Michael Camilleri

Temple University, Philadelphia, Pennsylvania, United States

Are you Michael Camilleri?

Claim your profile

Publications (723)5256.63 Total impact

  • Gastroenterology 05/2014; 146(5):S-364. · 13.93 Impact Factor
  • Michael Camilleri, Andres Acosta
    Gastroenterology 04/2014; · 12.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Our aim was to conduct a pilot case-control study of RNA expression profile using RNA sequencing of rectosigmoid mucosa of 9 females with irritable bowel syndrome-diarrhea [IBS-D] with accelerated colonic transit and 9 female healthy controls. Mucosal total RNA was isolated, purified, and next generation pair-end sequencing was performed using Illumina TruSeq. Analysis was carried out using: a targeted approach towards 12 genes previously associated with IBS, and a hypothesis-generating approach. Of the 12 targeted genes tested, patients with IBS-D had decreased mRNA expression of TNFSF15 (fold change controls to IBS-D: 1.53, p=0.01). Overall, up- and downregulated mRNA expressions of 21 genes (p values 10(-5) to 10(-8); p values with FDR shown) were potentially relevant to IBS-D: neurotransmitters [P2RY4 (p=0.001), VIP (p=0.02)]; cytokines [CCL20 (p=0.019)]; immune function [C4BPA complement cascade (p=0.0187)], and IFIT3 [interferon-related, p=0.016]; mucosal repair and cell adhesion [TFF1 (trefoil protein, p= 0.012)], RBP2 (retinol binding protein, p=0.017), FN1 (fibronectin, p=0.009)]; and ion channel functions [GUCA2B (guanylate cyclase, p= 0.017), PDZD3 (PDZ domain-containing protein 3, p=0.029)]. Ten genes associated with functions related to pathobiology of IBS-D were validated by RT-PCR: There was significant correlation in fold changes of the selected genes (Rs=0.73, p=0.013). Up- or downregulation of P2RY4, GUC2AB, RBP2, FNI and C4BPA genes were confirmed on RT-PCR, which also revealed upregulation of FXR and ASBT. RNA seq and RT-PCR analysis of rectosigmoid mucosa in IBS-D show transcriptome changes that provide the rationale for validation studies to explore the role of mucosal factors in the pathobiology of IBS-D.
    AJP Gastrointestinal and Liver Physiology 04/2014; · 3.65 Impact Factor
  • Source
    Michael Camilleri
    [Show abstract] [Hide abstract]
    ABSTRACT: The gastrointestinal tract is a vast neuroendocrine organ with extensive extrinsic and intrinsic neural circuits that interact to control its function. Circulating and paracrine hormones (amine and peptide) provide further control of secretory, absorptive, barrier, motor and sensory mechanisms that are essential to the digestion and assimilation of nutrients, and the transport and excretion of waste products. Specialized elements of the mucosa (including enteroendocrine cells, enterocytes and immune cells) and the microbiome interact with other intraluminal contents derived from the diet, and with endogenous chemicals that alter the gut's functions. The totality of these control mechanisms is often summarized as the brain-gut axis. In irritable bowel syndrome, which is the most common gastrointestinal disorder experienced by patients, there may be disturbances at one or more of these diverse control mechanisms. Patients present with abdominal pain in association with alteration of bowel function. This review documents advances in understanding the pathophysiological mechanisms in the brain-gut axis in patients with IBS. It is anticipated that identification of the one or more disordered functions in clinical practice will usher in a renaissance in IBS, leading to effective therapy tailored to the needs of the individual patient.
    The Journal of Physiology 03/2014; · 4.38 Impact Factor
  • Andres Acosta, Michael Camilleri
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity is a complex disease that results from increased energy intake and decreased energy expenditure. The gastrointestinal system plays a key role in the pathogenesis of obesity and facilitates caloric imbalance. Changes in gastrointestinal hormones and the inhibition of mechanisms that curtail caloric intake result in weight gain. It is not clear if the gastrointestinal role in obesity is a cause or an effect of this disease. Obesity is often associated with type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Obesity is also associated with gastrointestinal disorders, which are more frequent and present earlier than T2DM and CVD. Diseases such as gastroesophageal reflux disease (GERD), cholelithiasis, or nonalcoholic steatohepatitis are directly related to body weight and abdominal adiposity. Our objective is to assess the role of each gastrointestinal organ in obesity and the gastrointestinal morbidity resulting in those organs from the effects of obesity.
    Annals of the New York Academy of Sciences 03/2014; · 4.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND & AIMS: SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5. METHODS: We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. RESULTS: Missense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS. CONCLUSIONS: About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
