Nightshade Vegetables: A Dietary Trigger for Worsening Inflammatory Bowel Disease and Irritable Bowel Syndrome?

The Solanaceae family of plants, commonly known as Nightshade vegetables or Nightshades, contains a diverse range of crops of over 2000 members with significant culinary, economic, and cultural importance. Familiar edible Nightshades include tomatoes, peppers, eggplants, and white potatoes. Many pharmacologically active compounds used in traditional medicine, including atropine and hyoscyamine, are derived from Nightshades. In addition to these beneficial pharmacologic agents, Nightshade-derived glycoalkaloid compounds, a key defense mechanism against predation, have been shown to disrupt intestinal epithelium and to potentially activate mast cells in the gut mucosa, leading to adverse symptoms in humans. There is a new appreciation that mast cell activation is an allergic inflammatory mechanism contributing both to pain in irritable bowel syndrome (IBS) and to gut inflammation in inflammatory bowel disease (IBD). Given their ubiquity in Western diets and their shared glycoalkaloid active compounds, edible Nightshades are attracting new interest as a potential trigger for worsening gut symptoms in functional and inflammatory gastrointestinal disorders. Here, we review the limited existing literature on the adverse effects of Nightshade consumption, including the effects of Nightshade-derived glycoalkaloids on IBD gut inflammation, and the under-recognized contribution of Nightshades to food allergies and allergic cross-reactivity. We then highlight new evidence on the contributions of mast cell activation to GI disorder pathogenesis, including potential linkages between Nightshade antigens, intestinal mast cells, and GI dysfunction in IBS and IBD.

Complete Resolution of Mucosal Neutrophils Associates With Improved Long-Term Clinical Outcomes of Patients With Ulcerative Colitis.

BACKGROUND & AIMS: We investigated correlations between histologic features of the colonic mucosa in patients with ulcerative colitis (UC) and clinical outcomes during a 3-year follow-up period. METHODS: We obtained baseline biopsies from all colorectal segments (n = 889) from 281 patients with UC enrolled in a prospective study at a single center from 2009 through 2013. Biopsies were assessed in a blinded manner using validated histologic scoring systems (the Geboes score, Nancy histopathologic index, and Robarts histopathologic index). Clinical, endoscopic, and histologic data were collected and tested for correlations with systemic corticosteroid use, hospitalization, and colectomy within 3 years of the index colonoscopy. RESULTS: We found histologic evidence of UC activity (Geboes score ≥ 2B.1) in biopsies from 182 patients (65%) and endoscopic evidence of UC activity in 149 patients (53%) (substantial agreement, κ = 0.60). Histologic features of UC activity were associated with increased rates of systemic corticosteroid use, colectomy, and hospitalization in the entire cohort (P < .05 for all) and associated with increased rates of systemic corticosteroid use in an analysis limited to patients in endoscopic remission (P < .001). In patients in endoscopic remission, only histologic activity was independently associated with use of systemic corticosteroids (multivariate odds ratio, 6.34; 95% CI, 2.20-18.28; P = .001). Similar results were seen when the entire cohort was analyzed. Compared with patients without histologic evidence of UC activity, patients with only a small number of mucosal neutrophils still had higher rates of systemic corticosteroid use (P < .001). CONCLUSIONS: Histologic evidence of UC activity, including small numbers of neutrophils in the colonic mucosa, is the only factor independently associated with use of systemic corticosteroids. Complete resolution of neutrophil-associated inflammation should be a target for treatment of UC.

Peripheral Eosinophilia in Patients With Inflammatory Bowel Disease Defines an Aggressive Disease Phenotype.

