New diagnostic strategies to distinguish Crohn's disease and gastrointestinal tuberculosis.

PURPOSE OF REVIEW: Despite advances in our radiological, histological and microbiological armamentarium, distinguishing between Crohn's disease (CD) and intestinal tuberculosis (ITB), especially in a TB endemic country, continues to be a challenging exercise in a significant number of patients. This review aims to summarize current available evidence on novel diagnostic techniques which have a potential to fill the gap in our knowledge of differentiating between ITB and CD. RECENT FINDINGS: Both ITB and CD are associated with altered host immune responses, and detection of these altered innate and adaptive immune cells has potential to distinguish ITB from CD. ITB and CD have different epigenetic, proteomic and metabolomic signatures, and recent research has focused on detecting these differences. In addition, the gut microbiome, which is involved in mucosal immunity and inflammatory responses, is considerably altered in both ITB and CD, and is another potential frontier, which can be tapped to discriminate between the two diseases. With technological advancements, we have newer radiological modalities including perfusion CT and dual-layer spectral detector CT enterography and evidence is emerging of their role in differentiating ITB from CD. Finally, time will tell whether the advent of artificial intelligence, with rapidly accumulating data in this field, will be the gamechanger in solving this puzzle of diagnostic dilemma between ITB and Crohn's disease. SUMMARY: Recent advances need to be clinically validated before they can be used as novel diagnostic measures to differentiate Intestinal TB from CD.

A hepatocyte-specific transcriptional program driven by Rela and Stat3 exacerbates experimental colitis in mice by modulating bile synthesis.

Hepatic factors secreted by the liver promote homeostasis and are pivotal for maintaining the liver-gut axis. Bile acid metabolism is one such example wherein, bile acid synthesis occurs in the liver and its biotransformation happens in the intestine. Dysfunctional interactions between the liver and the intestine stimulate varied pathological outcomes through its bidirectional portal communication. Indeed, aberrant bile acid metabolism has been reported in inflammatory bowel disease (IBD). However, the molecular mechanisms underlying these crosstalks that perpetuate intestinal permeability and inflammation remain obscure. Here, we identify a novel hepatic gene program regulated by Rela and Stat3 that accentuates the inflammation in an acute experimental colitis model. Hepatocyte-specific ablation of Rela and Stat3 reduces the levels of primary bile acids in both the liver and the gut and shows a restricted colitogenic phenotype. On supplementation of chenodeoxycholic acid (CDCA), knock-out mice exhibit enhanced colitis-induced alterations. This study provides persuasive evidence for the development of multi-organ strategies for treating IBD and identifies a hepatocyte-specific Rela-Stat3 network as a promising therapeutic target.

Gut colonization with antibiotic resistance Escherichia coli pathobionts leads to disease severity in ulcerative colitis.

AIM: Escherichia coli is a Gram-negative commensal of human gut. Surprisingly, the role of E. coli in the pathogenesis of ulcerative colitis (UC) has not been explored till date. METHODS: Human gut microbiota composition and meta-gut resistome was evaluated using metagenomics. Antibiotic susceptibility of E. coli isolates against different class of antibiotics was investigated. Further, the genome sequence analysis of E. coli isolates was performed to get insight into the antimicrobial resistance (AMR) mechanism and virulence factors. Gut proteome of UC and non-UC was examined to understand the effect of resistant bacteria on host physiology. RESULTS: In UC patients, meta-gut resistome was found to be dominated by AMR genes (829) compared to healthy control (HC) [518]. Metagenome study revealed higher prevalence of AMR genes in rural population (378 in HC; 607 in UC) compared to urban (340 in HC; 578 in UC). Approximately, 40% of all E. coli isolates were multi-drug resistant with higher prevalence in UC (43.75%) compared to HC (33.33%). Up-regulated expression of antimicrobial human proteins (lactotransferrin, azurocidin, cathepsin G, neutrophil elastase, and neutrophil defensin 3) and immuneproteins (Protein S100-A9 and Protein S100-A8) suggest microbial infection in UC gut. CONCLUSIONS: In addition to the conventional culturomics method, multi-omics strategy provides deeper insights into the disease etiology, emergence of pathobionts, andits role in the disruption of the healthy gut environment in UC patients.

