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).

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.

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.

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.