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Chronic noncancer pain (CNCP) affects up to 20% of adults and can interfere with activities of daily living. Up to 4% of adults in the United States receive chronic opioid therapy and up to 57% of patients on long-term opioids for CNCP report opioid-induced constipation (OIC). OIC is essentially constipation occurring after starting opioid treatment. While laxatives are traditionally the first-line therapy for OIC, 81% of patients taking daily laxatives and opioids still reported OIC and considered that it negatively affected their quality of life. Naldemedine is a peripherally acting µ-opioid receptor antagonists (PAMORA) approved for the treatment of OIC in patients with CNCP. This article reviews the mechanism of action, efficacy, and safety of naldemedine in CNCP patients. Naldemedine improves OIC in patients with CNCP by acting as an opioid receptor antagonist in the gastrointestinal tract. It does not interfere with the analgesic properties of opioids or cause withdrawal symptoms since these effects are centrally mediated, and naldemedine does not cross the blood brain barrier. Naldemedine showed significant and sustained improvement in frequency of bowel movements, quality of life, and constipation-related symptoms. It is generally well tolerated with a higher incidence of gastrointestinal adverse events of mild or moderate severity such as diarrhea, abdominal pain, or vomiting compared to placebo. While there are no randomized, controlled trials that compare head-to-head pharmacological therapies used for treatment of OIC, network meta-analysis shows that naldemedine has an overall good benefit-risk profile compared to the other approved medications.

AbstractBackgroundRecent studies with functional endoluminal imaging probe (EndoFLIP®) measure physiologic characteristics of the pylorus. EndoFLIP® has the potential to select optimal candidates for gastric peroral endoscopic myotomy (G‐POEM). Normative values of the pylorus using EndoFLIP® have not been established.MethodsTwenty‐four healthy volunteers (20–56 years old; 15 females) underwent unsedated, transoral EndoFLIP® measurements of the pylorus after 8 h of fasting. Measurements of diameter (DM), balloon pressure, and distensibility index (DI) of the pylorus were obtained twice over 5 min at 40, 50, and 60 ml balloon distensions.Key ResultsPyloric DM at 40, 50, and 60 ml balloon distensions were 13.0 ± 2.5, 14.3 ± 1.8, and 17.2 ± 2.0 mm, respectively. DM with 60 ml distension was notably higher than with 40 and 50 ml distensions. Pyloric DI at 40, 50, and 60 ml distensions were 10.9 ± 4.8, 11.3 ± 5.8, and 11.1 ± 4.3 mm2/mm Hg, respectively (p = 0.86). Linear regression and Bland–Altman plots showed similar distribution of the DM and DI during the second minute compared with the full 5‐min measurements at 50 ml distension, as well as between two sequential measurements using 50 ml distension. With 50 ml balloon distension, intraindividual coefficients of variation (COVintra) for DM and DI were 13.8% and 29.6%, respectively, and interindividual COV (COVinter) were 12.6% and 51.3%, respectively. Similar reproducibility was obtained with 40 ml balloon distension.Conclusions and InferencesUnsedated EndoFLIP® can be used to characterize human fasting pyloric diameter and distensibility, with best performance observed with 40 ml and 50 ml distensions and data collection during the second minute. Normative values reported serve as reference values for future studies.

Bile acids are amphipathic, detergent molecules. The detergent effects of di-α-hydroxy-bile acids are relevant to several colonic diseases. The aims were to review the concentrations of bile acids reaching the human colon in health and disease, the molecular structure of bile acids that determine detergent functions and the relationship to human diseases (neuroendocrine tumors, microscopic colitis, active celiac disease, and ulcerative colitis, Crohn’s disease and ileal resection), the relationship to bacterial uptake into the mucosa, mucin depletion, and epithelial damage, the role of bile acids in mucosal inflammation and microscopic colitis, and the role of sulfation of bile salts in detoxification or prevention of the detergent effects of bile acids. The concentrations of bile acids reaching the human colon range from 2 to 10 mM; di-α-hydroxy bile acids are the only bile acids with detergent effects that include mucin depletion, mucosal damage, bacterial uptake, and microscopic inflammation that may be manifest in diseases associated with no overt inflammation of the mucosa, such as bile acid diarrhea, ileal diseases such as neuroendocrine tumors, ileal resection, and nonalcoholic steatohepatitis. Sulfation inactivates colonic secretion due to primary bile acids, but it may render secondary bile acids proinflammatory in the colon. Other evidence in preclinical models of inflammatory bowel disease (IBD) suggests reduced sulfation causes barrier dysfunction, inflammation, or carcinogenesis. These advances emphasize relevance and opportunities afforded by greater understanding of the chemistry and metabolism of bile acids, which stands to be further enhanced by research into the metabolic interactions of microbiota with bile acids.