Multi-centric evaluation of Truenat MTB and MTB-RIF Dx assays for diagnosis of extrapulmonary tuberculosis.

Extra-pulmonary TB (EPTB) is difficult to diagnose due to paucibacillary nature of disease. Current study evaluated accuracy of Truenat MTB and MTB-Rif Dx (TN), for detection of Mycobacterium tuberculosis and resistance to rifampicin. Samples were collected from 2103 treatment naive adults with presumptive EPTB, and tested by smear microscopy, liquid culture (LC) (MGIT-960) and GeneXpert MTB/RIF (GX) (Microbiological Reference Standards, MRS). TN results were compared to MRS and Composite Reference Standards (CRS, Microbiology, histopathology, radiology, clinical features prompting decision to treat, response to treatment). CRS grouped patients into 551 confirmed, 1096 unconfirmed, and 409 as unlikely TB. TN sensitivity and specificity was 73.7% and 90.4% against GX. Against LC, Overall sensitivity of GX was 67.6%, while that of TN was 62.3%. Highest sensitivity by TN was observed in pus samples (89%) and highest specificity (92%) in CSF samples, similar to GX. TN sensitivity was better in fluid and biopsy samples and slightly inferior for lymph node aspirates compared to GX. TN sensitivity for RIF resistance detection was slightly superior to GX. TN and GX results were further compared to Clinical Reference Standards. TN detected 170 TB patients initiated on treatment missed by GX, while GX detected 113 such patients missed by TN. Of 124 samples with RIF resistance discordance between GX and TN, GX reported 103/124 as sensitive, 3/124 as indeterminate and 18 as resistant (13/18 samples had low/very low DNA load) while TN reported RIF resistance indeterminate in 103/111 low/very low DNA load samples. Due to paucibacillary nature of EPTB samples, culture yield was poor and phenotypic drug susceptibility testing failed to resolve the discordance. The study establishes TN at par with GX and can be utilized for quick and accurate diagnosis of EPTB.

Outcomes following reoperative bariatric surgery following laparoscopic sleeve gastrectomy at a tertiary care centre.

INTRODUCTION: Laparoscopic sleeve gastrectomy (SG) is the most common bariatric surgical procedure worldwide. Approximately 20%-30% of patients present with weight loss failure or reflux following SG, which might require reoperative surgery. We present the surgical outcomes and complications following reoperative bariatric surgery at a tertiary care centre. PATIENTS AND METHODS: Prospectively collected data of all patients undergoing reoperative bariatric surgery from 2008 to 2021 were analysed retrospectively. Weight loss, resolution of comorbidities and complications following reoperative surgery were evaluated. RESULTS: Twenty-six patients were included in the study. The mean age was 38.8 (10.8) years. The primary procedure performed was laparoscopic SG in all cases. Nine patients underwent Roux en Y gastric bypass (RYGB) (one banded RYGB) and 14 underwent one anastomosis gastric bypass (OAGB) (three-banded OAGB). Three patients underwent resleeve. The most common indication was weight loss failure (65.3%). Fifteen patients were diagnosed to have hiatal hernia intraoperatively and concomitant repair was performed. The mean body mass index before revision surgery was 42.7 (9.8). It was 32.6 (5.7) kg/m2 and 33.0 (6.1) kg/m2 at 1 and 3 years, respectively. Age and pre-revision surgery excess weight correlated with weight loss (r = -0.79 and r = 0.99, respectively). Leak and bleeding occurred in one and two patients, respectively. There were two band-related complications and one 30-day mortality. CONCLUSION: Re-operative bariatric surgery following SG has adequate weight loss with acceptable complication rates. Band placement in re-operative surgery might lead to a higher complication rate.

Development and Validation of a Tool for Assessing Adherence to Gluten-Free Diet in Patients With Celiac Disease.

