/IL-17A + TNF-α ratios at baseline were associated with the presence of histologic mucosal healing (O.R. 1.29, 95% CI 1.02-1.62, P = .03). A higher ratio of serum IL-4 + IL-10 to IL-6 + TNF-α was associated with a reduced risk of clinical relapse (O.R. 0.72, 95% CI 0.58-0.89, P = .003), and longer time to relapse (p = .03), over the 12-month follow-up period. This ratio during remission had an AUC of 0.7 in predicting later clinical relapse.Vitamin D is associated with anti-inflammatory serum cytokine profiles. Anti-inflammatory cytokine patterns may mediate the protective effects of higher serum vitamin D levels in patients with ulcerative colitis.

  View details for DOI 10.1016/j.cyto.2017.12.023

  View details for PubMedID 29324259

  View details for PubMedCentralID PMC5808893

• Vitamin D in inflammatory bowel disease: more than just a supplement. Current opinion in gastroenterology Gubatan, J. n., Moss, A. C. 2018; 34 (4): 217–25

  Abstract

  The aim of this review is to explore the protective role of vitamin D on the gastrointestinal tract, summarize the epidemiology of vitamin D deficiency in inflammatory bowel disease (IBD), and highlight recent studies examining the impact of low vitamin D and vitamin D supplementation on IBD clinical outcomes.Vitamin D protects the gut barrier by regulating tight junction proteins and inhibiting intestinal apoptosis. Vitamin D enhances innate immunity by inducing antimicrobial peptides and regulates adaptive immunity by promoting anti-inflammatory T cells and cytokines. Vitamin D may also alter the gut microbiota. The prevalence of vitamin D deficiency in IBD is 30-40%. Predictors of vitamin D deficiency in IBD include non-white ethnicity, IBD-related surgery, BMI more than 30, female sex, and pregnancy. Low vitamin D is associated with increased disease activity, inflammation, and clinical relapse. The effect of vitamin D supplementation on IBD clinical outcomes is inconclusive.Vitamin D plays a protective role on gut health. Vitamin D deficiency in IBD is prevalent and associated with poor outcomes. The benefits of vitamin D supplementation in IBD is unclear. Measuring novel vitamin D metabolites and vitamin D absorption in IBD patients may help guide future studies.

  View details for DOI 10.1097/MOG.0000000000000449

  View details for PubMedID 29762159

• Reply. Clinical gastroenterology and hepatology Gubatan, J. M., Moss, A. C. 2017

  View details for DOI 10.1016/j.cgh.2017.03.037

  View details for PubMedID 28377073

• Low Serum Vitamin D During Remission Increases Risk of Clinical Relapse in Patients With Ulcerative Colitis. Clinical gastroenterology and hepatology Gubatan, J., Mitsuhashi, S., Zenlea, T., Rosenberg, L., Robson, S., Moss, A. C. 2017; 15 (2): 240-246 e1

  Abstract

  Vitamin D levels have been associated with disease activity in patients with ulcerative colitis (UC), but it is unclear whether they affect the risk of disease relapse. We sought to determine the association between baseline vitamin D levels during a period of clinical remission and risk of subsequent UC relapse.We performed a physician-blinded prospective study of 70 patients with UC in clinical remission followed up after a surveillance colonoscopy at a tertiary academic medical center. Serum samples were collected at the time of colonoscopy and baseline endoscopic and histologic activity were determined. Levels of 25-hydroxy-vitamin D were measured using an enzyme-linked immunosorbent assay. The primary outcome was rate of clinical relapse, determined over 12 months.The mean baseline vitamin D level was lower among patients with relapse (29.5 ng/mL) than without (50.3 ng/mL) (P = .001). Remission vitamin D level (≤35 ng/mL) was associated with a risk of clinical relapse (odds ratio, 1.25; 95% confidence interval [CI], 1.01-1.56; P = .044) over 12 months, independent of endoscopic or histologic grade at enrollment. A receiver operating characteristic curve of vitamin D levels for the outcome of relapse had an area under the curve of 0.72; and a serum level of 35 ng/mL or less had a sensitivity of 70% (95% CI, 46%-88%) and a specificity of 74% (95% CI 57%-83%) for predicting risk of clinical relapse.Serum levels of vitamin D of 35 ng/mL or less during periods of clinical remission increase the risk of UC relapse. Clinical trials to obtain vitamin D levels higher than this threshold should be considered.

  View details for DOI 10.1016/j.cgh.2016.05.035

  View details for PubMedID 27266980

  View details for PubMedCentralID PMC5136522

• Cannabis Abuse Is Increasing and Associated with Increased Emergency Department Utilization in Gastroenterology Patients DIGESTIVE DISEASES AND SCIENCES Gubatan, J., Staller, K., Barshop, K., Kuo, B. 2016; 61 (7): 1844-1852

  Abstract

  The role of cannabinoids in gastrointestinal diseases is controversial and of great interest, yet their use in patients has not been critically examined.To determine the prevalence and effects of cannabis abuse on healthcare utilization, as measured by emergency department (ED) visits, in a large, tertiary gastroenterology practice.All patients seen in the gastroenterology clinic at a tertiary care center during a 27-year period (1986-2013) were included in our study to determine the overall prevalence of cannabis abuse. We matched cannabis abusers 1:2 with non-abusing controls to determine the effect of cannabis on ED utilization, our primary outcome. We used multivariate linear regression to adjust for confounders and define the independent effect of cannabis abuse on ED utilization.Our prevalence study cohort included 190,303 GI clinic patients with an overall cannabis abuse prevalence of 0.80 % (1520 patients). From 1986 to 2012, the prevalence of cannabis abuse in this clinic increased by 0.73 % (0.03 %/year) (p < 0.0001). From the 1520 cannabis abusers identified, 467 patients were randomly selected as cases and were matched to 934 controls. From this retrospective cohort, the median ED visits/year for cannabis abusers was 1.88 versus 0.89 for non-abusers (p < 0.0001). After multivariate adjustment, cannabis abuse was associated with a 1.47-fold increase (95 % CI 1.23-1.76, p < 0.0001) in median ED visits/year.Reported cannabis abuse in GI clinic patients is less prevalent than in the adult US population, but is increasing. Cannabis abuse among gastroenterology patients is associated with increased ED visits.

