Publications by authors named "Michael Camilleri"

563 Publications

Diagnosis and Treatment of Irritable Bowel Syndrome: A Review.

JAMA 2021 Mar;325(9):865-877

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

Importance: The prevalence of irritable bowel syndrome (IBS) in the United States is between 7% and 16%, most common in women and young people, with annual direct costs estimated at more than $1 billion dollars in the United States. Traditionally, the diagnosis of IBS has been based on the positive identification of symptoms that correlate with several different syndromes associated with disorders such as IBS diarrhea, IBS constipation, functional diarrhea, functional constipation, chronic functional abdominal pain, or bloating. Several peripheral and central mechanisms initiate gastrointestinal motor and sensory dysfunctions leading to IBS symptoms. Those dysfunctions may require evaluation in patients whose symptoms do not respond to first-line treatments.

Observations: Validation studies of consensus symptom-based criteria have identified deficiencies that favor a simpler identification of the predominant symptoms of abdominal pain, bowel dysfunction, and bloating and exclusion of alarm symptoms such as unintentional weight loss, rectal bleeding, or recent change in bowel function. Symptom-based diagnosis of IBS is enhanced with additional history for symptoms of somatoform and psychological disorders and alarm symptoms, physical examination including digital rectal examination, and screening tests to exclude organic disease (by measuring hemoglobin and C-reactive protein concentrations). The initial treatment plan should include patient education, reassurance, and first-line treatments such as fiber and osmotic laxatives for constipation, opioids for diarrhea, antispasmodics for pain and for management of associated psychological disorders. For patients who do not respond to those IBS treatments, testing for specific functional disorders may be required in a minority of patients with IBS. These disorders include rectal evacuation disorder, abnormal colonic transit, and bile acid diarrhea. Their identification is followed by individualized treatment, such as pelvic floor retraining for rectal evacuation disorders, sequestrants for bile acid diarrhea, and secretory agents for constipation, although there is only limited evidence that this individualized management approach is effective.

Conclusions And Relevance: Advances in the identification of specific dysfunctions as causes of individual symptoms in the "IBS spectrum" leads to the potential to enhance the diagnosis and management of symptoms for the majority of patients for whom first-line therapies of IBS and management of comorbid psychological disorders are insufficient.
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http://dx.doi.org/10.1001/jama.2020.22532DOI Listing
March 2021

Letter: elobixibatting for the long run-authors' reply.

Aliment Pharmacol Ther 2021 Mar;53(6):769-770

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

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http://dx.doi.org/10.1111/apt.16290DOI Listing
March 2021

Gastrointestinal motility disorders in neurologic disease.

J Clin Invest 2021 Feb;131(4)

The extrinsic and autonomic nervous system intricately controls the major functions of the gastrointestinal tract through the enteric nervous system; these include motor, secretory, sensory, storage, and excretory functions. Disorders of the nervous system affecting gastrointestinal tract function manifest primarily as abnormalities in motor (rather than secretory) functions. Common gastrointestinal symptoms in neurologic disorders include sialorrhea, dysphagia, gastroparesis, intestinal pseudo-obstruction, constipation, diarrhea, and fecal incontinence. Diseases of the entire neural axis ranging from the cerebral hemispheres to the peripheral autonomic nerves can result in gastrointestinal motility disorders. The most common neurologic diseases affecting gastrointestinal function are stroke, parkinsonism, multiple sclerosis, and diabetic neuropathy. Diagnosis involves identification of the neurologic disease and its distribution, and documentation of segmental gut dysfunction, typically using noninvasive imaging, transit measurements, or intraluminal measurements of pressure activity and coordination of motility. Apart from treatment of the underlying neurologic disease, management focuses on restoration of normal hydration and nutrition and pharmacologic treatment of the gut neuromuscular disorder.
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http://dx.doi.org/10.1172/JCI143771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880310PMC
February 2021

Relationship of Motor Mechanisms to Gastroparesis Symptoms: Towards Individualized Treatment.