Abstract Background and Aim Elobixibat is a locally acting inhibitor of the ileal bile acid transporter. We compared bile acid metabolism between healthy subjects and patients with chronic constipation and assessed changes in the bile acid profile after elobixibat administration in the latter group. Methods Healthy subjects ( n = 10) and patients with chronic constipation ( n = 19) were assessed as inpatients for 7 days, during which they received meals containing ~60 g/day of fat. Patients with chronic constipation remained as inpatients for a further 7 days for once‐daily elobixibat administration. Assessments included concentrations of fecal and serum bile acids, serum 7α‐hydroxy‐4‐cholesten‐3‐one (C4) and fibroblast growth factor 19, and bowel movements and constipation symptoms. Results Fecal total and primary bile acids were significantly lower in patients with chronic constipation versus healthy subjects. Serum C4 and fibroblast growth factor 19 levels were comparable between groups. Elobixibat treatment increased fecal total and primary bile acids and decreased levels of fecal lithocholic acid and serum total as well as secondary bile acids in patients with chronic constipation. Bowel movements and other constipation‐related symptoms were also improved by elobixibat to levels almost comparable with those of healthy subjects. Conclusions Despite comparable C4 levels, patients with chronic constipation demonstrated decreased levels of fecal bile acids versus healthy subjects. Elobixibat treatment increased fecal bile acid excretion and reduced serum bile acid concentrations. The improvement of constipation after elobixibat treatment was associated with increased total bile acids, particularly primary bile acids.

Abstract Background Most prevalent gastrointestinal symptoms in multiple sclerosis (MS) relate to lower bowel dysfunction, often in association with bladder manifestations. Objective To assess clinical and objective gastrointestinal motor dysfunctions in patients with MS. Methods This was a single‐center, retrospective study of 166 patients evaluated between 1996 and 2020. We reviewed characterization of the MS, gastrointestinal and neurological symptoms, measurements of gastrointestinal and colonic transit, and anorectal manometry. Key Results At the time of the gastrointestinal evaluations of the 166 patients with MS (138 women; 83%), 111 were in the relapsing‐remitting phase and 52 were in the progressive phase. In 3 patients, disease phase was not assigned due to insufficient data. Constipation was identified in 82% (136/166) of patients. Most [103/116 (88%)] patients with bladder symptoms also had constipation or fecal incontinence. Delayed gastric emptying at 4 h and colonic transit at 24 h was identified in 16% and 7% of the cohort, respectively; 22% had accelerated gastric emptying. On anorectal manometry, resting anal sphincter pressure >90 mm Hg and rectoanal pressure differential below −50mm Hg suggested evacuation disorder in patients with constipation. Conclusions and Inferences In addition to slow colonic transit and anorectal dysfunction leading to constipation in MS, 22% of patients had accelerated gastric emptying.

AbstractPain relief remains a significant challenge in the management of irritable bowel syndrome (IBS): “Does anything really help relieve the pain in patients with IBS?”. Interventions aimed at pain relief in patients with IBS include diet, probiotics or antibiotics, antidepressants, antispasmodics, and drugs targeting specific gastrointestinal receptors such as opioid or histamine receptors. In the systematic review and meta‐analysis published in this journal, Lambarth et al. examined the literature on the role of oral and parenteral anti‐neuropathic agents in the management of pain in patients with IBS. This review article appraises their assessment of the efficacy of the anti‐neuropathic agents amitriptyline, pregabalin, gabapentin, and duloxetine in the relief of abdominal pain or discomfort, and impact on overall IBS severity and quality of life. This commentary provides an update of current evidence on the efficacy of the dietary and pharmacological treatments that are available or in development, as well psychological and cognitive behavioral therapy for pain in IBS. Advances in recent years augur well for efficacious treatments that may expand the therapeutic arsenal for pain in IBS.

AbstractBackgroundCertain autoimmune bullous dermatoses are mediated by autoantibodies of the IgG4 subclass. We determined the diagnostic impact of adding IgG4 to our conventional direct immunofluorescence (DIF) panel.MethodsFor all cases submitted to our referral laboratory for DIF over 1 month (n = 630), we performed IgG4 testing and collected consecutive biopsy specimens showing definite or indeterminate linear or cell‐surface deposition of IgG, IgG4, and/or C3. On retrospective blinded review, we classified the pattern and whether the findings were definite, indeterminate, or negative. When present, substantial background staining was recorded.ResultsSeventy DIF specimens met the inclusion criteria. Of 22 (31.4%) specimens equivocal for linear or cell‐surface deposition, 9 (40.9%) had definitive IgG4 findings, either linear (3 of 14 equivocal linear cases; 21.4%) or cell‐surface (6 of 8 equivocal cell‐surface cases; 75.0%). Background deposition was substantial in 14 cases (20.0%) for IgG but in none for C3 or IgG4.ConclusionIgG4 allowed the classification of over 40% of DIF cases that were otherwise equivocal by IgG and C3. IgG4 staining showed lower levels of non‐specific background staining than IgG or C3. IgG4 appears to contribute most value in cases with cell‐surface deposition or with equivocal linear IgG deposition and negative C3 results.

