Camilleri, Michael

Altered intestinal permeability plays a role in many pathological conditions. Intestinal permeability is a component of the intestinal barrier. This barrier is a dynamic interface between the body and the food and pathogens that enter the gastrointestinal tract. Therefore, dietary components can directly affect this interface, and many metabolites produced by the host enzymes or the gut microbiota can act as signaling molecules or exert direct effects on this barrier. Our aim was to examine the effects of diet components on the intestinal barrier in health and disease states. Herein, we conducted an in-depth PubMed search based on specific key words (diet, permeability, barrier, health, disease, and disorder), as well as cross references from those articles. The normal intestinal barrier consists of multiple components in the lumen, epithelial cell layer and the lamina propria. Diverse methods are available to measure intestinal permeability. We focus predominantly on human in vivo studies, and the literature is reviewed to identify dietary factors that decrease (e.g., emulsifiers, surfactants, and alcohol) or increase (e.g., fiber, short-chain fatty acids, glutamine, and vitamin D) barrier integrity. Effects of these dietary items in disease states, such as metabolic syndrome, liver disease, or colitis are documented as examples of barrier dysfunction in the multifactorial diseases. Effects of diet on intestinal barrier function are associated with precise mechanisms in some instances; further research of those mechanisms has potential to clarify the role of dietary interventions in treating diverse pathologic states.

AbstractA sequence of consensus‐based Rome criteria for irritable bowel syndrome (IBS) has been published since 1989. The fundamental definition based on abdominal pain in association with bowel dysfunction has been consistent. However, two major changes occurred in the Rome II and IV criteria. The former change involved “splitting off” of symptoms that were not consistently associated with pain, such as functional, constipation, diarrhea, and bloating. In Rome IV, the main changes were the exclusion of discomfort (in contrast to pain) and the more stringent frequency criteria for the pain to be eligible for diagnosis of IBS (specifically, on average, at least 1 day per week in the last 3 months). Validation studies of the consensus, symptom‐based criteria have identified multiple deficiencies that question the rationale for “splitting” the different syndromes, and favor a simpler identification of the classical symptoms of abdominal pain, bowel dysfunction, and bloating, and exclusion of alarm symptoms. Advances in the identification of actionable biomarkers related to the symptoms suggestive of functional gastrointestinal disorders have the potential to usher a change in practice from positive diagnosis of symptom complexes followed by empirical treatment to identification of the mechanisms causing the symptoms and targeted therapy.

AbstractAbstractThere are ten good reasons why it is important to think about abnormalities in bile acid control in inflammatory bowel disease. Before reviewing these reasons, it is relevant to review essential elements in the enterohepatic circulation, synthesis and actions of bile acids.

Goals: To evaluate the diagnostic yield of colonoscopy and esophagogastroduodenoscopy with biopsies and to identify predictors of positive colonic histology in patients with chronic diarrhea. Background: Colonoscopy with biopsies is performed in chronic diarrhea with negative initial work-up. Study: We reviewed electronic medical records of 1022 consecutive patients with chronic diarrhea referred for a first colonoscopy (including 25% open-access referrals). Predictors of positive colonic histology were investigated using logistic regression. Results: Four hundred thirteen patients with macroscopically normal colon were divided into derivation (n=275) and validation (n=138) cohorts. All patients underwent colonoscopy; 369 had ileoscopy (biopsies in 43%), and 289 underwent esophagogastroduodenoscopy (duodenal biopsies in 93%). In patients with endoscopically normal colon, histology was positive in 13.3%: 10.6% microscopic colitis; 1.5% other colitides. Among 358 patients with negative histology, the recorded diagnoses were: 48% unexplained, 25% irritable bowel syndrome, 5.6% small intestinal bacterial overgrowth, and 4.7% bile acid diarrhea. The rates of diagnoses based on positive histologies were 4% for ileal and 5% for duodenal biopsies. Older age [odds ratio (OR)=1.05] was a positive predictor, whereas body mass index (OR=0.93) and duration of diarrhea (OR=0.98) were negative predictors of positive histology. A clinical diagnostic scoring system could correctly predict 41% to 54% of patients with normal colonic histology, with a false-negative rate of 0.8% to 2.6% and a negative predictive value of 95% to 98%. Conclusions: Positive colonic biopsies were detected in <15% of patients with chronic diarrhea with normal colonoscopy; a clinical score correctly predicts likelihood of normal histology in about half the patients.