Am J Physiol Gastrointest Liver Physiol 2021 Feb 10. Epub 2021 Feb 10.

Gastroenterology and Hepatology, Mayo Clinic, United States.

Following a classical paper by Dr. Keith A. Kelly published in this journal, and over the past 40 years, there has been increased understanding of the functions of different regions of the stomach, specifically the fundus, antrum, and pylorus. Several of the important physiological principles were based on in vivo animal studies that led to the appreciation of regional function and control mechanisms. These include the roles of the extrinsic parasympathetic vagal innervation, the gastric enteric nervous system and electrical syncytium consisting of pacemaker cells and smooth muscle cells, and duodenogastric reflexes providing feedback regulation following the arrival of food and hydrogen ions stimulating the release of hormones and vagal afferent mechanisms that inhibit gastric motility and stimulate pyloric contractility. Further insights on the role of regional motor functions in gastric emptying were obtained from observations in patients following diverse gastric surgeries or bariatric procedures, including fundoplication, Billroth I and sleeve gastrectomy, and sleeve gastroplasty. Antropyloroduodenal manometry as well as measurements of pyloric diameter and distensibility index provided important assessments of the role of antral hypomotility and pylorospasm, and these constitute specific targets for individualized treatment of patients with gastroparesis. Moreover, in patients with upper gastrointestinal symptoms suggestive of gastroparesis, the availability of measurements of gastric accommodation as well as pharmacological agents to reduced gastric sensitivity or enhance gastric accommodation provide additional specific targets for individualized treatment. It is anticipated that, in the future, such physiological measurements will be applied in patients to optimize choice of therapy, possibly including identifying the best candidate for pyloric interventions.
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http://dx.doi.org/10.1152/ajpgi.00006.2021DOI Listing
February 2021

Liraglutide reduces attenuation coefficient as a measure of hepatic steatosis during 16 weeks' treatment in nondiabetic obese patients: A pilot trial.

JGH Open 2021 Feb 30;5(2):193-198. Epub 2020 Dec 30.

Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), and Division of Gastroenterology and Hepatology, Department of Medicine Mayo Clinic Rochester Minnesota USA.

Background And Aim: Liraglutide, a long-acting GLP-1 analog, is approved for the treatment of obesity with improvements in fasting blood glucose, hemoglobin A1c, and cardiovascular health. Our aim was to measure the impact of liraglutide dose for obesity on hepatic steatosis measured by ultrasound.

Methods: A single-center, randomized, double-blind, placebo-controlled pilot trial was undertaken in nondiabetic obese, otherwise healthy patients aged 18-65 years. Participants were randomly assigned to receive subcutaneous liraglutide (3.0 mg) or placebo over 16 weeks with dose escalation following US Food and Drug Administration guidelines. Both groups received standardized nutritional and behavioral counseling during the 16 weeks. Hepatic fat content was measured by ultrasound at baseline, 8 weeks, and 16 weeks as an attenuation coefficient (ACE). Effects of treatment were assessed using t-test for the entire groups and for patient subgroup with baseline ACE >0.66 (indicating significant steatosis).

Results: Among 30 patients (93% female) enrolled, 16 were randomized to placebo and 14 to liraglutide. Baseline body mass indices (BMIs) and average age were similar in the two groups. After 16 weeks, the liraglutide group had a significant improvement in steatosis ACE scores (-0.068 ± 0.02 -0.0077 ± 0.02 placebo, = 0.05). Change in steatosis was positively correlated with change in BMI (R = 0.402, = 0.0007). Within the liraglutide group, patients with baseline ACE >0.66 had improvement in ACE (-0.134 ± 0.03) compared to those without significant steatosis (-0.041 ± 0.02, = 0.05).

Conclusions: In this pilot trial, liraglutide, 3.0 mg over 16 weeks, reduced hepatic steatosis; a reduction in hepatic steatosis is correlated with BMI reduction, and effects are particularly evident in those with a significant degree of steatosis by ultrasound imaging.
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http://dx.doi.org/10.1002/jgh3.12464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857298PMC
February 2021

Peristomal pemphigoid: A single-center retrospective cohort study.