INTRODUCTION: Life-long adherence to gluten-free diet (GFD) and its assessment is essential for patients with celiac disease (CeD). We have developed and validated a tool for assessing adherence to GFD which can be used by both physicians and dietitians. METHODS: Phase 1: Development, content validation, and assessment of reliability of tool. Phase 2: Validation of tool against standard dietary evaluation (SDE) (gold standard), immunoglobulin A - anti-tissue transglutaminase antibodies (IgA anti-tTG Ab), and gluten immunogenic peptides in urine. Overall, 380 biopsy-confirmed patients with CeD (derivation cohort: n = 100 [phase 1], n = 210 [phase 2] and independent validation cohort, n = 70) were recruited. RESULTS: Of an initial 90-point questionnaire, 84 items (Celiac Disease: Compliance Assessment Test [CD-CAT.v1]) were retained after content validation and pilot testing. In phase 1, upon administering CD-CAT.v1 on 100 patients, a comprehensive 35-item tool (CD-CAT.v2; α = 0.86) was obtained after removing items with low test-retest reliability and item-rest correlation values. In phase 2, upon administering CD-CAT.v2 on 210 patients, 22 items were removed having low correlation values (R < 0.4) with SDE. Finally, a 13-item tool (CD-CAT.v3; α = 0.84) was obtained with high criterion validity with SDE ( r = 0.806, P < 0.001), moderate convergent validity with celiac disease adherence test ( r = 0.602, P = 0.007), and moderate to weak correlation with urine gluten immunogenic peptides ( r = 0.46, P = 0.001) and IgA anti-tTG Ab ( r = 0.39, P = 0.008), respectively. The final 13-item tool also strongly correlated with SDE ( r = 0.78, P < 0.001) in an independent validation cohort of 70 patients with CeD. Principal component analysis identified 3 relevant subscales with a cumulative variance of 62%. The sensitivity and specificity of CD-CAT.v3 were 80% and 91%, respectively, with an area under curve of 0.905 with SDE. The obtained cutoff score of <19 from the receiver operating characteristic curve was further categorized as 13 = excellent, 14-18 = very good, 19-28 = average, and >28 = poor adherence to GFD. DISCUSSION: CD-CAT is a new and rapid tool for monitoring dietary adherence to GFD with high sensitivity and specificity, which can be administered by both physicians and dietitians.

Intravenous albumin infusion does not augment the response rate to a combination of exclusive enteral nutrition and intravenous steroids in acute severe ulcerative colitis: a randomized controlled trial.

INTRODUCTION: 30-40% patients with acute severe ulcerative colitis (ASUC) fail intravenous (IV) steroids requiring medical rescue therapy/colectomy. Low baseline albumin predicts steroid non-response, and exclusive enteral nutrition (EEN) has been shown to improve steroid response and albumin levels. Albumin infusion due to its anti-inflammatory and anti-oxidant properties might further improve steroid response in ASUC, which was evaluated in present study. METHODS: In this open-label randomized controlled trial, patients with ASUC were randomized in 1:1 ratio to albumin + standard of care (SOC) + EEN vs. SOC + EEN (Jan2021 - Feb2023). Both arms received 5 days of EEN with 400 mg IV hydrocortisone/day. Patients in albumin arm were administered 5 days of 20% w/v intravenous albumin (100 ml). Primary outcome was 1) steroid failure (need for rescue medical therapy or colectomy) and 2) proportion of patients with adverse events. RESULTS: Sixty-one patients (albumin-30, SOC-31)(mean age-31.6±0.4 years, male-57.4%), were included. Baseline characteristics were comparable. There was no difference in steroid failure between albumin and SOC arm(10/30(33.33 %) vs 13/31(41.94 %), p=0.49). No adverse events were reported with albumin infusions. Colectomy rate(10% vs 9.68%, P=1), response to salvage medical therapy (88.89% vs 76.92%, P=0.62) and median duration of hospitalization (10.5(7-16) vs 10(7-20), P=0.43) were also comparable. Long-term composite outcome of colectomy and re-admission rates was numerically higher in the albumin than SOC arm (37.04% vs 17.86%, p>0.05), although it did not reach statistical significance. CONCLUSION: There was no benefit of intravenous albumin infusion as an adjunct to IV steroids and EEN in patients with ASUC.

A phase I/II clinical trial of ex-vivo expanded human bone marrow derived allogeneic mesenchymal stromal cells in adult patients with perianal fistulizing Crohn's Disease.