OBJECTIVES: Peripheral blood eosinophilia (PBE) in inflammatory bowel disease (IBD) is associated with ulcerative colitis (UC) and active disease. Little data exist on the long-term impact of PBE on disease course. We aimed to investigate the multi-year patterns of PBE and its impact on disease severity in a large IBD cohort. METHODS: We performed a registry analysis of a consented, prospective, natural history IBD cohort at a tertiary center from 2009 to 2014. Demographics, comorbidities, disease activity, healthcare utilization, and time to hospitalization or surgical resection of patients who displayed PBE were compared to patients without PBE. RESULTS: Of the 2,066 IBD patients, 19.2% developed PBE. PBE was significantly associated with UC (P<0.001), extensive colitis (P<0.001), and shorter disease duration (P=0.03). Over six years, PBE patients had more active disease (Harvey-Bradshaw Index P=0.001; ulcerative colitis activity index P<0.001), concurrent C-reactive protein elevation (P<0.001), healthcare utilization (hospitalization P<0.001, IBD surgery P<0.001), and more aggressive medical therapy (prednisone P<0.001, anti-TNF P<0.001). Patients with PBE had a significantly reduced time to hospitalization in both UC (P<0.001) and Crohn's disease (CD) (P<0.001) and reduced time to colectomy in UC (P=0.003). On multivariable modeling, PBE remained significantly associated with hospitalization and surgery in both CD and UC. New diagnosis of UC with PBE was associated with increased steroid (P=0.007) and anti-TNF (P=0.001) requirement. CONCLUSION: This multi-year study of a large IBD cohort suggests that peripheral blood eosinophilia represents a biomarker of a distinct IBD subgroup, with a unique inflammatory signature, and at risk for worse clinical outcomes.

Efficacy of Ustekinumab and Vedolizumab Among Postoperative Crohn's Disease Patients as Postoperative Prophylaxis and Rescue Therapy: Real-world Data.

BACKGROUND: Almost half of patients with Crohn's disease (CD) require bowel surgeries in their lifetime. Due to the high risk of postoperative disease recurrence and high rate of previous antitumor necrosis factor (anti-TNF) failure, often alternative therapy options such as ustekinumab (UST) and vedolizumab (VDZ) are used. We aimed to evaluate the efficacy of UST and VDZ among postoperative CD patients as postoperative prophylaxis and rescue therapy. METHODS: Consented CD patients who underwent initial ileocecal resection and were treated with UST and VDZ were included in this study. Demographics, clinical characteristics, health care utilization, endoscopy scores, and surgery outcomes were collected. Postoperative early CD recurrence was defined as a Rutgeerts endoscopic score ≥i2 within the first 2 years. The rescue therapy group was defined as patients who received either UST or VDZ after having Rutgeerts endoscopic score ≥i2 postoperatively. RESULTS: During 2009 to 2019, 98 CD patients were treated with UST or VDZ postoperatively. Postoperative early recurrence rates were 5% (n = 1 out of 20) and 6% (1 out of 15) for the UST and VDZ groups, respectively. Two patients from the UST group and 1 patient from the VDZ group required bowel surgery during follow-up with median drug exposure of 51 (95% confidence interval [CI], 29-61) and 30 (95% CI, 14-63) months, respectively; 55% and 69% of patients had at least 1 point of improvement on postoperative endoscopic Rutgeerts score, respectively, for UST and VDZ. Only 3 out of 40 and 1 out of 23 patients required bowel surgery during follow-up while receiving UST and VDZ as rescue therapy. CONCLUSIONS: Both UST and VDZ were effective as postoperative therapies either as prophylaxis or rescue therapy.

This retrospective 11-year data examines the efficacy of ustekinumab and vedolizumab among postoperative Crohn's disease patients. When utilizing postoperative Rutgeerts score, this study confirms that both ustekinumab and vedolizumab were effective as postoperative therapies either as prophylaxis or rescue therapy.

Granuloma Presence at Initial Surgery Predicts Need for Repeat Surgery Independent of Rutgeerts Score in Crohn's Disease.

