Publications by authors named "Michael Camilleri"

639 Publications

ACG Clinical Guideline: Gastroparesis.

Am J Gastroenterol 2022 Aug 3;117(8):1197-1220. Epub 2022 Jun 3.

University of Louisville, Louisville, Kentucky, USA.

Gastroparesis is characterized by symptoms suggesting retention of food in the stomach with objective evidence of delayed gastric emptying in the absence of mechanical obstruction in the gastric outflow. This condition is increasingly encountered in clinical practice. These guidelines summarize perspectives on the risk factors, diagnosis, and management of gastroparesis in adults (including dietary, pharmacological, device, and interventions directed at the pylorus), and they represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation process. When the evidence was not appropriate for Grading of Recommendations, Assessment, Development, and Evaluation, we used expert consensus to develop key concept statements. These guidelines should be considered as preferred but are not the only approaches to these conditions.
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http://dx.doi.org/10.14309/ajg.0000000000001874DOI Listing
August 2022

Effects of liraglutide on gastrointestinal functions and weight in obesity: A randomized clinical and pharmacogenomic trial.

Obesity (Silver Spring) 2022 08;30(8):1608-1620

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Objective: This study aimed to determine the effects of a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, and placebo subcutaneously over 16 weeks on weight and gastric functions and to evaluate associations of single-nucleotide polymorphisms in GLP1R (rs6923761) and TCF7L2 (rs7903146) with effects of liraglutide.

Methods: The study conducted a randomized, parallel-group, placebo-controlled, 16-week trial of liraglutide, escalated to 3 mg subcutaneously daily in 136 otherwise healthy adults with obesity. Weight, gastric emptying of solids (GES), gastric volumes, satiation, and body composition measured at baseline and after treatment were compared in two treatment groups using analysis of covariance.

Results: Liraglutide (n = 59) and placebo (n = 65) groups completed treatment. Relative to placebo, liraglutide increased weight loss at 5 and 16 weeks (both p < 0.05), slowed time to half GES (T ) at 5 and 16 weeks (both p < 0.001), and increased fasting gastric volume (p = 0.01) and satiation (p < 0.01) at 16 weeks. GES T was positively correlated with weight loss on liraglutide (both p < 0.001). After 16 weeks of liraglutide, GLP1R rs6923761 (AG/AA vs. GG) was associated with reduced percent body fat (p = 0.062), and TCF7L2 rs7903146 (CC vs. CT/TT) was associated with lower body weight (p = 0.015).

Conclusions: Liraglutide, 3 mg, induces weight loss with delay in GES T and reduces calorie intake. Slowing GES and variations in GLP1R and TCF7L2 are associated with liraglutide effects in obesity.
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http://dx.doi.org/10.1002/oby.23481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9335902PMC
August 2022

Fifty-point IBS-SSS responders but persistence of moderate severity IBS in over 40% of those on diet.

Gut 2022 Jul 26. Epub 2022 Jul 26.

Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA

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http://dx.doi.org/10.1136/gutjnl-2022-328211DOI Listing
July 2022

Association between CYP metabolizer phenotypes and selective serotonin reuptake inhibitors induced weight gain: a retrospective cohort study.

BMC Med 2022 07 26;20(1):261. Epub 2022 Jul 26.

Precision Medicine for Obesity Program and Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.

Background: Prescription medications such as selective serotonin reuptake inhibitors (SSRIs), commonly used to treat depression, are associated with weight gain. The role of pharmacogenomics in predicting SSRI-induced weight gain is unclear.

Methods: In this retrospective cohort study from participants in the Mayo Clinic RIGHT study who were prescribed citalopram, paroxetine, sertraline, or fluoxetine, our aim was to evaluate the association of metabolizer phenotype and total body weight after 6 months of SSRIs initiation. We evaluated the metabolizer phenotypes (poor/intermediate, normal, and rapid/ultra-rapid) of the cytochromes P450 enzymes genes: CYP2C9, CYP2C19, and CYP2D6 known to influence the metabolism of SSRI medications: CYP2C19 for citalopram, CYP2D6 for paroxetine, CYP2D6 and CYP2C19 for sertraline, and CYP2D6 and CYP2C9 fluoxetine. In addition, we assessed the association of metabolizer phenotype and total body weight change at six months following SSRI prescription using parametric analysis of covariance adjusted for baseline body weight and multivariate regression models.

Results: CYP2C19 poor/intermediate metabolizers prescribed citalopram gained significantly more weight than normal or rapid/ultra-rapid metabolizers at 6 months (TBWG %: 2.6 [95% CI 1.3-4.1] vs. 0.4 [95% CI -0.5 - 1.3] vs. -0.1 [-95% CI -1.5-1.1]; p = 0.001). No significant differences in weight outcomes at six months of treatment with paroxetine, sertraline, or fluoxetine were observed by metabolizer status.