BACKGROUND: Perianal fistulas (PF) affect one-third patients with Crohn's disease (CD) with limited therapeutic options. There is dearth of literature on safety and efficacy of bone marrow-derived mesenchymal stromal cells (BMSCs) in this population. METHODS: An open-label, phase I/II, single-arm study was conducted involving local administration of human allogeneic bone marrow-derived mesenchymal stromal cells in perianal fistula of patients with Crohn's disease refractory to standard therapies. Clinical severity and biomarkers were assessed at baseline and periodically until week 104 , and MRI at week 24 and 104. Primary and secondary objectives were to assess safety and efficacy respectively. Fistula remission was complete closure of fistula openings with < 2 cm perianal collection on MRI, and fistula response was decrease in drainage by ≥ 50%. Change in perianal disease activity index, quality-of-life and Van Assche index on MRI over time was assessed using mixed-effect linear regression model. RESULTS: Ten patients (male:8, mean age:27.4 ± 12.0years) were recruited. Self-resolving procedure-related adverse events occurred in three patients, with no follow-up adverse events. In intention to treat analysis at week 24, two patients (20%) achieved fistula remission and seven (70%) had fistula response. At week 52, two (20%) patients were in remission and seven (70%) maintained response. At 104 weeks, two (20%) patients maintained response and one (10%) was in remission. Statistically significant decrease in perianal disease activity index (P = 0.008), Van Assche Index (P = 0.008) and improvement in quality-of-life (P = 0.001) were observed over time. CONCLUSIONS: Allogeneic BMSCs are safe and effective for the treatment of perianal fistulizing CD with significant improvement in clinical severity and radiological healing. TRIAL REGISTRATION: The study was prospectively registered on Clinical trials registry - India (CTRI), CTRI/2020/01/022743 on 14 January 2020, http://ctri.nic.in .

Ten missteps in the management of inflammatory bowel disease in Asia: An expert report by the Asian Pacific Association of Gastroenterology Working Group on Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is rapidly emerging in the Asia Pacific region. However, there are many challenges in the diagnosis and management of this condition. The Asian Pacific Association of Gastroenterology (APAGE) Working Group on IBD conducted a round table meeting to identify 10 common mistakes in the management of IBD in Asia. To summarize, many physicians still over rely on a definitive histological diagnosis before starting treatment and do not fully establish disease extent such as perianal and proximal gastrointestinal involvement in Crohn's disease (CD) or extent of involvement in ulcerative colitis (UC). It is also essential to actively look for evidence of extra-intestinal manifestations, which may influence choice of therapy. In terms of conventional therapy, underuse of topical 5 aminosalicylates (5-ASAs) in UC and inappropriate dosing of corticosteroids are also important considerations. Acute severe UC remains a life-threatening condition and delay in starting rescue therapy after inadequate response to intravenous steroids is still common. Anti-tumor necrosis factors should be considered first line in all cases of complex perianal fistulizing CD. Most patients with IBD are on potent immunosuppressive therapy and should be screened for latent infections and offered vaccinations according to guidelines. Under-recognition and management of significant complications such as anemia, osteoporosis, malnutrition, and thromboembolism should also be addressed. Colonoscopy is still not properly performed for dysplasia/cancer surveillance and for evaluating post-op recurrence of CD. Another common misstep is inappropriate withdrawal of medications during pregnancy leading to increased complications for the mother and the newborn.

Combined or High Dose Immunosuppression in Inflammatory Bowel Disease patients who are NUDT15 Homozygous Harbors Risk of Developing Invasive Fungal Infections: A Case Series.

NUDT15 homozygous mutations predispose patients to severe leucopenia, which invites risk of disseminated fungal infections when high doses or a combination of immunosuppressives are administered in this patient population.

Gluten-free foods are expensive and nutritionally imbalanced than their gluten-containing counterparts.