BACKGROUND: Approximately half of Crohn's disease (CD) patients experience recurrence and need for repeat resections, highlighting need for prognostic biomarkers. Presence of epithelioid granuloma on surgical tissue and high Rutgeerts endoscopic score are associated with postoperative CD clinical recurrence. We sought to evaluate presence of epithelioid granuloma at first surgery and Rutgeerts score as a combined risk assessment for CD surgical recurrence. METHODS: Our study included consented CD patients who underwent initial ileocecal resection and were prospectively followed postoperatively. From 2009 to 2019, 418 CD patients underwent initial ileocecal resection with >4 years of follow-up, including postoperative endoscopic assessment (Rutgeerts score). RESULTS: Postoperative CD patients were grouped based on granuloma presence (30.6%; n = 128) or absence (69.4%; n = 290). Endoscopic recurrence (defined as Rutgeerts score ≥i2) was similar between the granuloma (26%) and no granuloma (25%) groups, respectively (P = .82). Patients with granuloma and CD endoscopic recurrence at first postoperative endoscopy had higher number of bowel surgeries compared with all other groups (no granuloma or CD endoscopic recurrence, P = .007; no granuloma but CD endoscopic recurrence present, P = .04; granuloma present and no CD endoscopic recurrence, P = .04). Epithelioid granuloma presence was associated with 1.65 times higher risk of subsequent surgery independently from first postoperative endoscopic recurrence Rutgeerts score. CONCLUSIONS: Granuloma presence on initial surgical histology is immediately available and identifies high-risk CD patients who may benefit from early postoperative treatment, and these precision intervention trials are warranted.

This study shows the presence of epithelioid granuloma as a risk factor for repeat Crohn's disease­related surgery, which is independent of first postoperative Rugteerts score. These 11-year observational data provide a risk factor that is immediately available after surgery and identifies high-risk CD patients who may benefit from early postoperative treatment.

High Sugar-Sweetened Beverage Consumption Is Associated with Increased Health Care Utilization in Patients with Inflammatory Bowel Disease: A Multiyear, Prospective Analysis.

BACKGROUND: Dietary factors like sugar-sweetened beverage (SSB) consumption are known to influence disease course in a variety of illnesses; however, long-term outcomes are not well documented for inflammatory bowel disease. OBJECTIVE: Does high consumption of SSBs lead to high healthcare utilization (ie, hospitalizations and emergency department visits), inflammation, and disease severity in patients with inflammatory bowel disease? DESIGN: A prospective cohort study was conducted from 2015 to 2019. Patients enrolled in the discovery study cohort were followed for 3 years, whereas patients in the validation cohort were followed for 2 years. They underwent nutrition assessment and received routine care. Dietary intakes of SSBs and fiber were quantified by a validated, self-reported questionnaire. PARTICIPANTS/SETTING: For the discovery study cohort, 1133 adult patients were recruited from the University of Pittsburgh Medical Center Digestive Disease Clinic in Pittsburgh, PA. Eligible patients had a preexisting diagnosis of Crohn's disease or ulcerative colitis and had at least annual follow-up at this tertiary referral center. High SSB consumption was defined as 7 or more SSBs per week. Moderate was defined as > 2 but < 7 SSBs per week. Low SSB consumption was defined as 2 or fewer SSBs per week. MAIN OUTCOME MEASURES: Primary outcome was time to hospitalization and emergency department visits. Secondary outcomes assessed laboratory markers of disease severity and inflammation. Tertiary outcomes assessed time to hospitalization and emergency department visits in a subsequent independent cohort of patients. STATISTICAL ANALYSIS PERFORMED: Multivariable logistic regression, Kaplan-Meier, and Cox proportional hazards modeling RESULTS: The discovery cohort included of 1,133 adult patients with inflammatory bowel disease (58% women, 70% with Chron's disease, 30% with ulcerative colitis, median age 46 years). Low SSB consumption, moderate SSB consumption, and high SSB consumption occurred in 57%, 17%, and 26% in the discovery cohort, respectively. Among patients without active disease at enrollment, high SSB consumption was associated with decreased time to hospitalization and emergency department visits when compared with low SSB consumption (hazard ratio 1.55, 95% CI 1.06 to 2.27; and hazard ratio 1.53, 95% CI 1.10 to 2.13). In terms of disease severity and inflammatory biomarkers, high SSB consumption was associated with increase odds of elevated erythrocyte sedimentation rate (odds ratio 2.04, 95% CI 1.31 to 3.18), elevated C-reactive protein level (odds ratio 1.60, 95% CI, 1.07-2.37), eosinophilia (odds ratio 1.88, 95% CI 1.06 to 3.335), and monocytosis (odds ratio 1.81, 95% CI 1.18 to 2.79) when compared with low SSB consumption after adjusting for baseline differences. Lastly, the validation cohort produced similar results to our primary outcome (ie, high SSB consumption was associated with decreased time to hospitalization and emergency department visits when compared with low SSB consumption). CONCLUSIONS: High SSB consumption was associated with decreased time to hospitalization and emergency department visits. Furthermore, high SSB consumption is associated with disease severity biomarkers and inflammation. Prospective studies assessing the therapeutic influence of nutrition counseling and decreased SSB consumption on long-term inflammatory bowel disease clinical course are warranted.