SummaryBackgroundIn primary bile acid diarrhoea, feedback by farnesoid X receptor (FXR) and fibroblast growth hormone 19 (FGF19) on hepatic bile acid production is impaired.AimsTo evaluate the safety, mechanisms and efficacy of negative feedback by FXR activation with tropifexor, a non‐bile acid FXR agonist, in patients with primary bile acid diarrhoea.MethodsIn this double‐blind, multicentre, randomised, cross‐over study, patients received tropifexor 60 µg or placebo once daily for 14 days in each of two treatment periods. Primary objectives included tropifexor safety and tolerability, and on stool frequency and form. Other assessments included pharmacokinetic and pharmacodynamic measures, biochemical markers and gastrointestinal transit.ResultsTwenty patients (tropifexor 60 µg/placebo [N = 10]; placebo/tropifexor 60 µg [N = 10]) were enrolled. Adverse event rates were lower with tropifexor vs placebo (52.9% vs 73.7%). No patient had pruritus during tropifexor intake. There were no significant differences in stool frequency, stool form or loperamide use between treatments. Tropifexor increased FGF19 and decreased 7α‐hydroxy‐4‐cholesten‐3‐one (C4) levels for up to 8 h. Plasma tropifexor concentrations peaked at 5 hours post‐dose on days 1 and 12. At day 12, tropifexor caused reduction in peak total bile acid concentration (33%, P = 0.032) and exposure (36%, P = 0.005). Moreover, tropifexor showed a significant increase in ascending colon half‐emptying time (P = 0.036).ConclusionsTropifexor 60 µg once daily had acceptable safety and tolerability. Changes in FGF19 and C4 showed effective target engagement; however, higher doses may be required to observe stool frequency changes. Slowing of ascending colon emptying suggests therapeutic potential of tropifexor in patients with primary bile acid diarrhoea.ClinicalTrials.gov number: NCT02713243.

SummaryBackgroundElobixibat, a novel inhibitor of apical sodium‐dependent bile acid transporter for treating chronic constipation, increases colonic bile acid concentrations, stimulating bowel function. However, it is not clear which bile acids are altered, or whether altered gut microbiota are associated with functional effects that may alter bowel function.AimsTo investigate the effects of elobixibat on changes in the faecal concentrations of total and individual bile acids and in faecal microbiota.MethodsThis was a prospective, single‐centre study. After baseline period, patients received 10 mg daily of elobixibat for 2 weeks. We evaluated the effects on bowel function, changes in faecal bile acid concentrations and composition of gut bacteria, before and after elobixibat administration.ResultsIn the 30 patients analysed, the frequency of pre‐ and post‐treatment bowel movements per fortnight was 7 and 10 (P < 0.001), respectively. The pre‐treatment faecal bile acid concentration increased significantly from 10.9 to 15.0 µg/g stool post‐treatment (P = 0.030), with a significant increase in faecal deoxycholic acid (pre‐treatment 3.94 µg/g stool to post‐treatment 5.02 µg/g stool, P = 0.036) and in glycine‐conjugated deoxycholic and chenodeoxycholic acids. Shannon index was significantly decreased, but there were no significant changes at the genus and phylum levels.ConclusionsShort term treatment with elobixibat increased the concentrations of total bile acids and deoxycholic acid and decreased the diversity of faecal microbiota. The biological effects of elobixibat are associated with its effects on secretory bile acids, rather than the structural changes of an altered faecal microbiota.

AbstractThe microscopic features of patch stage Kaposi sarcoma (KS) and interstitial granuloma annulare (GA) may be difficult to differentiate, because both may exhibit a subtle “busy” dermis due to infiltration of spindled cells between collagen bundles. The clinical distinction is particularly challenging in human immunodeficiency virus (HIV)‐affected individuals, as the incidence of GA appears to be greater in the HIV‐infected population. KS is the most common neoplasm in this population. Despite the significant decrease in the incidence of KS since the advent of highly active antiretroviral therapy (HAART), KS tends to occur with late onset and indolent progression in patients with preserved immune function and minimal viral load. We present a 47‐year‐old homosexual HIV‐positive man, under virologic and immunologic control on long‐term HAART therapy, with a 5‐year history of progressive red‐brown patches and plaques on the legs, feet, hands, and trunk. Prior skin biopsy specimens were interpreted as interstitial GA. Histopathology on new skin biopsy specimens along with review specimens supported the diagnosis of plaque and patch stages of KS, respectively, supported by immunohistochemical expression of human herpes virus‐8 (HHV‐8). This case underscores the importance of maintaining a high suspicion for KS in progressive, treatment‐recalcitrant skin lesions, particularly in HIV‐infected individuals.

LINKED CONTENTThis article is linked to Camilleri et al and Hasler papers. To view these articles, visit https://doi.org/10.1111/apt.15711 and https://doi.org/10.1111/apt.15792.