J Am Acad Dermatol 2021 Jan 25. Epub 2021 Jan 25.

Departments of Dermatology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.01.066DOI Listing
January 2021

Human Intestinal Barrier: Effects of Stressors, Diet, Prebiotics, and Probiotics.

Clin Transl Gastroenterol 2021 Jan 25;12(1):e00308. Epub 2021 Jan 25.

Division of Gastroenterology and Hepatology, Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, Minnesota.

The objectives of this article are to understand the effects of stressors (nonsteroidal antiinflammatory drug, exercise, and pregnancy) and components in the diet, specifically prebiotics and probiotics, on intestinal barrier function. Stressors generally reduce barrier function, and these effects can be reversed by supplements such as zinc or glutamine that are among the substances that enhance the barrier. Other dietary factors in the diet that improve the barrier are vitamins A and D, tryptophan, cysteine, and fiber; by contrast, ethanol, fructose, and dietary emulsifiers increase permeability. Effects of prebiotics on barrier function are modest; on the other hand, probiotics exert direct and indirect antagonism of pathogens, and there are documented effects of diverse probiotic species, especially combination agents, on barrier function in vitro, in vivo in animal studies, and in human randomized controlled trials conducted in response to stress or disease. Clinical observations of benefits with combination probiotics in inflammatory diseases have simultaneously not appraised effects on intestinal permeability. In summary, probiotics and synbiotics enhance intestinal barrier function in response to stressor or disease states. Future studies should address the changes in barrier function and microbiota concomitant with assessment of clinical outcomes.
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http://dx.doi.org/10.14309/ctg.0000000000000308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7838004PMC
January 2021

Every Breath Test You Take: Practical Advice on Breath Testing Used to Detect Small Intestinal Bacterial Overgrowth.

Dig Dis Sci 2021 Feb 11;66(2):331-333. Epub 2021 Jan 11.

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.

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http://dx.doi.org/10.1007/s10620-020-06776-4DOI Listing
February 2021

Kaposi sarcoma misdiagnosed as granuloma annulare: A case of mistaken identity.

J Cutan Pathol 2021 Feb 28;48(2):318-321. Epub 2020 Sep 28.

Departments of Dermatology, Mayo Clinic, Rochester, Minnesota, USA.

The 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.
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http://dx.doi.org/10.1111/cup.13815DOI Listing
February 2021

International Union of Basic and Clinical Pharmacology. CX. Classification of Receptors for 5-hydroxytryptamine; Pharmacology and Function.

Pharmacol Rev 2021 Jan;73(1):310-520

Neuropharmacology Research Group, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (N.M.B., A.R.); Department of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia (N.M.B., D.H.); Department of Pharmacology, Georgetown University Medical Center, Washington, DC (G.P.A.); Institut de Génomique Functionnelle, Université Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France (C.B., J.B., S.C.-D., S.C., P.M.); Université de Montpellier, Montpellier, France (C.B., J.B., S.C.-D., S.C., P.M.); C.E.N.T.E.R. Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, Minnesota (M.C.); Center for Addiction Research and Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, Texas (K.A.C., R.M.H.); School of Life Sciences, Medical School, Queen's Medical Centre, The University of Nottingham, Nottingham, United Kingdom (K.C.F.); Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York (M.G.); Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida, Malta (G.D.G.); Department of Physiology, Department of Obstetrics and Gynaecology, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada (N.M.G., E.K.L.); Department of Psychiatry, University of California San Diego, La Jolla, California (A.L.H.); Theranyx, Marseille, France (G.H.); Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, New York (K.H.-D.); Ecole Polytechnique Fédérale de Lausanne, Institute of Chemical Sciences and Engineering, Lausanne, Switzerland (R.H., H.V.); Department of Pharmacy-Drug Science, University of Bari Aldo Moro, Bari, Italy (E.L., M.L.); Department of Pharmacology, Faculty of Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway (F.O.L.); Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom (S.C.R.L.); INSERM UMR-S 1270, Paris, France (L.M., A.R.); Sorbonne Université, Paris, France (L.M., A.R.); Institut du Fer à Moulin, Paris, France (L.M., A.R.); Drug Development, Grunenthal GmbH, Aachen, Germany (A.C.M.); Tucson, Arizona (D.L.N.); Departments of Psychiatry and Behavioral Sciences and Pharmacology, University of Washington, Seattle, Washington (J.F.N.); Neurolixis Inc., Dana Point, California (A.N.-T.); Université Grenoble Alpes, Institut de Biologie Structurale, Grenoble, France (H.N.); CNRS, Institut de Biologie Structurale, Grenoble, France (H.N.); Commissariat à l'Energie Atomique et aux Energies Alternatives, DSV, Institut de Biologie Structurale, Grenoble, France (H.N.); Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina (B.L.R.); Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom (G.J.S.); Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York (M.T.); Department of Pharmacology, University of Oxford, Oxford, United Kingdom (T.S.); Cinvestav-Coapa, Pharmacobiology, Mexico City, Tlalpan, Mexico (C.M.V.); Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (S.W.W.); The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia (D.H.); and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California (D.H.).