    Gastroenterology 03/2014; 146(7):1659-1668. · 13.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Melanocortin 4 receptor (MC4R) has a major role in energy homeostasis. The rs17782313 polymorphism, mapped 188 kb downstream from MC4R, has been associated with satiety, higher body mass index (BMI) and total calorie intake in adults. To assess the association of rs17782313 with gastric functions, satiation, or satiety, we studied 178 predominantly Caucasian overweight and obese people: 120 females, 58 males; mean BMI 33.4 ± 5.3 kg/m(2) (SD); age 37.7 ± 11.2 years. Quantitative traits assessed were gastric emptying (GE) of solids and liquids; fasting and postprandial gastric volume; satiation by maximum tolerated volume and 4 symptoms by 100-mm visual analog scales (VAS); and satiety by ad libitum buffet meal. Associations of genotype and quantitative traits were assessed by analysis of covariance (using gender and BMI as covariates), based on a dominant [TC (n = 72) - CC (n = 12) vs. TT (n = 94)] genetic model. rs17782313(C) was associated with postprandial satiation symptoms (median Δ total VAS 26.5 mm, p = 0.036), reduced proportion of solid GE at 2 h (median Δ 6.7 %, p = 0.008) and 4 h (median Δ 3.2 %, p = 0.006), and longer t ½ (median Δ 6 min, p = 0.034). Associations of rs17782313 with obesity may be explained by reduced satiation and GE. The role of MC4R mechanisms in satiation and gastric function deserves further study.
    Genes & Nutrition 03/2014; 9(2):384. · 3.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Patients with disorders of gastrointestinal function may undergo unnecessary treatment if misdiagnosed as motility disorders. To report on clinical features, medical, surgical and psychiatric co-morbidities, and prior treatments of a patient cohort diagnosed concurrently with non-psychogenic rumination syndrome and pelvic floor dysfunction (also termed rectal evacuation disorder). From a consecutive series (1994-2013) of 438 outpatients with rectal evacuation disorders in the practice of a single gastroenterologist at a tertiary care center, 57 adolescents or adults were diagnosed with concomitant rumination syndrome. All underwent formal psychological assessment or completed validated questionnaires. All 57 patients (95% female) fulfilled Rome III criteria for rumination syndrome; rectal evacuation disorder was confirmed by testing of anal sphincter pressures and rectal balloon evacuation. Prior to diagnosis, most patients underwent multiple medical and surgical treatments (gastrostomy, gastric fundoplication, other gastric surgery, ileostomy, colectomy) for their symptoms. Psychological co-morbidity was identified in 93% of patients. Patients were managed predominantly with psychological and behavioral approaches: diaphragmatic breathing for rumination and biofeedback retraining for pelvic floor dysfunction. Awareness of concomitant rectal evacuation disorder and rumination syndrome and prompt identification of psychological co-morbidity are keys to instituting behavioral and psychological methods to avoid unnecessary treatment.
    United European gastroenterology journal. 02/2014; 2(1):138-146.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Gastrointestinal (GI) infections resulting from bacterial, viral, and parasitic pathogens predispose to postinfectious irritable bowel syndrome (PI-IBS) and other functional GI disorders. Existing literature supports the role of enterochromaffin cell hyperplasia, serotonin synthesis and reuptake, impaired barrier function, altered immune activation, and potentially mast cell activation in the pathophysiology of PI-IBS. The objective of this review was to summarize from the literature the characteristics of the pathogens commonly implicated in PI-IBS, their acute enteritis phases, and the changes seen in the postinfectious phase that may contribute toward development of IBS. A limitation of our current understanding is that the postinfectious GI sequelae reported in prior studies followed epidemic diarrheal outbreaks often involving more than one pathogen, or the studies focused on highly selected, tertiary referral patients. Understanding the mechanisms, natural history, and optimized management of individuals suffering PI-IBS following the more typical sporadic infection requires larger studies of PI-IBS following GI infections encountered in community settings. These studies should include genetic, physiological, and molecular studies to provide more generalizable information that can ultimately be used to diagnose, manage, and potentially prevent the development of PI-IBS.
    Neurogastroenterology and Motility 02/2014; 26(2):156-167. · 2.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite advances in understanding the roles of adiposity, food intake, GI and adipocyte-related hormones, inflammatory mediators, the gut-brain axis and the hypothalamic nervous system in the pathophysiology of obesity, the effects of different therapeutic interventions on those pathophysiological mechanisms are controversial. There are still no low-cost, safe, effective treatments for obesity and its complications. Currently, bariatric surgical approaches targeting the GI tract are more effective than non-surgical approaches in inducing weight reduction and resolving obesity-related comorbidities. However, current guidelines emphasise non-surgical approaches through lifestyle modification and medications to achieve slow weight loss, which is not usually sustained and may be associated with medication-related side effects. This review analyses current central, peripheral or hormonal targets to treat obesity and addresses challenges and opportunities to develop novel approaches for obesity.