OBJECTIVES: Nutritional quality of gluten-free (GF) food products is very important, as patients with celiac disease consume these products for lifelong. There is paucity of data on the nutritional content and cost of GF food products compared with their gluten-containing (GC) counterparts from India (Asia). DESIGN: After a detailed market survey, packaged and labeled GF food products (n=485) and their packaged GC counterparts (n=790) from the supermarkets of Delhi (India) and e-commerce websites were included. Nutritional content and cost/100 g food (in US dollars) were calculated using the information on food label. RESULTS: Gluten-free food products were 232% (range: 118% to 376%) more expensive than their GC counterparts. Energy content of all GF food products was similar to their GC counterparts, except cereal-based snacks (GF: 445 kcal vs. GC: 510 kcal, p<0.001). The protein content was significantly lower in GF pasta and macaroni products (single-grain: GF: 6.5 g vs. GC:11. 5 g, p-0.002; multigrain: GF:7.6 g vs. GC:11.5 g, p-0.027), cereal flours (single-grain: GF: 7.6 g vs. GC: 12.3 g, p<0.001; multigrain: GF:10.9 g vs. GC: 14.1 g, p-0.009) and nutritional bars (GF: 21.81 g vs. GC:26 g, p-0.028) than their GC counterparts. Similarly, the dietary-fiber content of GF pasta and macaroni products, cereal flours, cereal premix and nutritional bars of GF foods was significantly lower than their GC counterparts. Gluten-free bread and confectionary items, biscuits and cookies and snacks had higher total fats and trans-fat content than their GC counterparts. Gluten-free cereal-based snacks had higher sodium content than their GC counterparts (GF: 820 mg vs. GC:670 mg; p<0.001). CONCLUSION: GF foods are significantly more expensive, contain less protein and dietary fiber and higher fat, trans-fat and sodium than their GC counterparts. Strategies must be developed to reduce the cost and improve the nutritional profile of GF foods.

Reproductive functions and pregnancy outcome in female patients with celiac disease.

BACKGROUND AND AIM: Abnormalities in the reproductive functions are often ignored while evaluating a patient with celiac disease (CeD). We evaluated the entire reproductive functions in female patients with CeD. METHODS: In a case control study between 2020 and 2021 using detailed questionnaire, we evaluated reproductive functions (age at menarche, menstrual pattern, fertility, pregnancy outcome and menopause) in biopsy-proven female patients with CeD of age >10 years. The questionnaire was administered either in person or telephonically. Age-matched healthy female controls (twice the number) were also recruited. RESULTS: Of 1086 CeD patients, 470 were females and 288 were included. As compared with controls (n = 586), females with CeD had higher age at menarche (14.6 ± 2.0 vs 13.6 ± 1.5 years; P = 0.001), delayed menarche (30.8% vs 11.4%; P = 0.001), abnormal menstrual pattern (39.7% vs 25.8%; P < 0.001), involuntary delay in conception at > 1 year (33.8% vs 11.8%; P = 0.01), current infertility rate (10.5% vs 5.2%;P = 0.028), and poorer overall pregnancy outcomes (abortion [23.5% vs 12.8%; P = 0.001], pre-term birth [16.3% vs 3.7%; P = 0.001]). CONCLUSIONS: Either one or more aspect of reproductive functions and pregnancy outcome is affected adversely in three-fourth female patients with CeD.

Patients with Celiac Disease Have High Prevalence of Fatty Liver and Metabolic Syndrome.

OBJECTIVE: In recent years, patients with celiac disease (CeD) have been reported to have a high prevalence of fatty liver and metabolic syndrome. We conducted a systematic review and meta-analysis to assess the prevalence of fatty liver and metabolic syndrome in patients with CeD and effect of gluten-free diet in them. METHODS: The PubMed, Embase and the Cochrane Library databases were searched for original studies upto November 18, 2022. We included full-text articles published in the English language after 1990 that used well-defined criteria for CeD, fatty liver and metabolic syndrome. A random effects model was used to calculate pooled prevalence. RESULTS: Of 350 studies identified, 11 studies (n = 2578) were included in the analysis. On analysis of both cross-sectional and longitudinal studies, pooled prevalence of fatty liver and metabolic syndrome in treatment-naïve patients with CeD were 18.2% (95% CI 8.3-30.8%, n = 1237) and 4.3% (95% CI 2.4-6.7, n = 1239) and in those on GFD of varying duration was 28.2% (95% CI 20.7-36.4%, n = 1368) and 21.3% (95% CI 11.7-32.9%, n = 2193), respectively. There was no difference in the prevalence of fatty liver and metabolic syndrome between low- or high-income group countries. CONCLUSIONS: Patients with CeD have a high prevalence of fatty liver and metabolic syndrome which increases further with the initiation of GFD. Patients with CeD should thus be screened and monitored for development of fatty liver and metabolic syndrome. They should be counselled appropriately regarding their diet and inclusion of physical activity in their lifestyle.