5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role 5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.
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http://dx.doi.org/10.1124/pr.118.015552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770494PMC
January 2021

Review article: Elobixibat: a novel treatment for chronic constipation.

Aliment Pharmacol Ther 2021 01 9;53(2):234-242. Epub 2020 Dec 9.

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

Background: A subset of patients with chronic constipation has associated slow colonic transit and reduced faecal bile acid excretion. In addition to traditional approaches to treat chronic constipation, a novel therapeutic option is to increase the colonic concentration of intraluminal bile acids. This can be achieved through inhibition of the ileal bile acid transporter.

Aim: To evaluate the evidence for efficacy and safety of an ileal bile acid transport inhibitor in the treatment of chronic constipation METHODS: We reviewed published literature on elobixibat, based on a PubMed search.

Results: Elobixibat is a novel ileal bile acid transport inhibitor that has demonstrated efficacy in proof of concept studies in experimental animals as well as phase 1, 2 and 3 trials in humans. Phase 4 studies have now documented that the beneficial effects are related to increase in the secretory bile acids in the colon as measured by stool bile acid content. The studies documented efficacy in patients with severe constipation, which is often associated with slow colonic transit. These changes in bile acid composition were associated with minor differences in the faecal microbiota in patients treated with elobixibat compared to placebo. Elobixibat appears to be safe. The only adverse effects of note are associated with its pharmacological actions in patients with chronic constipation,namely the induction of diarrhoea and abdominal pain.

Conclusion: This new class of compound appears to be safe and efficacious in the treatment of chronic constipation.
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http://dx.doi.org/10.1111/apt.16143DOI Listing
January 2021

Gastric Motor Functions in Patients With Mood Disorders and Functional Gastroduodenal Symptoms.

Psychosom Med 2021 Feb-Mar 01;83(2):171-176

From the Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology (Maselli, Camilleri), Mayo Clinic, Rochester, Minnesota; and Division of Gastroenterology (Park), Chonnam National University Hospital, Gwangju, South Korea.

Objective: Functional gastroduodenal symptoms (FGDSs) may result from perturbations in gastric emptying (GE) and gastric accommodation (GA), which are variably affected by acute stress. This study aimed to examine whether individuals who have both mood disorder and FGDS exhibit differences in GE and GA using standardized, validated, and reproducible noninvasive methods.

Methods: Using a data retrieval program, 1554 individuals at a single center were identified after having undergone measurements of GE by scintigraphy of a 99mTc-radiolabeled egg (320 kcal, 30% fat meal) and GA by single-photon emission computed tomography to assess the underlying pathophysiology in FGDS. An extensive medical record review identified 267 of these individuals as having diagnoses of depression, anxiety, or comorbid anxiety/depression (CAD). Differences in GE and GA as related to the presence of anxiety or depressive disorders were analyzed using one-way analysis of variance on ranks and Mann-Whitney tests for the two-group comparisons.