Conclusions: Weight gain observed with citalopram may be mediated by CYP2C19 metabolizer status.
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http://dx.doi.org/10.1186/s12916-022-02433-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9317126PMC
July 2022

Epidemiology and Healthcare Utilization in Patients with Gastroparesis: A Systematic Review.

Clin Gastroenterol Hepatol 2022 Jul 20. Epub 2022 Jul 20.

Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, MN. Electronic address:

Aim: Systematic review of epidemiological data to understand the prevalence, incidence, etiologies, and hospitalizations related to gastroparesis (GP).

Methods: Studies of the epidemiology of GP published in all languages, years, and countries from five databases in January 2022 using prespecified search strategies.

Results: Thirteen studies (data from 1994 - 2019) were included. All but one study (from the UK) was based in USA. Prevalence of definite GP (symptoms plus delayed gastric emptying) ranged 13.8-267.7 per 100,000 adults, and incidence 1.9-6.3 per 100,000 person-years. The estimated 10-year cumulative incidence of GP in type 1 diabetes (DM) and type 2 DM was 5.2% and 1.0%, respectively. Across studies, GP was more common among females and those with DM. Rates of hospitalizations and ED visits for GP are increasing, ranging from 2- to 18-fold over approximately two decades. Mortality rates for patients with possible or definite GP were higher compared to the general population, with primary causes of death in GP being cardiovascular, respiratory failure, and malignancy. Multiple studies observed improved inpatient mortality over the mid-1990s to late-2000s. Limitations include the case identification in most studies (76.9%) utilized solely ICD codes or clinical record diagnoses; two studies (15.4%) used objective evaluation to diagnose GP. Only four studies (30.8%) used non-specialized community databases; the remaining 9 studies used inpatient, Emergency Department (ED), or disease-specific databases.

Conclusion: There is a paucity of high-quality, demographically diverse, and population-based studies to accurately describe the epidemiology of GP. Future studies with valid GE measurement are needed to better characterize the epidemiology and natural history of GP.
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http://dx.doi.org/10.1016/j.cgh.2022.07.011DOI Listing
July 2022

Comprehensive Characterization of Antral and Pyloric Contractions by High Resolution Manometry: Applied Physiology in Suspected Gastroparesis.

Am J Physiol Gastrointest Liver Physiol 2022 Jul 12. Epub 2022 Jul 12.

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States.

Delayed gastric emptying may result from diverse pathophysiological mechanisms including antral hypomotility and pylorospasm. With increasing use of gastric peroral endoscopic myotomy and preliminary evidence of efficacy, our aim was to assess the motor functions of the distal antrum and pylorus in patients with symptoms of gastroparesis using high resolution antropyloroduodenal manometry (HR-ADM). Sixteen patients with symptoms suggestive of gastroparesis underwent HR-ADM with 13 sensors, 1cm apart, placed across the antropyloroduodenal (APD) junction and 2 sensors, 10cm apart, in descending and distal duodenum. The 1-hour postprandial motility was quantitated as contraction frequency/minute, average amplitude, and motility index (MI). Six healthy volunteers served as controls. In the patient group, the HR-ADM identified postprandial antral hypomotility, isolated pyloric pressure waves, and tonic elevation of baseline pressure in pylorus. Patients had significantly reduced frequency of the full-hour postprandial antral contractions/minute compared to healthy volunteers [1.52 (0.97, 1.67) vs. 2.04 (1.70, 2.67), p=0.005], as well as reduced MI [9.65 (8.29, 10.31) vs. 11.04 (10.65, 11.63), p=0.002]. The average contraction amplitude was numerically, but not significantly reduced [51.9 (21.9, 74.9) vs. 73.0 (59.8, 82.7), p=0.14]. Bland-Altman plots showed similar distribution of antral contraction frequency and MI during the first and second postprandial 30-minute periods for both patients and controls. High resolution ADM can characterize a variety of postprandial antral contractile and pyloric motility dysfunctions. This technique shows promise to provide guidance for the selection of optimal treatment of patients with gastroparesis.
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http://dx.doi.org/10.1152/ajpgi.00119.2022DOI Listing
July 2022

Treatment of IBS Using FMT: A Step Forward?

Gastroenterology 2022 Jul 6. Epub 2022 Jul 6.

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN.