Rab7-dependent regulation of goblet cell protein CLCA1 modulates gastrointestinal homeostasis.

Inflammation in ulcerative colitis is typically restricted to the mucosal layer of distal gut. Disrupted mucus barrier, coupled with microbial dysbiosis, has been reported to occur prior to the onset of inflammation. Here, we show the involvement of vesicular trafficking protein Rab7 in regulating the colonic mucus system. We identified a lowered Rab7 expression in goblet cells of colon during human and murine colitis. In vivo Rab7 knocked down mice (Rab7KD) displayed a compromised mucus layer, increased microbial permeability, and depleted gut microbiota with enhanced susceptibility to dextran sodium-sulfate induced colitis. These abnormalities emerged owing to altered mucus composition, as revealed by mucus proteomics, with increased expression of mucin protease chloride channel accessory 1 (CLCA1). Mechanistically, Rab7 maintained optimal CLCA1 levels by controlling its lysosomal degradation, a process that was dysregulated during colitis. Overall, our work establishes a role for Rab7-dependent control of CLCA1 secretion required for maintaining mucosal homeostasis.

Methylation study of tumor suppressor genes in human aberrant crypt foci, colorectal carcinomas, and normal colon.

BACKGROUND: Aberrant crypt foci (ACF) are the earliest preneoplastic lesions in human colon, identifiable on chromoendoscopic screening. Our objective was to evaluate the %methylation of APC, CDKN2A, MLH1, RASSF1, MGMT, and WIF1 tumor suppressor genes (TSG) in ACF, corresponding colorectal carcinomas (CRC), and normal colonic mucosal controls. METHODS: In this study, macroscopically normal-appearing mucosal flaps were sampled 5-10 cm away from the tumor mass from 302 fresh colectomy specimens to identify ACF-like lesions. Thirty-five cases with multiple ACFs were selected (n 35) as the main study group, with corresponding sections from CRC (n 35) as disease controls, and mucosal tissue blocks from 20 colectomy specimens (normal controls), operated for non-neoplastic pathologies. Genomic DNA was extracted, and methylation-specific polymerase chain reaction (PCR) was performed on a customized methylation array model. %Methylation data were compared among the groups and with clinicopathological parameters. Selected target mRNA and protein expression studies were performed. RESULTS: %Methylation of TSGs in ACF was intermediate between normal colon and CRC, although a statistically significant difference was observed only for the WIF1 gene (P < 0.01). Also, there was increased nuclear ß-catenin expression and upregulation of CD44-positive cancer-stem cells in ACF and CRCs than in controls. Right-sided ACFs and dysplastic ACFs had a higher %methylation of CDKN2A (P < 0.01), whereas hyperplastic ACFs had a higher %methylation of RASSF1 (P 0.04). The topographic characteristics of ACFs did not correlate with TSG %methylation. CONCLUSIONS: Early epigenetic methylation of WIF1 gene is one of the mechanisms for ACF development in human colon.

Correlation between intestinal stem cell niche changes and small bowel crypt failure in patients with treatment-naïve celiac disease.