    Gut 01/2014; · 13.32 Impact Factor
  • Madhusudan Grover, Michael Camilleri
    Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 01/2014; · 5.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Vagal interruption causes weight loss in humans and decreases endogenous glucose production in animals. However, it is unknown if this is due to a direct effect on glucose metabolism. We sought to determine if vagal blockade using electrical impulses alters glucose metabolism in humans.
    Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 01/2014; 7:305-12.
  • Michael Camilleri
    [Show abstract] [Hide abstract]
    ABSTRACT: Bile acids (BA) are actively reabsorbed in the terminal ileum by the apical Na(+)-dependent bile salt transporter. This review addresses the epidemiology, pathophysiology, diagnosis and treatment of BA diarrhea (BAD). BAD is typically caused by ileal resection or disease; 25-33% of patients with chronic functional diarrhea or irritable bowel syndrome-diarrhea (IBS-D) have BAD, possibly from deficiency in the ileal hormone, FGF-19, which normally provides feedback inhibition of BA synthesis. Diagnosis of BAD is typically based on reduced BA retention of radiolabeled BA ((75)SeHCAT), increased BA synthesis (serum C4) or increased fecal BA loss. In clinical practice, diagnosis is often based on response to BA sequestrants (e.g., cholestyramine or colesevelam). Diagnostic tests for BA malabsorption (BAM) need to be used more extensively in clinical practice. In the future, farnesoid X receptor agonists that stimulate ileal production of FGF-19 may be alternative treatments of BAD.
    Expert review of gastroenterology & hepatology 01/2014; 8(1):49-61.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background & Aims SCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of Nav1.5. Methods We performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without (controls). Mutant forms of SCN5A were expressed in HEK-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study (GWAS) was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls. Results Missense mutations were found in SCN5A in 13/584 patients (2.2%, probands). Diarrhea-predominant IBS (IBS-D) was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (IBS-C, 31%) than IBS-D (10%, P<.05). Electrophysiologic analysis showed that 10/13 detected mutations disrupted NaV1.5 function (9 reduced and 1 increased function); p.A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current; administration of mexiletine to 1 carrier of this mutation (who had IBS-C) normalized their bowel habits. In the GWAS and 4 replicated studies, the SCN5A locus was strongly associated with IBS. Conclusions About 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
    Gastroenterology 01/2014; · 12.82 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Highly selective 5-HT4 agonists have been suggested for the treatment of chronic constipation (CC). To assess the effects of highly selective 5-HT4 agonists (prucalopride, velusetrag or naronapride) on patient-important clinical efficacy outcomes and safety in adults with CC. We searched the medical literature in January 2013 using MEDLINE/Pubmed, Embase, Cochrane Library, and Web of Science/Scopus for randomised, controlled trials of highly selective 5-HT4 agonists in adults with CC, with no minimum duration of therapy (maximum 12 weeks) or date limitations. Data were extracted from intention-to-treat analyses, pooled using a random-effects model, and reported as relative risk (RR), mean differences, or standardised mean differences with 95% confidence intervals (CI). Main outcomes included stool frequency, Patient-Assessment of Constipation Quality of Life (PAC-QOL), PAC of symptoms (PAC-SYM) and adverse events. Thirteen eligible trials were identified: 11 prucalopride, 1 velusetrag, 1 naronapride. Relative to control, treatment with highly selective 5-HT4 agonists was superior for all outcomes: mean ≥3 spontaneous complete bowel movements (SCBM)/week (RR = 1.85; 95% CI 1.23-2.79); mean ≥1 SCBM over baseline (RR = 1.57; 95% CI 1.19, 2.06); ≥1 point improvement in PAC-QOL and PAC-SYM scores. The only active comparator trial of prucalopride and PEG3350 suggested PEG3350 is more efficacious for some end points. Adverse events were more common with highly selective 5-HT4 agonists, but were generally minor; headache was the most frequent. Most trials studied prucalopride. Demonstration of efficacy on patient-important outcomes and a favourable safety profile support the continued use and development of highly selective 5-HT4 agonists in the treatment of chronic constipation.