Results: Sixty-three patients with anxiety, 134 with depression, and 70 with CAD were identified. GE at 1 hour was slower (p = .04) and GE at 2 hours numerically decreased (p = .07) for depression compared with anxiety. GA was diminished for CAD compared with anxiety (p = .04) and depression (p = .009). There were no differences in fasting gastric volume or GE at 4 hours.

Conclusions: In this study examining GE and GA in anxiety and depressive disorders among patients with FGDS, the combined presence of anxiety and depression was associated with impaired GA compared with patients with depression or anxiety alone, and early GE seemed to be slower in those with depression compared with patients with anxiety.
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http://dx.doi.org/10.1097/PSY.0000000000000891DOI Listing
December 2020

Food Residue During Esophagogastroduodenoscopy Is Commonly Encountered and Is Not Pathognomonic of Delayed Gastric Emptying.

Dig Dis Sci 2020 Nov 25. Epub 2020 Nov 25.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55905, USA.

Background And Aims: Retained gastric food (RGF) identified during esophagogastroduodenoscopy (EGD) is often attributed to gastroparesis. This retrospective study evaluated the prevalence of RGF, risk factors for RGF, and the association between RGF and delayed gastric emptying (GE).

Methods: The prevalence and odds ratios for RGF in patients with structural foregut abnormalities or medical risk factors for delayed GE were determined from 85,116 EGDs performed between 2012 and 2018. The associations between RGF, delayed GE, and medical comorbidities were evaluated in 2991 patients without structural abnormalities who had undergone EGD and gastric emptying scintigraphy. The relationship between medication use and RGF was evaluated in 249 patients without structural or medical risk factors for RGF.

Results: RGF was identified during 3% of EGDs. The odds of RGF were increased in patients with type 1 diabetes (12%, OR 1.7, P ≤ 0.001), type 2 diabetes (6%, OR 1.4, P ≤ 0.001), gastroparesis (14%, OR 4.8, P ≤ 0.001), amyloidosis (5%, OR 1.7, P ≤ 0.001), and structural foregut abnormalities (6%, OR 2.6, P ≤ 0.001). Overall, the PPV of RGF for delayed GE was 55%. However, the PPV varied from 32% in patients without risk factors to 79% in patients with type 1 diabetes. Opioids, cardiovascular medications, and acid suppressants were associated with RGF.

Conclusions: RGF is common during EGD. The PPV of RGF for delayed GE varies depending on underlying risk factors (type 1 diabetes, type 2 diabetes, gastroparesis, and amyloidosis). Acid suppressants or antacids, cardiovascular medications, and opioids are associated with RGF independent of delayed GE.
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http://dx.doi.org/10.1007/s10620-020-06718-0DOI Listing
November 2020

Irritable bowel syndrome.

Lancet 2020 11 10;396(10263):1675-1688. Epub 2020 Oct 10.

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

Irritable bowel syndrome is a functional gastrointestinal disorder with symptoms including abdominal pain associated with a change in stool form or frequency. The condition affects between 5% and 10% of otherwise healthy individuals at any one point in time and, in most people, runs a relapsing and remitting course. The best described risk factor is acute enteric infection, but irritable bowel syndrome is also more common in people with psychological comorbidity and in young adult women than in the rest of the general population. The pathophysiology of irritable bowel syndrome is incompletely understood, but it is well established that there is disordered communication between the gut and the brain, leading to motility disturbances, visceral hypersensitivity, and altered CNS processing. Other less reproducible mechanisms might include genetic associations, alterations in gastrointestinal microbiota, and disturbances in mucosal and immune function. In most people, diagnosis can be made on the basis of clinical history with limited and judicious use of investigations, unless alarm symptoms such as weight loss or rectal bleeding are present, or there is a family history of inflammatory bowel disease or coeliac disease. Once the diagnosis is made, an empathetic approach is key and can improve quality of life and symptoms, and reduce health-care expenditure. The mainstays of treatment include patient education about the condition, dietary changes, soluble fibre, and antispasmodic drugs. Other treatments tend to be reserved for people with severe symptoms and include central neuromodulators, intestinal secretagogues, drugs acting on opioid or 5-HT receptors, or minimally absorbed antibiotics (all of which are selected according to predominant bowel habit), as well as psychological therapies. Increased understanding of the pathophysiology of irritable bowel syndrome in the past 10 years has led to a healthy pipeline of novel drugs in development.
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http://dx.doi.org/10.1016/S0140-6736(20)31548-8DOI Listing
November 2020

Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome.