OBJECTIVES: We hypothesized that crypt failure in the small bowel results in villous flattening in patients with celiac disease (CeD). We investigated whether alterations in the stem cell niche (ISC) are responsible for this phenomenon. MATERIALS AND METHODS: We included 92 duodenal (D2/3) biopsies from treatment-naive patients of CeD and 37 controls. All underwent screening for serum anti-tissue transglutaminase and endoscopic upper small bowel biopsy. Immunohistochemical markers were used to investigate ISC niche alterations, including LGR5 for crypt basal cells (CBC), Bmi1 for position 4+ cells, ß-Defensin for Paneth cells, R-spondin1 as WNT activator, transcription factor-4 as WNT transcription factor, BMP receptor1A as WNT inhibitor, fibronectin-1 as periepithelial stromal cell marker, H2AX as apoptosis marker, and Ki67 as proliferation marker. We also analyzed IgA anti-tTG2 antibody deposits by using dual-color immunofluorescence staining. RESULTS: We found that in biopsies from patients with treatment-naive CeD with modified Marsh grade 3a-3c changes, the epithelial H2AX apoptotic index was upregulated than in controls. LGR5+ crypt basal cells were upregulated in all modified Marsh grades compared to controls. However, the Ki67 proliferation index, expressions of WNT-activator RSPO1, and position-4 cell marker Bmi1 did not significantly alter in patients' biopsies as compared to controls ( P = 0.001). We also observed depletion of pericrypt stromal fibronectin-1 in patients with CeD compared to controls. In addition, we identified IgA anti-TG2 antibody deposits in pericrypt stroma. CONCLUSIONS: Our data suggests that ISC niche failure is a plausible hypothesis for villous flattening in patients with CeD, resulting from pericrypt IgA anti-TG2 antibody complex-mediated stromal depletion.

Gut bacteriome in inflammatory bowel disease: An update on recent advances.

Inflammatory bowel diseases (IBD) are chronic inflammatory gut disorders, majorly classified as ulcerative colitis and Crohn's disease. The complex, multifactorial etiopathogenesis of IBD involves genetic predisposition, environmental cues, aberrant mucosal immune response and a disturbed gut microbiota. Epidemiological trends, studies in gnotobiotic mice models and genome-wide association studies, identifying genes involved in microbial handling, together mount evidence in support of the gut microbiota playing a pivotal role in IBD pathogenesis. Both Crohn's disease and ulcerative colitis are characterized by severe dysbiosis of the gut microbiome, marked by an expansion of detrimental taxa and concomitant depletion of beneficial members. IBD is characterized by reduction in abundances of bacterial genera involved in production of short-chain fatty acids, bio-transformations of bile acids and synthesis of indole-based tryptophan compounds such as Faecalibacterium, Ruminococcus, Coprococcus, Dorea, Parabacteroides, Eubacterium, Oscillibacter and Prevotella and elevation in members of phyla Proteobacteria and Actinobacteria. This imbalance not only results in exaggerated immune signaling towards the microbial antigens, but also results in an altered metabolomic milieu that triggers additional inflammatory cascades. The present review provides insights into the bacterial dysbiosis observed across different intestinal sites and their metabolomic imprints participating in IBD.

Barriers at various levels of human ecosystem for maintaining adherence to gluten free diet in adult patients with celiac disease.

INTRODUCTION: While lifelong and strict adherence to gluten-free diet (GFD) is essential for the successful treatment of celiac disease (CeD), only 30-50% of patients are able to maintain a good adherence to GFD. We determined factors influencing the adherence to GFD at various ecological levels including intra-personal, inter-personal, organizational, community and system-based levels in adult patients with CeD. METHODS: A questionnaire to assess the adherence was developed and it was administered in the CeD clinic to patients with CeD on GFD for >1 year. Adherence to GFD was assessed in a subset of patients (n = 320) using Celiac Disease Adherence Test (CDAT). RESULTS: Overall, 978 patients [median age: 29 years; females: 592] with CeD on GFD were recruited. They reported many barriers to adherence to GFD including intra-personal barriers such as lack of knowledge about GFD (19%), inadequate financial resources (27.2%) and lack of self-motivation/confidence (55.3%); inter-personal barriers such as intake of gluten-containing food upon forceful insistence of friends/family (23.4%); organizational barriers such as high cost (70.8%) and non-availability of GF-food products (48.6%); community-based barriers like consumption of gluten-containing food at religious occasions/festivals (11.1%) and social occasions (27.2%); and system-based barriers such as non-referral to dietitian for counseling (21.9%). As per CDAT, 204 (63.7%), 73(22.8%) and 43(13.4%) patients had good, average, and poor adherence to GFD, respectively. On multivariable analysis, occasional consumption of gluten, non-availability of GF-food while dining out and coercing by family and friends for consumption of GC-food were found to have highest odds for poor adherence to GFD. CONCLUSIONS: Non-referral to a dietitian for counseling, irregular follow-up visits, unavailability of flour mill, non-supportive family/friends, high cost and limited availability of GF-food are the most common barriers to adherence to GFD. There is a need to create infrastructure and develop strategies to overcome these diverse barriers at various levels of ecosystem and thereby facilitate better adherence to GFD.

