Ibironke Oduyebo

Chemical and Molecular Factors in Irritable Bowel Syndrome: Current Knowledge, Challenges and Unanswered Questions.

Several chemical and molecular factors in the intestine are reported to be altered and to have a potentially significant role in irritable bowel syndrome (IBS), particularly in IBS with diarrhea. These include bile acids; short-chain fatty acids; mucosal barrier proteins; mast cell products such as histamine, proteases, and tryptase; enteroendocrine cell products; and mucosal mRNAs, proteins, and microRNAs. This article reviews the current knowledge and unanswered questions in the pathobiology of the chemical and molecular factors in IBS. Evidence continues to point to significant roles in pathogenesis of these chemical and molecular mechanisms, which may therefore constitute potential targets for future research and therapy. However, it is still necessary to address the interaction between these factors in the gut and to appraise how they may influence hypervigilance in the central nervous system in patients with IBS.

Bile acid disease: the emerging epidemic

Purpose of review Our objective was to review advances in bile acids in health and disease published in the last 2 years. Bile acid diarrhea (BAD) is recognized as a common cause of chronic diarrhea, and its recognition has been facilitated by development of new screening tests. Recent findings Primary BAD can account for 30% of cases of chronic diarrhea. The mechanisms leading to BAD include inadequate feedback regulation by fibroblast growth factor 19 (FGF-19) from ileal enterocytes, abnormalities in synthesis or degradation of proteins involved in FGF-19 regulation in hepatocytes and variations as a function of the bile acid receptor, TGR5 (GPBAR1). 75SeHCAT is the most widely used test for diagnosis of BAD. There has been significant validation of fasting serum FGF-19 and 7 &agr;-hydroxy-cholesten-3-one (C4), a surrogate measure of bile acid synthesis. Bile acid sequestrants are the primary treatments for BAD; the farnesoid X-receptor-FGF-19 pathway provides alternative therapeutic targets for BAD. Bile acid-stimulated intestinal mechanisms contribute to the beneficial effects of bariatric surgery on obesity, glycemic control and the treatment of recurrent Clostridium difficile infection. Summary Renewed interest in the role of bile acids is leading to novel management of diverse diseases besides BAD.

Relationship of gastric emptying or accommodation with satiation, satiety, and postprandial symptoms in health

The contributions of gastric emptying (GE) and gastric accommodation (GA) to satiation, satiety, and postprandial symptoms remain unclear. We aimed to evaluate the relationships between GA or GE with satiation, satiety, and postprandial symptoms in healthy overweight or obese volunteers (total n = 285, 73% women, mean BMI 33.5 kg/m2): 26 prospectively studied obese, otherwise healthy participants and 259 healthy subjects with previous similar GI testing. We assessed GE of solids, gastric volumes, calorie intake at buffet meal, and satiation by measuring volume to comfortable fullness (VTF) and maximum tolerated volume (MTV) by using Ensure nutrient drink test (30 ml/min) and symptoms 30 min after MTV. Relationships between GE or GA with satiety, satiation, and symptoms were analyzed using Spearman rank (rs ) and Pearson (R) linear correlation coefficients. We found a higher VTF during satiation test correlated with a higher calorie intake at ad libitum buffet meal (rs = 0.535, P < 0.001). There was a significant inverse correlation between gastric half-emptying time (GE T1/2) and VTF (rs = -0.317, P < 0.001) and the calorie intake at buffet meal (rs = -0.329, P < 0.001), and an inverse correlation between GE Tlag and GE25% emptied with VTF (rs = -0.273, P < 0.001 and rs = -0.248, P < 0.001, respectively). GE T1/2 was significantly associated with satiation (MTV, R = -0.234, P < 0.0001), nausea (R = 0.145, P = 0.023), pain (R = 0.149, P = 0.012), and higher aggregate symptom score (R = 0.132, P = 0.026). There was no significant correlation between GA and satiation, satiety, postprandial symptoms, or GE. We concluded that GE of solids, rather than GA, is associated with postprandial symptoms, satiation, and satiety in healthy participants.NEW & NOTEWORTHY A higher volume to comfortable fullness postprandially correlated with a higher calorie intake at ad libitum buffet meal. Gastric emptying of solids is correlated to satiation (volume to fullness and maximum tolerated volume) and satiety (the calorie intake at buffet meal) and symptoms of nausea, pain, and aggregate symptom score after a fully satiating meal. There was no significant correlation between gastric accommodation and either satiation or satiety indices, postprandial symptoms, or gastric emptying.

Biomarkers as a diagnostic tool for irritable bowel syndrome: where are we?

ABSTRACT Introduction: Irritable bowel syndrome (IBS) is a common condition in clinical practice. There are currently no objective tests to rule in the disease, but rather tests to rule out other diseases. Biomarkers in IBS may provide the tools needed for diagnosis, prognosis and therapy. These include identification of differences in microbial composition, immune activation, bile acid composition, colonic transit, and alteration in sensation in subgroups of IBS patients. Areas covered: Studies included in our review were chosen based on a PubMed search for ‘biomarkers’ and ‘IBS’. We have reviewed the literature on biomarkers to appraise their accuracy, validity and whether they are actionable. We have not covered genetic associations as biomarkers in this review. Expert commentary: There is significant promise in the usefulness of biomarkers for IBS. The most promising actionable biomarkers are markers of changes in bile acid balance, such as elevated bile acid in the stool, and altered colonic transit. However, there is also potential for microbial studies and mucosal proteases as future actionable biomarkers.

Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial

OBJECTIVE: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose‐related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC). METHODS: Two‐dose NGM282 (1 and 6 mg, subcutaneously daily), parallel‐group, randomized, placebocontrolled, 14‐day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4, and TGR5 (GPBAR1). Statistical analysis: overall ANCOVA at &agr; = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (&agr; = 0.008). RESULTS: Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose‐related effects were seen with GC 24 h, but not with gastric emptying (GE) and GC 48 h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n = 0 with placebo, 2 with 1 mg, 9 with 6 mg), injection site reaction (n = 2 placebo, 4 with 1 mg, 8 with 6 mg), and diarrhea (n = 1 with 1 mg and 4 with 6 mg NGM282). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p = 0.056). CONCLUSION: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.

Effects of naloxegol on whole gut transit in opioid-naïve healthy subjects receiving codeine: A randomized, controlled trial

Nausea, vomiting, and constipation (OIC) are common adverse effects of acute or chronic opioid use. Naloxegol (25 mg) is an approved peripherally active mu‐opiate opioid receptor antagonist.