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http://dx.doi.org/10.1053/j.gastro.2022.06.087DOI Listing
July 2022

Editorial: tradipitant has promise for treating gastroparesis but leaves gastric function alone-authors' reply.

Aliment Pharmacol Ther 2022 Aug;56(3):542-543

Mayo Clinic, Rochester, Minnesota, USA.

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http://dx.doi.org/10.1111/apt.17098DOI Listing
August 2022

Histopathology of autoimmune bullous dermatoses: What's new?

Hum Pathol 2022 Jun 25. Epub 2022 Jun 25.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA; Department of Dermatology, Mayo Clinic, Rochester, MN, USA. Electronic address:

Autoimmune bullous dermatoses are characterized by the presence of tissue-bound and often circulating pathogenic autoantibodies targeting structural components of the skin and/or mucous membranes. The diagnostic workup for this heterogeneous group of disorders consists of a multi-step process, of which the light microscopic examination is a crucial component. This review is organized following a classification scheme that is based on two main histopathologic features, namely level of intraepithelial split and composition of the inflammatory infiltrate. Overall, we aim to place emphasis on the histopathologic clues that can assist pathologists in differential diagnosis and review the updates in the literature.
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http://dx.doi.org/10.1016/j.humpath.2022.06.021DOI Listing
June 2022

The Effect of Caloric Intake and Macronutrient Composition on Intestinal Cholesterol Absorption and Bile Acids in Patients with Obesity.

Am J Physiol Gastrointest Liver Physiol 2022 Jun 21. Epub 2022 Jun 21.

Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester MN, United States.

Obesity is associated with alterations in cholesterol and bile acid (BA) metabolism. However, the interaction between dietary intake, cholesterol absorption, and BA metabolism in patients with obesity remains unclear. We conducted a 4-week nutritional intervention non-randomized clinical trial with three different sequential diets for a week in the following order: Regular diet (RD), high calorie, high fat diet (HCHF), washout period on RD, and low-calorie low-fat diet (LCLF). We provided participants with meal replacements during HCHF and LCLF diets. A total of 16 participants completed the study (n=8 normal weight [NW]; n=8 with obesity [OB]). Overall, there was a significant increase in intestinal cholesterol uptake when changing from RD to HCHF and a reduction in intestinal cholesterol uptake from HCHF to LCLF. When analyzing by BMI groups, these findings were similar in patients with NW (RD to HCHF: p<0.007; HCHF to LCLF: p=0.02); however, in patients with obesity, the change in intestinal cholesterol uptake was only observed when changing from RD to HCHF (p=0.006). There was no correlation between cholesterol absorption and fecal bile acids or other markers of BA metabolism in all patients or the subgroups. Dietary caloric content had a significant effect on cholesterol absorption, however, this effect is blunted in patients with obesity. These data are consistent with the impaired effect of a low-fat diet on cholesterol absorption in obesity.
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http://dx.doi.org/10.1152/ajpgi.00108.2022DOI Listing
June 2022

Effects of Heterozygous Variants in the Leptin-Melanocortin Pathway on Roux-en-Y Gastric Bypass Outcomes: a 15-Year Case-Control Study.

Obes Surg 2022 08 3;32(8):2632-2640. Epub 2022 Jun 3.

Precision Medicine for Obesity Program, Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Charlton 8-142, 200 First St. S.W, Rochester, MN, 55902, USA.

Introduction: Heterozygous variants in the leptin-melanocortin pathway are associated with obesity. However, their effect on the long-term outcomes after Roux-en-Y gastric bypass (RYGB) is still unknown.

Methods: In this matched case-control study, 701 participants from the Mayo Clinic Biobank with a history of RYGB were genotyped. Sixty-three patients had a heterozygous variant in the leptin-melanocortin pathway. After excluding patients with potential confounders, carriers were randomly matched (on sex, age, body mass index [BMI], and years since surgery) with two non-carrier controls. The electronic medical record of carriers and matched non-carriers was reviewed for up to 15 years after RYGB.

Results: A total of 50 carriers and 100 matched non-carriers with a history of RYGB were included in the study. Seven different genes (LEPR, PCSK1, POMC, SH2B1, SRC1, MC4R, and SIM1) in the leptin-melanocortin pathway were identified. At the time of surgery, the mean age was 50.8 ± 10.6 years, BMI 45.6 ± 7.3 kg/m, and 79% women. There were no differences in postoperative years of follow-up, Roux limb length, or gastric pouch size between groups. Fifteen years after RYGB, the percentage of total body weight loss (%TBWL) in carriers was - 16.6 ± 10.7 compared with - 28.7 ± 12.9 in non-carriers (diff = 12.1%; 95% CI, 4.8 to 19.3) and the percentage of weight regain after maximum weight loss was 52.7 ± 29.7 in carriers compared with 29.8 ± 20.7 in non-carriers (diff = 22.9%; 95% CI, 5.3 to 40.5). The nadir %TBWL was lower - 32.1 ± 8.1 in carriers compared with - 36.8 ± 10.4 in non-carriers (diff = 4.8%; 95% CI 1.8 to 7.8).