Cell 2020 Sep 10;182(6):1460-1473.e17. Epub 2020 Sep 10.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2020.08.007DOI Listing
September 2020

Effects of dietary components on intestinal permeability in health and disease.

Am J Physiol Gastrointest Liver Physiol 2020 11 9;319(5):G589-G608. Epub 2020 Sep 9.

Clinical Enteric Neuroscience Translational and Epidemiological Research, Mayo Clinic, Rochester, Minnesota.

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.
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http://dx.doi.org/10.1152/ajpgi.00245.2020DOI Listing
November 2020

Ten Reasons to Think about Bile Acids in Managing Inflammatory Bowel Disease.

J Crohns Colitis 2020 Aug 31. Epub 2020 Aug 31.

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

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http://dx.doi.org/10.1093/ecco-jcc/jjaa175DOI Listing
August 2020

Development of a Score to Predict Positive Colonic Histology in Chronic Diarrhea Assessed in Open-access Colonoscopy.

J Clin Gastroenterol 2020 Aug 21. Epub 2020 Aug 21.

Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER).

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.
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http://dx.doi.org/10.1097/MCG.0000000000001414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897333PMC
August 2020

A Pilot Study Examining the Effects of GLP-1 Receptor Blockade Using Exendin-(9,39) on Gastric Emptying and Caloric Intake in Subjects With and Without Bariatric Surgery.

Metab Syndr Relat Disord 2020 11 20;18(9):406-412. Epub 2020 Aug 20.

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, Minnesota, USA.

Obesity causes significant morbidity and mortality and continues to be a significant public health concern. Unfortunately, lifestyle modification and pharmacotherapy do not produce durable results. This has led to bariatric surgical procedures playing an increasingly prominent role in the management of medically complicated obesity. Roux-en-Y gastric bypass and sleeve gastrectomy are the most commonly performed bariatric surgeries in North America and produce mechanical restriction with accelerated gastrointestinal transit accompanied by increased postprandial secretion of glucagon-like peptide-1 (GLP-1). GLP-1 is a gastrointestinal hormone that delays gastric emptying and causes satiety and weight loss. This raises the possibility that the postprandial rise in GLP-1 might affect feeding behavior over and above the mechanical restriction produced by bariatric surgery. We, therefore, sought to determine the effects of GLP-1 receptor blockade using exendin-9,39-a competitive antagonist of the actions of GLP-1 at its receptor-on caloric intake and gastrointestinal transit in subjects after sleeve gastrectomy and after Roux-en-Y gastric bypass compared with weight-matched controls. GLP-1 receptor blockade did not alter caloric intake in people after bariatric surgery. However, caloric intake was decreased in age-, weight- and sex-matched control subjects, and the mechanisms require further study. Given the known effects of GLP-1 on gastric accommodation, future studies should ascertain effects of GLP-1 receptor blockade on gastric accommodation, which might be a useful and novel strategy to decrease caloric intake in humans with an intact upper gastrointestinal tract. The Clinical Trial Resigtration number is NCT02779075.
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http://dx.doi.org/10.1089/met.2020.0049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698854PMC
November 2020

Irritable Bowel Syndrome: Straightening the road from the Rome criteria.

Neurogastroenterol Motil 2020 11 17;32(11):e13957. Epub 2020 Aug 17.

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

A 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.
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http://dx.doi.org/10.1111/nmo.13957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7640950PMC
November 2020

Correction to: Gastroparesis Following Immune Checkpoint Inhibitor Therapy: A Case Series.