Coconut Water Induces Clinical Remission in Mild to Moderate Ulcerative Colitis: Double-blind Placebo-controlled Trial.

BACKGROUND & AIMS: Coconut water (CW) is anti-inflammatory, can manipulate the gut microbiome, and is a rich source of potassium. Gut microbiome modulation improves outcomes in ulcerative colitis (UC), and potassium possesses in vitro anti-inflammatory property. We evaluated the effect of CW as an adjunct therapy for patients with mild-moderate UC. METHODS: This single-center, double-blind, placebo-controlled trial randomized patients with mild to moderate (Simple Clinical Colitis Activity Index [SCCAI]: 3-9) endoscopically active UC (Ulcerative Colitis Endoscopic Index of Severity [UCEIS] >1) in 1:1 ratio to CW + standard medical therapy (SMT) vs placebo + SMT. Four hundred mL of CW was administered for 8 weeks. Primary outcome measure was clinical remission (SCCAI ≤2), and secondary outcome measures were clinical response (SCCAI decline ≥3) and adverse events at 8 weeks. Microbiome was analyzed at baseline and 8 weeks. RESULTS: Of 121 patients screened, 95 were included for modified intention to treat analysis (CW, n = 49; placebo, n = 46) (mean age, 37.2 ± 11.2 years; males, 54.1%; disease duration, 48 months [interquartile range (IQR), 24-90 months]; pancolitis, 26.1%; SCCAI, 5 [IQR, 4-6]; UCEIS, 4 [IQR, 3-5]). Clinical response (57.1% vs 28.3%; odds ratio [OR], 3.4; 95% confidence interval [CI], 1.4-7.9; P = .01), remission (53.1% vs 28.3%; OR, 2.9; 95% CI, 1.2-6.7; P = .02), and proportion of patients with fecal calprotectin (FCP) <150 µg/g (30.6% vs 6.5%; OR, 6.3; 95% CI, 1.7-23.6; P = .003) were significantly higher in CW. The relative abundance of bacterial taxa that had a significant or trend towards negative correlation with SCCAI, UCEIS, or FCP increased at 8 weeks in CW, and this effect was independent of disease activity and dietary fiber. Adverse events were comparable, and no patient developed hyperkalemia. CONCLUSIONS: CW was more effective than placebo for induction of clinical remission in patients with mild to moderate UC. The trial was prospectively registered on Clinical Trials Registry of India (ctri.nic.in, Number: CTRI/2019/03/01827).

Impact of delay in the diagnosis on the severity of celiac disease.

BACKGROUND AND AIM: Celiac disease (CeD) has now become a global disease with a worldwide prevalence of 0.67%. Despite being a common disease, CeD is often not diagnosed and there is a significant delay in its diagnosis. We reviewed the impact of the delay in the diagnosis on the severity of manifestations of CeD. METHODS: We reviewed clinical records of 726 consecutive patients with CeD from the Celiac Clinic database and the National Celiac Disease Consortium database. We extracted specific data including the demographics, symptoms at presentation, time of onset of symptoms, time to diagnosis from the onset of the symptoms, and relevant clinical data including fold-rise in anti-tissue transglutaminase antibody (IgA anti-tTG Ab) and severity of villous and crypt abnormalities as assessed using modified Marsh classification. RESULTS: The median duration between the onset of symptoms and the diagnosis of CeD was 27 months (interquartile range 12-60 months). A longer delay in the diagnosis of CeD from the onset of symptoms was associated with lower height for age, lower hemoglobin, higher fold rise in IgA Anti tTG titers, and higher severity of villous and crypt abnormalities. About 18% of patients presented with predominantly non-gastrointestinal complaints and had a longer delay in the diagnosis of CeD. CONCLUSIONS: There is a significant delay in the diagnosis of CeD since the onset of its symptoms. The severity of celiac disease increases with increasing delay in its diagnosis. There is a need to keep a low threshold for the diagnosis of CeD in appropriate clinical settings.