Elevated serum globulin fraction as a biomarker of multiyear disease severity in inflammatory bowel disease.

Background: Serum protein reflects albumin and globulin levels, both of which can be altered in inflammatory bowel disease (IBD). The implications of a high globulin fraction in IBD are unknown. We hypothesized that a high globulin fraction may function independently of albumin as a biomarker of disease severity in IBD patients over a multiyear period. Methods: This was an observational study from a prospective IBD registry of a tertiary care center. High globulin fraction was defined as an elevated globulin level >4 g/dL. Data collected included patient demographics, medication exposures, quality-of-life scores, disease activity, emergency department visits, telephone calls, hospitalizations, and IBD-related surgeries over a 4-year period. Comparisons between patients with a high globulin fraction and those without were performed using Pearson's chi-squared, Student's and Mann-Whitney tests. Multivariate analyses were used to assess the relationship between high globulin fraction and healthcare utilization. Results: A total of 1767 IBD patients with a 4-year follow up were included: 53.5% female, mean age 48.4±15.1 years, and 65.4% with Crohn's disease. Of these patients, 446 (25.2%) presented with elevated globulin fraction. Patients with a high globulin fraction were more likely to be hospitalized during the study period. This result remained significant after multivariate analysis for both Crohn's disease patients and those with ulcerative colitis. Conclusion: A high globulin fraction is independently associated with greater disease severity and healthcare utilization in IBD patients, and may function as a routinely available biomarker of a more severe future disease trajectory.

Validated Indices for Histopathologic Activity Predict Development of Colorectal Neoplasia in Ulcerative Colitis.

BACKGROUND AND AIMS: To correlate histologic activity in surveillance colonoscopies with the development of colorectal neoplasia in ulcerative colitis [UC]. METHODS: Colorectal biopsies during surveillance [N = 764] from 52 UC patients with colorectal neoplasia were compared to 122 patients without neoplasia enrolled in a prospective natural history registry. All biopsies were scored using validated histologic scoring systems (Geboes score, Nancy histopathologic index [NHI], and Robarts histopathologic index [RHI]). Clinical, endoscopic, and histologic data were correlated with the development of colorectal neoplasia. RESULTS: In multivariable analysis, mean RHI (hazard ratio [HR] 1.07 for each 1-unit increase in RHI, 95% confidence interval [CI] 1.03-1.12, p = 0.002) and mean NHI [HR 1.89 for each 1-unit increase in NHI, 95% CI 1.34-2.67, p = 0.002] for the entire surveillance period were significantly associated with colorectal neoplasia development. Shorter surveillance interval and increasing age were associated with increased risk of neoplasia development whereas mean Mayo endoscopic score was not significant. To generate a clinically useful measure of neoplasia risk, mean histologic activity in the preceding 5 years before the study endpoint was correlated with neoplasia development. In the preceding 5 years of surveillance, a mean RHI ≥ 8 had a 7.53-fold increased risk [95% CI 2.56-12.16, p < 0.001] and mean NHI ≥ 1.9 had a 5.89-fold increased risk [95% CI 2.18-15.92, p < 0.001] of developing colorectal neoplasia. CONCLUSIONS: Persistent histologic activity during multiple surveillance episodes is an independent predictor of colorectal neoplasia. Mean RHI and mean NHI during a 5-year colonoscopic surveillance period can be used to assess risk for colorectal neoplasia and optimize UC surveillance.