Conclusions: Carriers of a heterozygous variant in the leptin-melanocortin pathway have a progressive and significant weight regain in the mid- and long-term after RYGB. Genotyping patients experiencing significant weight regain after RYGB could help implement multidisciplinary and individualized weight loss interventions to improve weight maintenance after surgery.
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http://dx.doi.org/10.1007/s11695-022-06122-9DOI Listing
August 2022

Clinical trial: a single-centre, randomised, controlled trial of tradipitant on satiation, gastric functions, and serum drug levels in healthy volunteers.

Aliment Pharmacol Ther 2022 Jul 29;56(2):224-230. Epub 2022 May 29.

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota, USA.

Background: Tradipitant, an NK1 receptor antagonist, improved symptoms in patients with gastroparesis. It is unclear whether these effects are mediated centrally (e.g., vomiting centre) or on gastric functions. As a class, NK1 antagonists may retard gastric emptying (GE) or increase fasting and postprandial gastric volumes (GV).

Aim: To evaluate the effects of tradipitant relative to placebo on gastric motor functions, satiation, postprandial symptoms, and pharmacokinetics.

Methods: We conducted a randomised, double-blind, placebo-controlled, single-centre study of tradipitant 85 mg or matching placebo b.i.d. for 9 consecutive days in 24 healthy volunteers. During the last 2 days of treatment, participants underwent scintigraphic measurements of GE of 320 kcal egg meal, fasting and postprandial GV by SPECT, and satiation by nutrient drink ingested to maximum tolerated volume (MTV) and symptoms 30 min later. Treatments were compared by Wilcoxon rank sum test. The study had 80% power to detect group differences of 23.6% in GV and 29.2% in GE T .

Results: The two groups of healthy participants were well balanced based on demographic features, age, and BMI. There were nonsignificant positive correlations between blood levels of tradipitant and accommodation GV and GE at 4 h. There were no significant effects of tradipitant, 85 mg b.i.d. for 9 days compared to placebo on GE, GV, satiation, or symptoms 30 min after MTV.

Conclusion: Tradipitant, 85 mg b.i.d., does not significantly affect gastric motor functions (GV or GE). Importantly, there was no retardation of GE by tradipitant, which is important in relation to its potential use in patients with gastroparesis.

Clinic Trials Registry: ClinicalTrials.gov #NCT04849559.
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http://dx.doi.org/10.1111/apt.17065DOI Listing
July 2022

Choosing G-POEM or other treatments for gastroparesis.

Gut 2022 May 23. Epub 2022 May 23.

Gastroenterology, Mayo Clinic, Rochester, Minnesota, USA

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http://dx.doi.org/10.1136/gutjnl-2022-327545DOI Listing
May 2022

Comparison of biochemical, microbial and mucosal mRNA expression in bile acid diarrhoea and irritable bowel syndrome with diarrhoea.

Gut 2022 May 17. Epub 2022 May 17.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Objective: There are altered mucosal functions in irritable bowel syndrome with diarrhoea (IBS-D); ~30% of patients with IBS-D have abnormal bile acid (BA) metabolism (ABAM) and diarrhoea (summarised as BAD).

Aim: To compare biochemical parameters, gastrointestinal and colonic transit, rectal sensation and pathobiological mechanisms in IBS-D without ABAM and in BAD (serum 7C4>52 ng/mL).

Design: In patients with Rome III criteria of IBS-D, we compared biochemical features, colonic transit, rectal sensation, deep genotype of five BA-related genes, ileal and colonic mucosal mRNA (differential expression (DE) analysis) and stool dysbiosis (including functional analysis of microbiome). Results in BAD were compared with IBS-D without ABAM.

Results: Compared with 161 patients with IBS-D without ABAM, 44 patients with BAD had significantly faster colonic transit, lower microbial alpha diversity, different compositional profile (beta diversity) and higher Firmicutes to Bacteroidetes ratio with evidence of decreased expression of bile acid thiol ligase (involved in transformation of primary to secondary BAs) and decreased sulfatases. In BAD (compared with IBS-D without ABAM), terminal ileal biopsies showed downregulation of (a BA transporter), and ascending colon biopsies showed upregulation in barrier-weakening genes (), serine protease inhibitors, immune activation, cellular differentiation and a cellular transporter (; BA binding). No DE of genes was documented in descending colon biopsies. The two groups had similar rectal sensation.