    Alimentary Pharmacology & Therapeutics 12/2013; · 4.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Study objectives were to: mine the complete exome to identify putative rare single nucleotide variants (SNVs) associated with irritable bowel syndrome-diarrhea (IBS D) phenotype; assess genes that regulate bile acids in IBS-D; explore univariate associations of SNVs with symptom phenotype and quantitative traits in independent IBS cohort. Using principal component analysis, we identified 2 groups of IBS-D (n=16) with increased fecal bile acids: rapid colonic transit or high bile acids synthesis. DNA was sequenced indepth, analyzing SNVs in bile acids genes (ASBT, FXR, OSTα/β, FGF19, FGFR4, KLB, SHP, CYP7A1, LRH-1, and FABP6). Exome findings were compared to 50 similar ethnicity controls. We assessed univariate associations of each SNV with quantitative traits and principal component analysis and associations between SNVs in KLB and FGFR4 and symptom phenotype in 405 IBS, 228 controls and colonic transit in 70 IBS-D, 71 IBS-C. Mining the complete exome did not reveal significant associations with IBS-D over controls. There were 54 SNVs in 10/11 bile acids-regulating genes, with no SNVs in FGF19; 15 non-synonymous SNVs were identified in similar proportions of IBS-D and controls. Variations in KLB (rs1015450, downstream) and FGFR4 (rs434434 [intronic], rs1966265, and rs351855 [non-synonymous]) were associated with colonic transit (rs1966265; P=.043), fecal bile acids (rs1015450; P=.064), and PCA groups (all 3 FGFR4 SNVs; P<.05). In the 633 person cohort, FGFR4 rs434434 was associated with symptom phenotype (P=.027) and rs1966265 with 24h colonic transit (P=.066). Thus, exome sequencing identified additional variants in KLB and FGFR4 associated with bile acids or colonic transit in IBS-D.
    AJP Gastrointestinal and Liver Physiology 11/2013; · 3.65 Impact Factor
  • Source
    M Camilleri, A Acosta
    Alimentary Pharmacology & Therapeutics 11/2013; 38(10):1320-1. · 4.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nausea and vomiting are thought to result from upper gastrointestinal dysfunctions. Our clinical observations led to the hypothesis that colonic motor dysfunction is associated with nausea and vomiting. We reviewed electronic medical records (EMR) of 149 patients presenting with complaints of nausea and/or vomiting in a tertiary gastroenterology practice to investigate the association with disorders of colonic motor or evacuation disorders. We extracted demographics, gastric emptying (GE in 149) and colonic transit (CT in 138) of solids, ascending colon emptying half-time (AC t1/2 ), rectal evacuation by anorectal manometry (ARM) in 91 and balloon expulsion test (BE) in 55 patients. We estimated the proportions with delayed GE or CT, based on the 5th percentile of GE (in 319) and CT in 220 healthy volunteers using same method. Among 11 patients with nausea and/or vomiting with only GE measured, five had delayed and six normal GE. Among the 149 patients, 77 (52%) patients had evacuation disorders, confirmed by objective tests in 68 patients, and clinical examination in nine patients. In the 138 patients with both GE and CT measured, 106 (76%) had both normal GE and CT, 11 (8%) only delayed GE, 16 (11%) normal GE with delayed CT, and five (3%) delayed GE and CT. Among 21 patients (15%) with delayed CT, nine had slow AC t1/2 and 12 evacuation disorder. In patients with chronic nausea and/or vomiting in gastroenterology practice, evaluation of colonic motility and rectal evacuation should be considered, since about half the patients have abnormal functions that conceivably contribute to the presenting nausea and/or vomiting.
    Neurogastroenterology and Motility 10/2013; · 2.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In prior studies, pregabalin reduced rectal or colonic pain in patients with irritable bowel syndrome and healthy adults, suggesting reduction of afferent function. To assess effects of pregabalin on colonic compliance, sensory and motor functions in patients with constipation-predominant irritable bowel syndrome. In a pilot, double-blind, placebo-controlled, parallel-group study, we tested oral pregabalin, 200mg, in 18 patients with constipation-predominant irritable bowel syndrome. With a barostatically controlled polyethylene balloon in the left colon, we assessed sensation thresholds and colonic compliance using ascending method of limits, sensation ratings over 4 levels of distension, fasting and postprandial colonic tone and phasic motility. Analysis of covariance (adjusted for the corresponding pre-drug response) was used to compare placebo and pregabalin. After 45% participants completed studies, we conducted an interim analysis to assess the conditional power to detect pre-specified treatment effects given the observed variation and treatment group differences based on the planned sample size for the trial. Pregabalin did not significantly affect colonic compliance, sensation thresholds, sensation ratings, fasting or postprandial tone or motility index. The study was stopped for futility to detect an effect on visceral pain with the planned design and sample size. Pregabalin, 200mg, might not reduce distension-related colonic pain in constipation-predominant irritable bowel syndrome patients.
    Digestive and Liver Disease 10/2013; · 2.89 Impact Factor
  • Journal of Nuclear Medicine 10/2013; · 5.56 Impact Factor