Correlation of anemia status with worsening bowel damage as measured by Lémann Index in patients with Crohn's disease.

BACKGROUND: There is evidence that anemia in Crohn's disease (CD) is a predictor of disease severity. AIM: To evaluate if patterns of anemia over time showed correlation with aggressive disease trajectory, as characterized by change in Lémann Index (LI), which is a metric that quantifies bowel damage. METHODS: CD patients with 5 year (y) follow-up from a prospective registry were included. LI was calculated from the first (LI1) and last (LI2) clinical encounters. The change in score (LI2-LI1) or the Delta LI (DLI) was recorded. Patterns of anemia, healthcare utilization and disease activity scores were analyzed. RESULTS: A total of 389 CD patients with 5y follow-up formed the study population [median age 40y (IQR: 31-53); 57.3% female; median disease duration 12y (IQR: 6-20.5), overall surgical exposure 69%]. Patients with anemia had significantly higher LI1, LI2, DLI and also significantly higher healthcare utilization and indices of disease activity, than patients without anemia (p<0.001). CD patients with anemia for any duration during the study had OR of 2.15 (95% CI 1.29-3.57, p=0.003) for worsening bowel damage over the 5y. CONCLUSION: Based on a longitudinal analysis of CD patients, anemia status over time shows significant correlation with increasing Lémann index and aggressive disease trajectory.

Group-Based Trajectory Modeling of Healthcare Financial Charges in Inflammatory Bowel Disease: A Comprehensive Phenotype.

OBJECTIVES: Inflammatory bowel disease (IBD) is a heterogeneous group of chronic inflammatory gastrointestinal conditions with variable disease courses often requiring significant healthcare expenditures. We aimed to identify disease trajectory patterns based on longitudinal financial expenditures and to assess the association of classic disease activity parameters with financial charges. METHODS: This was an analysis of a consented, prospective, natural history IBD registry (2009-2013) from a tertiary IBD center of 2,203 patients and their associated medical charges excluding pharmacy expenses. We applied group-based trajectory modeling to longitudinal healthcare financial charges to determine patterns of charges. We assessed the association between charge patterns and disease activity, quality of life, healthcare utilization, and medication requirement. RESULTS: The final model included 1,600 IBD patients with 5-year charges. We identified six distinct trajectories over the study period. Consistently High charges were associated with Crohn's disease (66.0% Consistently High patients, P<0.01), perianal involvement (22.6%, P<0.01), ulcerative colitis extent (89.7% extensive, P=0.01), prior IBD surgery (52.5%, P<0.01), and depression/anxiety (36.2%, P<0.01). Compared with other trajectories, Consistently High charges had higher 5-year disease activity indices (Harvey-Bradshaw P<0.01; ulcerative colitis activity index P<0.01), elevated C-reactive protein rates (72.3%, P<0.01), IBD surgery (64.5%, P<0.01), hospitalization (97.2%, P<0.01), corticosteroid (70.9%, P<0.01) and antitumor necrosis factor requirement (50.4%, P<0.01), and worse quality of life (P<0.01). Annual trends in parameters were reflected in temporal changes in financial charges. The majority of financial burden stemmed from inpatient care. CONCLUSIONS: Healthcare financial charges represent a novel phenotype in IBD that reflect trends in classic disease activity parameters and allow for subgroup identification of temporal disease trajectories.