Conclusion: Though sharing clinical symptoms with IBS-D, BAD is associated with biological differences and mechanisms that have potential to enhance diagnosis and treatment targeting barrier dysfunction, inflammatory and microbial changes.
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http://dx.doi.org/10.1136/gutjnl-2022-327471DOI Listing
May 2022

Cannabidiol for Functional Dyspepsia With Normal Gastric Emptying: A Randomized Controlled Trial.

Am J Gastroenterol 2022 08 9;117(8):1296-1304. Epub 2022 May 9.

Clinical Enteric Neuroscience and Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Introduction: Cannabidiol (CBD), a CBR2 agonist with limited psychic effects, antagonizes CB1/CB2 receptors. Allelic variation CNR1 (gene for CBR1) rs806378 and FAAH rs324420 were associated with altered gut motility and sensation. This study aimed to compare the pharmacodynamics and clinical effects of a 4-week treatment with pharmaceutical-grade CBD vs placebo and assess the interactions of FAAH and CNR1 gene variants on the effects of CBD in patients with functional dyspepsia (FD).

Methods: We performed a randomized, double-blinded, placebo-controlled (1:1 ratio) study of CBD b.i.d. (20 mg/kg/d according to the US Food and Drug Administration escalation guidance) in FD patients with nondelayed gastric emptying (GE) at baseline. Symptoms were assessed by validated daily symptom diary (0-4 scale for upper abdominal pain, nausea, and bloating), weekly assessment of adequate relief, Leuven Postprandial Distress Scale (8 symptoms, adjectival scores rated 0-4 for severity), and quality of life (Short-Form Nepean Dyspepsia Index [average of 10 dimensions each on a 5-point scale]). After the 4-week treatment, all patients underwent measurements of GE of solids, gastric volumes, and Ensure nutrient satiation test. Statistical analysis compared 2 treatments for all endpoints and the effects of CBD in association with FAAH rs324420 and CNR1 rs806378.

Results: CBD and placebo effects on physiological functions and patient response outcomes were not significantly different. There were borderline CBD treatment-by-genotype interactions: rs806378 CNR1 with Leuven Postprandial Distress Scale ( P = 0.06) and GE solids ( P = 0.12).

Discussion: Approved doses of CBD used off-label do not relieve FD with normal baseline GE of solids or alter gastric motor functions and satiation. CBD treatment-by-gene interactions suggest potential benefits for postprandial distress with CNR1 rs806378 T allele.
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http://dx.doi.org/10.14309/ajg.0000000000001805DOI Listing
August 2022

Update on the role of naldemedine in opioid-induced constipation in patients with chronic noncancer pain.

Therap Adv Gastroenterol 2022 28;15:17562848221078638. Epub 2022 Apr 28.

Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Mayo Clinic, Charlton Bldg., Rm. 8-110, 200 First Street S.W., Rochester, MN 55905, USA.

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.
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http://dx.doi.org/10.1177/17562848221078638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9058332PMC
April 2022

Differential mRNA expression in ileal and colonic biopsies in irritable bowel syndrome with diarrhea or constipation.

Am J Physiol Gastrointest Liver Physiol 2022 08 3;323(2):G88-G101. Epub 2022 May 3.

Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota.

Altered mucosal functions are documented in jejunal or colorectal mucosa from patients with irritable bowel syndrome (IBS). Our aim was to quantify ileal, ascending, and rectosigmoid colon mucosal expression of genes in IBS-diarrhea (D) and IBS-constipation (C). Forty-four patients with IBS-D, 30 with IBS-C, and 30 healthy volunteers underwent colonoscopic ileal, ascending, and rectosigmoid colon biopsies. Biopsies were stored in RNA at -80 °C, purified with on-column DNase, cDNA libraries prepared from 100-200 ng of total RNA, sequenced on Illumina NovaSeq 6000, and analyzed on Illumina's RTA version 3.4.4. Normalized mRNA expression was obtained using MAP-RSeq bioinformatics pipeline. Differential expressions in the groups (Log2-fold change) were measured using the bioinformatics package edgeR 2.6.2, corrected for false discovery rate ( <0.05). There were 30 females with IBS-C and 31 females and 13 males with IBS-D. In IBS-D and IBS-C groups, there were differential expressions of 181 genes in ascending colon and 199 genes in rectosigmoid colon. The majority were gene upregulations in IBS-D with functions reflecting activation of inflammation genes, TRPV1 (visceral hypersensitivity) and neurotransmitters/receptors (specifically purinergic, GABA, and cannabinoid). Although gene differential expressions in the ascending and rectosigmoid colon mucosa of the two groups were different, the diverse upregulated genes involved immune functions, receptors, transmitters, ion channels, and transporters. Conversely, there was reduced expression of PI15 and PI16 genes that inhibit proteases. In patients with IBS-D and IBS-C, differential expressions of genes related to immune, transmitter, nociceptive, protease inhibition, channel, and transporter functions suggest opportunities to reverse the pathobiology and treat patients with IBS. This study compares gene expression in mucosa of the terminal ileum, right colon, and left colon in patients with diarrhea- or constipation-predominant irritable bowel syndrome (IBS) and contrasts expression between these two disease entities and also between each entity and mucosa from healthy controls. The study shows there is differential expression of genes related to immune, transmitter, nociceptive, ion channel, and transporter functions, as well as reduced serine protease inhibition, in patients with IBS.
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http://dx.doi.org/10.1152/ajpgi.00063.2022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9291427PMC
August 2022