Dig Dis Sci 2020 Aug 7. Epub 2020 Aug 7.

Division of Gastroenterology, Hepatology, and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA.

The original version of the article unfortunately contained an error in the Table 2. In the column 'Motilityimmune-related adverse event' of Table 2, the term 'Intestinal pseudo-obstruction' was inadvertently removed in the final version. Corrected Table 2 is given below.
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http://dx.doi.org/10.1007/s10620-020-06515-9DOI Listing
August 2020

Parkinson disease and the gut: new insights into pathogenesis and clinical relevance.

Nat Rev Gastroenterol Hepatol 2020 11 31;17(11):673-685. Epub 2020 Jul 31.

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

The classic view portrays Parkinson disease (PD) as a motor disorder resulting from loss of substantia nigra pars compacta dopaminergic neurons. Multiple studies, however, describe prodromal, non-motor dysfunctions that affect the quality of life of patients who subsequently develop PD. These prodromal dysfunctions comprise a wide array of gastrointestinal motility disorders including dysphagia, delayed gastric emptying and chronic constipation. The histological hallmark of PD - misfolded α-synuclein aggregates that form Lewy bodies and neurites - is detected in the enteric nervous system prior to clinical diagnosis, suggesting that the gastrointestinal tract and its neural (vagal) connection to the central nervous system could have a major role in disease aetiology. This Review provides novel insights on the pathogenesis of PD, including gut-to-brain trafficking of α-synuclein as well as the newly discovered nigro-vagal pathway, and highlights how vagal connections from the gut could be the conduit by which ingested environmental pathogens enter the central nervous system and ultimately induce, or accelerate, PD progression. The pathogenic potential of various environmental neurotoxicants and the suitability and translational potential of experimental animal models of PD will be highlighted and appraised. Finally, the clinical manifestations of gastrointestinal involvement in PD and medications will be discussed briefly.
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http://dx.doi.org/10.1038/s41575-020-0339-zDOI Listing
November 2020

Refractory Constipation: How to Evaluate and Treat.

Gastroenterol Clin North Am 2020 09 14;49(3):623-642. Epub 2020 Jun 14.

Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Charlton Building, Room 8-110, Rochester, MN 55905, USA.

Patients are often referred for treatment of refractory constipation that may result from uncontrolled underlying disease or ineffective treatment. This article reviews clinical testing in patients with refractory constipation, differentiating subtypes of primary chronic idiopathic constipation, and common pitfalls in assessment of refractory chronic constipation. The constipation may also be refractory because of significant associated diseases affecting the colon and resulting in slow transit constipation. The choice of therapy is best guided by the subtype. Management of refractory constipation requires correct diagnosis and individualized treatment, which may rarely include conservative surgery (loop ileostomy).
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http://dx.doi.org/10.1016/j.gtc.2020.05.002DOI Listing
September 2020

Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea.

Aliment Pharmacol Ther 2020 09 23;52(5):808-820. Epub 2020 Jul 23.

Division of Digestive Diseases, Imperial College London, London, UK.

Background: In primary bile acid diarrhoea, feedback by farnesoid X receptor (FXR) and fibroblast growth hormone 19 (FGF19) on hepatic bile acid production is impaired.

Aims: To 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.

Methods: In 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.

Results: Twenty 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).

Conclusions: Tropifexor 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.
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http://dx.doi.org/10.1111/apt.15967DOI Listing
September 2020

Epidemiology of gastroparesis: important answers and still more questions.

Gut 2021 Apr 21;70(4):631-632. Epub 2020 Jul 21.

Department of Medicine, Mayo Clinic Rochester, Rochester, Minnesota, USA

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http://dx.doi.org/10.1136/gutjnl-2020-322140DOI Listing
April 2021

The benefit of elobixibat in chronic constipation is associated with faecal deoxycholic acid but not effects of altered microbiota.

Aliment Pharmacol Ther 2020 09 20;52(5):821-828. Epub 2020 Jul 20.