ABSTRACTBackgroundBile acids are central to enterohepatic signaling pathways activated through natural receptors, farnesoid X receptor [FXR mediates synthesis of fibroblast growth factor‐19 (FGF‐19)], and G protein‐coupled bile acid receptor 1 (GPBAR1, also known as TGR5). Although bile acid diarrhea (BAD) is more commonly encountered in ileal resection or disease, there is evidence documenting “idiopathic” BAD in about 20% of adolescents and 30% of adults presenting with chronic, non‐bloody diarrhea often attributed to irritable bowel syndrome. Mechanism(s) leading to increased hepatic synthesis and colonic bile acid levels in “idiopathic” BAD include reduced synthesis of FGF‐19 by the ileal mucosa, or genetic variation in hepatocyte proteins klotho β and FGF receptor 4 (FGFR4) that mediate negative feedback of bile acid synthesis. Purpose: The objective of this review is to summarize the diagnosis of BAD in adults and adolescents. In addition to 75SeHCAT retention for diagnosis of BAD, studies have validated fasting serum 7αC4 and FGF‐19, respectively, by‐product and inhibitor of hepatic bile acid synthesis, as well as fecal bile acid measurements. These assays are widely available through reference laboratories, and they are being simplified (eg, measurement of primary fecal bile acids in a random stool sample). BAD has also been identified as a co‐factor contributing to persistent diarrhea in other diseases in remission including inflammatory bowel disease, microscopic colitis, celiac disease, and neuroendocrine tumors. In summary, advances in diagnosis of BAD provide opportunities for generalists and pediatric and adult gastroenterologists to provide targeted treatment for BAD presenting as chronic non‐bloody diarrhea.

Abstract Background Adipose-derived mesenchymal stromal cells (AMSCs) represent attractive cellular therapeutics for treatment of various diseases including osteoarthritis and bone degeneration. Preparation and characterization of AMSCs show donor-to-donor variability that indicating that AMSCs are heterogeneous populations of cells. Cell surface markers to identify MSCs, such as CD44, CD90, and CD105, are relatively invariable among AMSCs and do not reflect the heterogeneity of AMSC populations. CD36, a multifunctional surface receptor associated with transport of oxidized low-density lipoproteins and fatty acids, is also expressed by AMSCs but this marker is considerable more variable. Therefore, we assessed whether CD36 can be used to identify subpopulations in AMSCs. Methods Clinical-grade AMSCs were isolated from patient fat biopsies, cultured under xenobiotic-free conditions using human platelet lysate and sorted by flow cytometry or magnetic cell sorting to characterize CD36 expression. CD36 enriched, CD36 depleted, and unsorted AMSCs were characterized using cellular and molecular techniques including proliferation, multilineage potential, RNA-sequencing and bioinformatics, metabolomics, and sensitivity to the CD36 inhibitor sulfosuccinimidyl oleate (SSO). Results CD36 exhibited biphasic expression on AMSCs grown in human platelet lysate. Enrichment of CD36+ AMSCs showed that CD36+ expression identifies a stable subpopulation. Transcriptomic analysis revealed enhancement of calcium transporter genes. Osteogenic differentiation of CD36+ enriched, CD36+ depleted, and unsorted AMSCs showed strikingly enhanced osteogenic calcium deposition and enhanced expression of alkaline phosphatase (ALPL) and osteoprotegrin (TNFRSF11B) in the CD36+ population. While lipid droplets were not altered, adipogenic differentiation showed upregulated gene expression of key adipogenic markers, including fatty acid-binding protein 4 (FABP4) and Adiponectin (ADIPOQ), with CD36+ enrichment. Treatment of CD36+ enriched AMSCs with the SSO showed reduced calcium deposition whereas CD36+ depleted AMSCs were unaffected. Conclusions CD36 exhibits variable expression amongst AMSCs. CD36+ enriched AMSCs are a stable subpopulation with enhanced osteogenic potential that linked to CD36 receptor function. These results may further refine production and clinical application of AMSC cellular therapeutics. Furthermore, the enhanced osteogenic potential of CD36+ AMSCs may be considered for therapeutic regeneration of bone.