Fasting pyloric diameter and distensibility by functional endoluminal imaging probe in unsedated healthy volunteers.

Neurogastroenterol Motil 2022 Apr 25:e14386. Epub 2022 Apr 25.

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

Background: Recent 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.

Methods: Twenty-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 Results: Pyloric 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 mm /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 (COV ) for DM and DI were 13.8% and 29.6%, respectively, and interindividual COV (COV ) were 12.6% and 51.3%, respectively. Similar reproducibility was obtained with 40 ml balloon distension.

Conclusions And Inferences: Unsedated 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.
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http://dx.doi.org/10.1111/nmo.14386DOI Listing
April 2022

Management of Gastroparesis.

Gastroenterol Hepatol (N Y) 2021 Nov;17(11):515-525

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

Gastroparesis is a gastrointestinal motility disorder characterized by nausea, vomiting, early satiation, postprandial fullness, bloating, and upper abdominal pain. The diagnosis requires documented delay in gastric emptying with an optimal test such as scintigraphy or stable isotope gastric emptying breath test in the absence of mechanical obstruction. The pathophysiologic mechanisms of gastroparesis are multifactorial, including antroduodenal hypomotility, pylorospasm, impaired gastric accommodation, and visceral hypersensitivity. The etiologies of gastroparesis are broad, but the most common subtypes are idiopathic, diabetic, and postsurgical. Less frequent etiologies are neurodegenerative disorder (Parkinson disease), myopathies (scleroderma, amyloidosis), and neoplastic syndrome. Symptoms of gastroparesis can be refractory and challenging to manage, leading to reduced quality of life and significant health care expenditure. This article introduces the epidemiology, clinical presentation, diagnosis, and differential diagnoses of gastroparesis, followed by a focused discussion on its management, including nutritional support, prokinetic and antiemetic agents, and emerging interventions directed at the pylorus. Robust sham-controlled trials are needed to evaluate the long-term efficacy of gastric peroral endoscopic myotomy. A multidisciplinary approach with individualized strategies based on characterization of the patho-physiology is deemed necessary to enhance clinical outcomes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9021159PMC
November 2021

Presentation of the Julius M. Friedenwald Medal to Timothy C. Wang, MD, AGAF.

Gastroenterology 2022 06 17;162(7):2086-2091. Epub 2022 Apr 17.

Division of Digestive and Liver Diseases, Department of Medicine, Herbert Irving Comprehensive Cancer Center, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New York. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2022.03.021DOI Listing
June 2022

Bile acid detergency: permeability, inflammation, and effects of sulfation.

Am J Physiol Gastrointest Liver Physiol 2022 05 8;322(5):G480-G488. Epub 2022 Mar 8.

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.

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.
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http://dx.doi.org/10.1152/ajpgi.00011.2022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8993532PMC
May 2022

Impact of elobixibat on serum and fecal bile acid levels and constipation symptoms in patients with chronic constipation.

J Gastroenterol Hepatol 2022 May 9;37(5):883-890. Epub 2022 Mar 9.

Mayo Clinic, Rochester, Minnesota, USA.

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.
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http://dx.doi.org/10.1111/jgh.15800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9311197PMC
May 2022

Safety and Efficacy of Eluxadoline in Patients with Irritable Bowel Syndrome-Diarrhea With or Without Bile Acid Diarrhea: Open-Label Study.

Dig Dis Sci 2022 Aug 5;67(8):3911-3921. Epub 2022 Feb 5.

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St. S.W., Charlton Building, Rm. 8-110, Rochester, MN, 55905, USA.