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

Background: Elobixibat, 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.

Aims: To investigate the effects of elobixibat on changes in the faecal concentrations of total and individual bile acids and in faecal microbiota.

Methods: This 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.

Results: In 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.

Conclusions: Short 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.
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http://dx.doi.org/10.1111/apt.15950DOI Listing
September 2020

Pharmacology, Clinical Effects, and Therapeutic Potential of Cannabinoids for Gastrointestinal and Liver Diseases.

Clin Gastroenterol Hepatol 2020 Jul 13. Epub 2020 Jul 13.

Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Cannabis and cannabinoids (such as tetrahydrocannabinol and cannabidiol) are frequently used to relieve gastrointestinal symptoms. Cannabinoids have effects on the immune system and inflammatory responses, as well as neuromuscular and sensory functions of digestive organs, including pancreas and liver. Cannabinoids can cause hyperemesis and cyclic vomiting syndrome, but they might also be used to reduce gastrointestinal, pancreatic, or hepatic inflammation, as well as to treat motility, pain, and functional disorders. Cannabinoids activate cannabinoid receptors, which inhibit release of transmitters from presynaptic neurons and also inhibit diacylglycerol lipase alpha, to prevent synthesis of the endocannabinoid 2-arachidonoyl glycerol. However, randomized trials are needed to clarify their effects in patients; these compounds can have adverse effects on the central nervous system (such as somnolence and psychosis) or the developing fetus, when used for nausea and vomiting during pregnancy. Cannabinoid-based therapies can also hide symptoms and disease processes, such as in patients with inflammatory bowel diseases. It is important for gastroenterologists and hepatologists to understand cannabinoid mechanisms, effects, and risks.
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http://dx.doi.org/10.1016/j.cgh.2020.04.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854774PMC
July 2020

Clinical Features and Associations of Descending Perineum Syndrome in 300 Adults with Constipation in Gastroenterology Referral Practice.

Dig Dis Sci 2020 12 14;65(12):3688-3695. Epub 2020 Jul 14.

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: Outlet obstruction constipation accounts for about 30% of chronic constipation (CC) cases in a referral practice.

Aims: To assess the proportion of patients with CC diagnosed with descending perineum syndrome (DPS) by a single gastroenterologist and to compare clinical, radiological, and associated features in DPS compared to patients with constipation.

Methods: We conducted a review of records of 300 consecutive patients evaluated for constipation by a single gastroenterologist from 2007 to 2019, including medical, surgical, and obstetrics history, digital rectal examination, anorectal manometry, defecation proctography (available in 15/23 with DPS), treatment, and follow-up. DPS was defined as > 3 cm descent of anorectal junction on imaging or estimated perineal descent on rectal examination. Logistic regression with univariate and multivariate analysis compared factors associated with DPS to non-DPS patients.

Results: Twenty-three out of 300 (7.7%, all female) patients had DPS; these patients were older, had more births [including more vaginal deliveries (84.2% vs. 31.2% in non-DPS, p < 0.001)], more instrumental or traumatic vaginal deliveries, more hysterectomies, more rectoceles on proctography (86.7% vs. 28.6% non-DPS, p = 0.014), lower squeeze anal sphincter pressures (p < 0.001), and lower rectal sensation (p = 0.075) than non-DPS. On univariate logistic regression, history of vaginal delivery, hysterectomy, and Ehlers-Danlos syndrome increased the odds of developing DPS. Vaginal delivery was confirmed as a risk factor on multivariate analysis.

Conclusions: DPS accounts for almost 10% of tertiary referral patients presenting with constipation. DPS is associated with age, female gender, and number of vaginal (especially traumatic) deliveries.
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http://dx.doi.org/10.1007/s10620-020-06394-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669713PMC
December 2020

Editorial: a need for glucose monitoring on prokinetic treatment with a ghrelin agonist in diabetic gastroparesis? Author's reply.

Aliment Pharmacol Ther 2020 08;52(3):546-547

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

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http://dx.doi.org/10.1111/apt.15866DOI Listing
August 2020