Oral Fluconazole Therapy in Patients With Active Ulcerative Colitis Who Have Detectable Candida in the Stool : A Double-Blind Randomized Placebo-controlled Trial.

BACKGROUND: There is an emerging role of fungal dysbiosis in the pathogenesis of inflammatory bowel disease. Prevalence of Candida in patients with active ulcerative colitis (UC) and the effect of fluconazole therapy in reducing disease activity of UC are not known. PATIENTS AND METHODS: All consecutive consenting patients with active UC defined as Mayo score ≥3 were evaluated for presence of Candida by stool culture and predictors for presence of Candida were identified. Those who had evidence of Candida in the stool were randomized to receive oral fluconazole 200 mg daily or placebo for 3 weeks along with standard medical therapy. Patients were assessed by clinical, sigmoidoscopy, and laboratory parameters at baseline and at 4 weeks. The primary outcome was clinical and endoscopic response at 4 weeks defined by a 3-point reduction in Mayo score. Secondary outcomes were reduction in fecal calprotectin, histologic response, and adverse events. RESULTS: Of the 242 patients with active UC, 68 (28%) patients had Candida in stool culture. Independent predictors for presence of Candida in patients with active UC were partial Mayo score of ≥3 and steroid exposure. Among those with Candida on stool culture (n=68), 61 patients fulfilled eligibility criteria and were randomized to receive fluconazole (n=31) or placebo (n=30). Three-point reduction in Mayo score though was numerically higher in the fluconazole group than the placebo group but was not statistically significant [5 (16.1%) vs. 1 (3.33%); P =0.19]. Postintervention median Mayo score was lower in fluconazole than placebo group [4 (3, 5) vs. 5 (4, 6); P =0.034]. Patients in fluconazole group had more often reduction in fecal calprotectin [26 (83.9%) vs. 11 (36.7%); P =0.001] and histologic scores [23 (74.1%) vs. 10 (33.3%); P =0.001] compared with placebo. All patients were compliant and did not report any serious adverse event. CONCLUSION: Candida colonization is found in 28% of patients with UC. Steroid exposure and active disease were independent predictors for the presence of Candida . There was no statistically significant difference in the number of patients who achieved 3-point reduction in Mayo score between 2 groups. However, clinical, histologic, and calprotectin levels showed significant improvement in fluconazole group.

Oral Nano Vitamin D Supplementation Reduces Disease Activity in Ulcerative Colitis: A Double-Blind Randomized Parallel Group Placebo-controlled Trial.

INTRODUCTION: Vitamin D possesses anti-inflammatory properties and could be beneficial in ulcerative colitis (UC). METHODS: We studied the effect of oral nano vitamin D3 supplementation on disease activity in active UC [ulcerative colitis disease activity index (UCDAI)≥3]. Patients with active UC and vitamin D <40 ng/mL were randomized to receive either oral nano vitamin D (60,000 IU/d×8 d) or placebo. They were evaluated for disease activity (UCDAI scores, C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin) at baseline and reassessed at 4 weeks. The response was defined as a 3-point reduction in UCDAI score at 4 weeks and reduction in inflammatory markers. RESULTS: The median vitamin D levels increased from 15.4 to 40.83 mg/dL in vitamin D group (P≤0.001) and marginally from 13.45 to 18.85 mg/dL (P=0.027) in controls. The 3-point reduction in UCDAI was seen more often in vitamin D group as compared with the control (53% vs. 13%; P=0.001). Increase in vitamin D levels correlated with reduction in UCDAI score (P≤0.001; ρ=-0.713), C-reactive protein (P≤0.001; ρ=-0.603), and calprotectin (P=0.004; ρ=-0.368). Patients who achieved target vitamin D of >40 ng/mL (n=17) more often had a 3-point reduction in UCDAI (80% vs. 20%; P≤0.001) and reduction in grade of severity from 60% to 35% (P=0.038). Vitamin D administration (odds ratio, 9.17; 95% confidence interval, 2.02-41.67) and baseline histologic activity (odds ratio, 1.92; 95% confidence intervals, 1.2-3.08) independently predicted response. CONCLUSIONS: Oral nano vitamin D supplementation in active UC is associated with a reduction in disease activity and severity grade and is seen more often in those who achieved a target vitamin D level of 40 ng/mL.

Hyperglycemia is associated with duodenal dysbiosis and altered duodenal microenvironment.

The gut microbiome influences the pathogenesis and course of metabolic disorders such as diabetes. While it is likely that duodenal mucosa associated microbiota contributes to the genesis and progression of increased blood sugar, including the pre-diabetic stage, it is much less studied than stool. We investigated paired stool and duodenal microbiota in subjects with hyperglycemia (HbA1c ≥ 5.7% and fasting plasma glucose > 100 mg/dl) compared to normoglycemic. We found patients with hyperglycemia (n = 33) had higher duodenal bacterial count (p = 0.008), increased pathobionts and reduction in beneficial flora compared to normoglycemic (n = 21). The microenvironment of duodenum was assessed by measuring oxygen saturation using T-Stat, serum inflammatory markers and zonulin for gut permeability. We observed that bacterial overload was correlated with increased serum zonulin (p = 0.061) and higher TNF-α (p = 0.054). Moreover, reduced oxygen saturation (p = 0.021) and a systemic proinflammatory state [increased total leukocyte count (p = 0.031) and reduced IL-10 (p = 0.015)] characterized the duodenum of hyperglycemic. Unlike stool flora, the variability in duodenal bacterial profile was associated with glycemic status and was predicted by bioinformatic analysis to adversely affect nutrient metabolism. Our findings offer new understanding of the compositional changes in the small intestine bacteria by identifying duodenal dysbiosis and altered local metabolism as potentially early events in hyperglycemia.