Background: Eluxadoline, a peripherally acting, mixed µ- and κ-opioid receptor (OR) agonist and δ-OR antagonist, is approved for treatment of adults with irritable bowel syndrome-diarrhea (IBS-D). About a third of IBS-D patients has bile acid diarrhea (BAD); opioids may stimulate TGR5 (bile acid) receptors.

Aim: To evaluate eluxadoline's efficacy on altered bowel functions and safety in IBS-D patients with or without BAD.

Methods: In a single-center, phase 4, parallel-group, open-label study, patients with IBS-D (cohort 1) and patients with BAD were treated with eluxadoline, 100 mg tablets BID, with food for 4 weeks. Patients recorded bowel functions by electronic daily diary. BAD was based on fasting serum 7αC4 (> 52.5 ng/mL) or concurrent criteria of increased total or primary fecal BAs excreted in 48 h. We assessed efficacy on treatment compared to baseline in the two cohorts. Primary outcome measures were changes from baseline in average stool consistency Bristol Stool Form Scale (BSFS) score (range 1-7) and safety.

Results: Mean changes from baseline in cohorts 1 and 2 (data presented in this order) were similar for: BSFS score averaged over 4 weeks' treatment (- 1.25 and - 1.09); daily bowel movement frequency (- 1.48 and - 0.79); daily urgent bowel movements (- 0.52 and - 0.80); IBS-QoL (5.9 and 13.6); serum 7αC4 (- 5.59 and - 8.78 ng/mL). There were no deaths, serious treatment-emergent adverse events, or discontinuations due to adverse events during the study.

Conclusion: Eluxadoline is similarly efficacious in the treatment of IBS-D and BAD, and it appears to be safe and efficacious as documented in large clinical trials.
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http://dx.doi.org/10.1007/s10620-022-07379-xDOI Listing
August 2022

Gastrointestinal motility disorders in patients with multiple sclerosis: A single-center study.

Neurogastroenterol Motil 2022 Aug 3;34(8):e14326. Epub 2022 Feb 3.

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Rochester, MN, USA.

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.
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http://dx.doi.org/10.1111/nmo.14326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9338921PMC
August 2022

GWAS of stool frequency provides insights into gastrointestinal motility and irritable bowel syndrome.

Cell Genom 2021 Dec 8;1(3):None. Epub 2021 Dec 8.

School of Biological Sciences, Monash University, Clayton, VIC, Australia.

Gut dysmotility is associated with constipation, diarrhea, and functional gastrointestinal disorders like irritable bowel syndrome (IBS), although its molecular underpinnings are poorly characterized. We studied stool frequency (defined by the number of bowel movements per day, based on questionnaire data) as a proxy for gut motility in a GWAS meta-analysis including 167,875 individuals from UK Biobank and four smaller population-based cohorts. We identify 14 loci associated with stool frequency (p ≤ 5.0 × 10). Gene set and pathway analyses detected enrichment for genes involved in neurotransmitter/neuropeptide signaling and preferentially expressed in enteric motor neurons controlling peristalsis. PheWAS identified pleiotropic associations with dysmotility syndromes and the response to their pharmacological treatment. The genetic architecture of stool frequency correlates with that of IBS, and UK Biobank participants from the top 1% of stool frequency polygenic score distribution were associated with 5× higher risk of IBS with diarrhea. These findings pave the way for the identification of actionable pathological mechanisms in IBS and the dysmotility syndromes.
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http://dx.doi.org/10.1016/j.xgen.2021.100069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8654685PMC
December 2021

Bile Acid Diarrhea Is Associated With Increased Intestinal Permeability Compared With Irritable Bowel Syndrome-Diarrhea.

Gastroenterology 2022 04 16;162(4):1343-1345.e1. Epub 2021 Dec 16.

Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, Minnesota. Electronic address:

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http://dx.doi.org/10.1053/j.gastro.2021.12.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934275PMC
April 2022

Association of Glucagon-like Peptide 1 Analogs and Agonists Administered for Obesity with Weight Loss and Adverse Events: A Systematic Review and Network Meta-analysis.

EClinicalMedicine 2021 Dec 27;42:101213. Epub 2021 Nov 27.

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN.

Background: Comparative effectiveness of 7 glucagon-like peptide 1 (GLP-1) agents on weight loss (WL) in obesity remains unknown.