Publication Stats

22k Citations
5,256.63 Total Impact Points

Institutions

  • 2013
    • Temple University
      Philadelphia, Pennsylvania, United States
  • 1989–2013
    • Mayo Foundation for Medical Education and Research
      • • Division of Gastroenterology and Hepatology
      • • College of Medicine
      • • Department of Medicine
      • • Mayo Medical School
      • • Department of Neurology
      Rochester, Michigan, United States
  • 1985–2013
    • Mayo Clinic - Rochester
      • • Department of Health Science Research
      • • Department of Hospital Internal Medicine
      Rochester, Minnesota, United States
  • 2012
    • Michigan State University
      East Lansing, Michigan, United States
    • The University of Western Ontario
      • Department of Clinical Neurological Sciences
      London, Ontario, Canada
  • 2011–2012
    • University of Michigan
      • • Division of Gastroenterology
      • • Medical School
      Ann Arbor, MI, United States
    • Karolinska Institutet
      • Institutionen för biovetenskaper och näringslära
      Solna, Stockholm, Sweden
  • 2010
    • Dartmouth–Hitchcock Medical Center
      Lebanon, New Hampshire, United States
  • 2009
    • Israelitisches Krankenhaus Hamburg
      Hamburg, Hamburg, Germany
    • Universidad de Extremadura
      Ara Pacis Augustalis, Extremadura, Spain
  • 2008–2009
    • University of Naples Federico II
      • Department of Pharmacy
      Napoli, Campania, Italy
    • University of Padova
      • Department of Information Engineering
      Padova, Veneto, Italy
  • 2005–2008
    • Rochester Clinical Research
      Rochester, New York, United States
  • 2007
    • St. Mary Medical Center
      Long Beach, California, United States
  • 2006
    • Kosin University
      • College of Medicine
      Pusan, Busan, South Korea
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 2001–2006
    • University of Minnesota Rochester
      Rochester, Minnesota, United States
  • 2004
    • GlaxoSmithKline plc.
      • Neurology Centre of Excellence for Drug Discovery
      London, ENG, United Kingdom
    • Harvard University
      Cambridge, Massachusetts, United States
    • University of Bologna
      Bolonia, Emilia-Romagna, Italy
  • 2003
    • University of Illinois at Chicago
      Chicago, Illinois, United States
    • Beth Israel Deaconess Medical Center
      • Division of Gastroenterology
      Boston, MA, United States
  • 1997
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      Chapel Hill, NC, United States