  View details for DOI 10.1007/s10620-016-4090-9

  View details for Web of Science ID 000379013300013

  View details for PubMedID 26935430

• Hypercalcemia associated with isolated bone marrow sarcoidosis in a patient with underlying monoclonal gammopathy of undetermined significance: case report and review of literature. Biomarker research Gubatan, J., Wang, X., Louissaint, A., Mahindra, A., Vanderpool, J. 2016; 4: 18-?

  Abstract

  Bone marrow sarcoidosis is extremely rare. The association between sarcoidosis and lymphoproliferative disorders has been previously speculated, although the diagnosis of sarcoidosis often precedes any hematological derangements.Here, we report for the first time, a case of a 57-year-old Caucasian woman with a previous diagnosis of monoclonal gammopathy of undetermined significance (MGUS) developing hypercalcemia and renal failure with workup notable for isolated bone marrow sarcoidosis and not multiple myeloma as expected. The patient was successfully managed with prednisone taper therapy with resolution of her hypercalcemia and repeat bone marrow biopsies demonstrating resolving granulomas.Our case illustrates the diagnostic challenges associated with bone marrow sarcoidosis and suggest that chronic immune stimulation in the bone marrow in the setting of MGUS may be associated with the development of localized sarcoidosis. The long term consequences of steroid therapy targeting sarcoidosis in this patient with underlying MGUS remain unknown. Greater surveillance and closer followup is planned in light of the increased risk of malignant transformation of MGUS into multiple myeloma in the setting of bone marrow sarcoidosis.

  View details for DOI 10.1186/s40364-016-0072-5

  View details for PubMedID 27651903

  View details for PubMedCentralID PMC5024499

• Hemorrhage from Extra-Antral Gastric Antral Vascular Ectasia in a Patient with Duodenal Heterotopic Gastric Mucosa. Case reports in gastrointestinal medicine Gubatan, J., Raines, N., Khosravi, H., Challies, T. L., Berzin, T. M. 2016; 2016: 4325302-?

  Abstract

  Gastric antral vascular ectasias (GAVE) have been increasingly recognized as an uncommon cause of chronic gastrointestinal bleeding and anemia, although their underlying pathogenesis is not completely well understood. Heterotopic gastric mucosa (HGM) has been reported to occur at various sites along the gastrointestinal tract and although relatively common, it is often asymptomatic. We report a case of a 60-year-old woman with a prior history of GAVE who developed melena and symptomatic anemia during her hospitalization following cardiac catheterization. Initial EGD demonstrated nonbleeding antral GAVE and a newly discovered duodenal mass. Duodenal mass biopsies were ultimately notable for HGM along with histologic features of extra-antral GAVE. The patient required blood transfusions and consequently had a small bowel endoscopy notable for fresh blood in the proximal small bowel. The patient underwent a small bowel push enteroscopy which demonstrated active bleeding of the duodenal mass and overlying oozing GAVE, which was cauterized with Argon-Plasma Coagulation with adequate hemostasis. We present for the first time a novel association between GAVE and HGM. Our case illustrates that extra-antral GAVE may occur with HGM in the duodenum. We explore potential mechanisms by which HGM may be involved in the pathogenesis of GAVE.

  View details for PubMedID 27830096

  View details for PubMedCentralID PMC5088272

• Multistrain influenza protection induced by a nanoparticulate mucosal immunotherapeutic MUCOSAL IMMUNOLOGY Tai, W., Roberts, L., Seryshev, A., Gubatan, J. M., Bland, C. S., Zabriskie, R., Kulkarni, S., Soong, L., Mbawuike, I., Gilbert, B., Kheradmand, F., Corry, D. B. 2011; 4 (2): 197-207

  Abstract

  All commercial influenza vaccines elicit antibody responses that protect against seasonal infection, but this approach is limited by the need for annual vaccine reformulation that precludes efficient responses against epidemic and pandemic disease. In this study we describe a novel vaccination approach in which a nanoparticulate, liposome-based agent containing short, highly conserved influenza-derived peptides is delivered to the respiratory tract to elicit potent innate and selective T cell-based adaptive immune responses. Prepared without virus-specific peptides, mucosal immunostimulatory therapeutic (MIT) provided robust, but short-lived, protection against multiple, highly lethal strains of influenza in mice of diverse genetic backgrounds. MIT prepared with three highly conserved epitopes that elicited virus-specific memory T-cell responses but not neutralizing antibodies, termed MITpep, provided equivalent, but more durable, protection relative to MIT. Alveolar macrophages were more important than dendritic cells in determining the protective efficacy of MIT, which induced both canonical and non-canonical antiviral immune pathways. Through activation of airway mucosal innate and highly specific T-cell responses, MIT and MITpep represent novel approaches to antiviral protection that offer the possibility of universal protection against epidemic and pandemic influenza.

  View details for DOI 10.1038/mi.2010.50

  View details for Web of Science ID 000287302700009

  View details for PubMedID 20736998