Methods: We performed a systematic review, network meta-analysis (NMA) utilizing the following data sources: MEDLINE, EMBASE, Scopus, Cochrane Central and clinical trial registries, from inception to March 2, 2021. The prespecified criteria for study inclusion were randomized clinical trials (RCTs) of ≥12 weeks' duration. The data appraisal and extraction were performed by two investigators independently, using the published reports. The main outcomes and statistical methods were weight loss over placebo (WLOP) and adverse events (AEs) among GLP-1 agents using random-effects NMA (frequentist approach); relative ranking using surface under the cumulative ranking (SUCRA) method and certainty of evidence using grading of recommendations, assessment, development and evaluations (GRADE).

Findings: 64 RCTs (from 2004 to 2021) included 27018 patients (median of age, 55.1 years old; 57.4% women; baseline weight 94.8kg and BMI 33.0kg/m; trial duration 26 weeks). Direct meta-analysis showed significant WLOP with: -1.44kg (95% CI, -2.14 to -0.74) with dulaglutide ≥1.5 mg; -1.82kg (-2.42 to -1.23) with exenatide immediate release (IR); -2.20kg (-4.31 to -0.08) with exenatide extended release (ER); -3.20kg (-6.53 to 0.15) with efpeglenatide; -2.72kg (-3.35 to -2.09) with liraglutide ≤1.8mg; -4.49kg (-5.26 to -3.72) with liraglutide >1.8mg; -0.62kg (-1.22 to -0.02) with lixisenatide; -4.33kg (-5.71 to -3.00) with semaglutide SQ <2.4mg; -9.88kg (-13.17 to -6.59) with semaglutide SQ 2.4mg; -2.73kg (-4.81 to -0.65) with semaglutide oral; and -1.71kg (-2.64 to -0.78) with taspoglutide. Highest WLOP were with semaglutide SQ 2.4mg and <2.4mg, and liraglutide >1.8mg (SUCRAs 100, 86.1, 82.8 respectively). Highest SUCRAs for discontinuation due to AEs were with taspoglutide and liraglutide >1.8mg. Risk of bias was high or unclear for random sequence generation (29.7%), allocation concealment (26.6%), and incomplete outcome data (26.6%). Heterogeneity (I >50%) in WL and AEs reflected magnitude, not direction of effect.
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http://dx.doi.org/10.1016/j.eclinm.2021.101213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633575PMC
December 2021

Impact of Bile Acid Diarrhea in Patients With Diarrhea-Predominant Irritable Bowel Syndrome on Symptoms and Quality of Life.

Clin Gastroenterol Hepatol 2021 Dec 4. Epub 2021 Dec 4.

Clinical Enteric Neuroscience Translational and Epidemiological Research, Division of Gastroenterology and Hepatology, Rochester, Minnesota. Electronic address:

Background & Aims: Bile acid diarrhea (BAD) affects approximately a quarter of patients with irritable bowel syndrome with diarrhea (IBS-D). We aimed to compare the demographics, bowel and somatic symptoms, and quality of life of patients with IBS-D, with or without BAD.

Methods: On one occasion, patients with IBS-D (positive for Rome III criteria) completed the following questionnaires: bowel disease questionnaire, Hospital Anxiety and Depression inventory, general quality of life (Symptom Checklist-90), and IBS-specific quality of life. A fasting serum C4 level higher than 52.5 ng/mL was used as a biomarker for BAD. Statistical analysis included a multiple variable logistic model to identify strong predictors of BAD in IBS-D.

Results: Among 219 patients (79% female) with IBS-D, 44 had BAD; the BAD group was significantly older and had a higher body mass index than the patients without BAD. Patients with BAD had more severe bowel dysfunction and impact on IBS-specific quality of life (need of toilet proximity) compared with patients with IBS-D without BAD. Patients with BAD were more likely than other IBS-D groups to receive antidiarrheals, bile acid binders, and antacid secretory agents. The severity of diarrhea and need of toilet proximity were predictors of BAD in IBS-D (P < .01). Patients with BAD were more likely to have a depression score higher than 8 on the Hospital Anxiety and Depression inventory.

Conclusions: There is a greater impact on bowel and somatic symptoms and quality of life in IBS-D with BAD compared with IBS-D without BAD. Screening for BAD in IBS-D is especially relevant, with more severe and frequent diarrhea along with urgency.
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http://dx.doi.org/10.1016/j.cgh.2021.11.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9166633PMC
December 2021

Guanylate cyclase-C agonists as peripherally acting treatments of chronic visceral pain.

Trends Pharmacol Sci 2022 02 2;43(2):110-122. Epub 2021 Dec 2.

Clinical Enteric Neuroscience Translational and Epidemiologic Research Program, Mayo Clinic, Rochester, MN, USA.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3',5'-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics.
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http://dx.doi.org/10.1016/j.tips.2021.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8760167PMC
February 2022
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