Relationship between Mayo endoscopic score and histological scores in ulcerative colitis: A prospective study.

BACKGROUND: The Mayo endoscopic score (MES) remains the most commonly used index in clinical practice, as well as in various clinical trials. Recently, two validated histological indices (Nancy Index [NI] and Robert Histological Index [RHI]) have been developed for ulcerative colitis (UC). We aim to study the relationship between MES with NI, RHI, and the established Geboes Index (GI) in patients with UC. METHODS: This was a prospective single-center study. MES was documented from the most involved area. Biopsy was taken from the same area and reported by a single gastrointestinal histopathologist who was blinded to the endoscopic score. Histological activity was reported using GI, NI, and RHI. Statistical analysis was performed using Spearman's correlation coefficient and Cohen's kappa coefficient using SPSS version 23. RESULTS: Median age of patients with UC (n = 96) was 36 years. Seventeen patients were in endoscopic remission (MES 0/1). Correlation coefficient between MES and GI/NI/RHI was only weak to moderate (rho = 0.381/0.389/0.442, respectively; P < 0.001 for all three correlations). In patients with endoscopic mucosal healing (n = 17), the agreement coefficient between MES and GI/RHI was weak (κ = 0.253/0.336, respectively; P = 0.001 for both agreements). However, there was no significant agreement coefficient between MES and NI (P = 0.573). CONCLUSION: MES moderately correlated with histological scores. RHI had the best correlation with MES among all histological indices. Endoscopic mucosal healing is not strongly correlated with histological healing. Histological examination should be performed even in patients with mucosal healing to detect ongoing histological activity.

Epidemiology of gallbladder cancer in India.

India is a high incidence area for gallbladder cancer (GBC) and contributes to about 10% of the global GBC burden. Within India, the incidence is high in North, North-East, Central and Eastern India, and less common in South and West India. The incidence has been on a steady rise in both genders. The presentation is often with advanced disease and carries dismal prognosis. GBC in India usually affects younger patients in the 5th and 6th decade in contrast to the west. Gallstones are present in 80% of the Indian patients with GBC and its presence increases the vulnerability of the GB to mucosal injury. The incidence of GBC is out of proportion to the prevalence of gallstones in the country. Additional co-factors such as older age, lower socio-economic status, chronic Salmonella typhi (S. typhi) infection, Helicobacter pylori (H. pylori) infection, exposure to pollutants, heavy metals, chemicals, adulterated mustard oil and smoking in patients with gallstones have been identified which promote carcinogenesis. These risk factors act in tandem in an additive manner resulting in higher incidence of GBC as well as hasten the development of GBC. Environmental risk factors such as soil and water contamination by industrial wastes, agricultural effluents and human sewage have been identified as putative risk factors. Combination of a toxic environment, vulnerable GB and a susceptible host play a key role in the pathogenesis of GBC in the country. Large multicentric comprehensive studies are required in India to assess the attributable risk of each of the identified putative risk factors. This will help in formulating cost effective national strategies in preventing GBC related mortality in the country. Meanwhile a high index of suspicion to pick up incidental GBC, and improved access to healthcare facilities to manage GS appropriately will help in reducing GBC related mortality.

Colonic mucosa-associated candida assessed by biopsy culture is associated with disease severity in ulcerative colitis: A prospective study.

OBJECTIVE: To evaluate the relationship of mucosa-associated candida (MAC) and disease severity in patients with ulcerative colitis (UC). METHODS: We prospectively investigated the presence, nature, and quantification of MAC in patients with UC and its relationship with disease severity. Consecutive patients with UC were assessed for clinical, endoscopic, histological features and serum markers of disease severity. All patients underwent mucosal brushing cytology, brushing culture, and biopsy culture for candida growth. MAC was considered present if mucosal biopsy culture grew candida. Candida spp. identification was performed by matrix-assisted laser desorption/ionization. Serum ß-D-glucan was measured with a Fungitell assay. Patients with irritable bowel syndrome who had undergone similar investigations were included as controls. RESULTS: Ninety-six patients with UC showed evidence of MAC more often than the controls (n = 20) based on biopsy culture (33.3% vs 5.0%, P = 0.011), brush cytology (30.2% vs 5.0%, P = 0.019), and brush culture (36.5% vs 10.0%, P = 0.021). Patients with UC had higher candida colony counts (≥103 CFU/mL) than controls (34.4% vs 5.0%, P = 0.007). Median ß-D-glucan values were higher in patients with UC than in controls (103.26 pg/mL vs 66.51 pg/mL, P = 0.011). The UC group with MAC had a higher median total Mayo score, C-reactive protein, fecal calprotectin, ß-D-glucan, and histological activity than those without MAC. CONCLUSIONS: Patients with UC more often show evidence of MAC and a higher candida colony count than controls. The presence of MAC is associated with high disease severity in patients with UC.