IS SMALL INTESTINAL BACTERIAL OVERGROWTH ASSOCIATED WITH FUNCTIONAL DYSPEPSIA?
Henry C Lin
Biomedical Research Institute Of New Mex, Albuquerque, Nm 87108
Grant 1R21DK078101-01A2 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Functional dyspepsia (FD) affects ~15% of the population. While numerous findings have been associated with these patients including reduced volume of tolerance to nutritive drinks, the pathophysiology and treatment of this condition remain unclear. Postprandial bloating is a key symptom of FD with patients noting abdominal distension after meals. Bloating is a symptom shared with irritable bowel syndrome (IBS), another functional bowel disorder with a prevalence of ~15%. Recently, we have shown that up to 84% of patients with IBS have an abnormal pattern of bacterial gas excretion on lactulose breath test (LBT) to suggest small intestinal bacterial overgrowth (SIBO). SIBO is the abnormal expansion of the indigenous gut bacterial flora proximally into the small intestine. SIBO is associated with leaky gut, bacterial translocation and immune activation to represent a shift in host-gut bacterial relationship. In this setting, bacterial fermentation takes place in both the small and large intestine resulting in excessive production of bacterial gases leading to bloating and distension. In a randomized, placebo- controlled antibiotic treatment of IBS, successful treatment of SIBO results in a significant improvement of both gastrointestinal symptoms such as bloating and extraintestinal symptoms such as fatigue. Objective We will determine the prevalence and association of SIBO, abnormal interdigestive motility, and hypersensitivity in FD. We will also determine the relationship between SIBO and hypersensitivity of FD using randomized antibiotic treatment. Research design We will compare in a cohort of FD patients and healthy controls breath testing, interdigestive motility and hypersensitivity. A nonabsorbable, small-bowel targeting antibiotic treatment will be administered in a randomized, double, blind, placebo-controlled manner. Methodology We will recruit patients with negative upper gastrointestinal endoscopy and negative 24h pH study who meet the inclusion criteria for FD along with healthy controls. We will compare symptom scores recorded on questionnaires, LBT results, small bowel manometry, and volume of tolerance of a nutritive drink before and after treatment of SIBO. Clinical relationships FD has been a perplexing and disabling disorder affecting ~15% of population. Current treatment is directed at symptom reduction but is characterized by poor efficacy. The identification of a gut bacterial explanation for FD will lead to the development of novel diagnostic and treatment approaches targeting SIBO. This will represent a major advance in the clinical care of FD patients. Public Health Relevance Functional dyspepsia with a prevalence of up to ~15% of the population is a common but poorly understood disorder without effective treatment. Bloating is a key complaint of these patients. In this proposal, we will test the hypothesis that excessive bacterial fermentation may play a role in the bloating and other dyspeptic symptoms of functional dyspepsia
Keywords: Abdomen; Abdominal; Address; Affect; After Care; After-Treatment; Aftercare; Allergy; Antibiotic Therapy; Antibiotic Treatment; Area; Bacteria resistance; Bacteria resistant; Bacterial Translocation; Bacterial resistant; Biochemistry, Manometry; Breath Tests; Caring; Cell Locomotion; Cell Migration; Cell Movement; Cellular Migration; Cephulac; Chronulac; Clinical; Clinical Research; Clinical Study; Colitis, Mucous; Colon, Irritable; Condition; D-Fructose, 4-O-beta-D-galactopyranosyl-; Data; Development; Diagnostic; Diffuse Myofascial Pain Syndrome; Digestive Diseases; Digestive System Diseases; Digestive System Disorders; Disease; Disorder; Distal; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Duodenum; Dysfunction; Dyspepsia; Endoscopy, Gastrointestinal; Excretory function; Fatigue; Feasibility Studies; Fermentation; Fibromyalgia; Fibromyositis-Fibromyalgia Syndrome; Fibrositis; Frequencies (time pattern); Frequency; Functional disorder; Future; Gases; Gastrointestinal Endoscopy; Gastrointestinal Tract, Small Intestine; Goals; Hydrogen Oxide; Hypersensitivity; Immune; Indigenous; Indigestion; Indigestions; Intestinal; Intestines; Intestines, Small; Irritable Bowel Syndrome; Lack of Energy; Lactulose; Large Intestine; Lead; MPD syndrome; Manometry; Measures; Method LOINC Axis 6; Methodology; Microbe; Motility; Motility, Cellular; Musculoskeletal System; Nausea; Nutrition; Nutritional Science; Oral; Outcome; Patients; Pattern; Pb element; Physiologic; Physiological; Physiology; Physiopathology; Placebo Control; Play; Population; Prevalence; Production; Public Health; Questionnaires; Randomized; Randomized Controlled Trials; Recruitment Activity; Reporting; Research; Research Design; Research Proposals; Rheumatism, Muscular; Role; Satiation; Satiations; Science of nutrition; Score; Small Intestines; Stomach; Study Type; Symptoms; Test Result; Testing; ULCN; Ulcer; Ulceration; Visceral; Water; Week; bacterial resistance; base; bowel; breath analysis; cell motility; cohort; digestive disorder; disease/disorder; drinking; excretion; experiment; experimental research; experimental study; fibromyalgia syndrome; gastric; gastrointestinal; gastrointestinal symptom; heavy metal Pb; heavy metal lead; improved; inclusion criteria; innovate; innovation; innovative; large bowel; microbial; myofascial pain dysfunction syndrome; new diagnostics; next generation diagnostics; novel; novel diagnostics; nutrition; overgrowth bacterial; pathophysiology; public health medicine (field); randomisation; randomization; randomized controlled study; randomly assigned; recruit; research study; resistance to Bacteria; resistance to Bacterial; resistant to Bacteria; resistant to Bacterial; response; satiety; small bowel; social role; spastic colon; study design; treatment of bacterial diseases; treatment of bacterial infectious disease
Project start date: 2008-04-15
Project end date: 2011-03-31
Budget start date: 15-APR-2008
Budget end date: 31-MAR-2010
PFA/PA: PA-06-301
1R21DK078101-01A2 (2008): $0
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Henry C Lin
REGULATION OF FED INTESTINAL MOTILITY BY FAT
Henry C Lin, Director Gastrointestinal Motility Progr
Cedars-sinai Medical Center Los Angeles, Ca 90048
Grant 5R29DK046459-05 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZRG4
Abstract: Optimal digestion and absorption of fat depend on regulated presentation of this nutrient to the absorptive sites of the small intestine. Intestinal transit is inhibited by fat in a load-dependent fashion to provide this controlled nutrient delivery whether the region of exposure to fat is limited to the proximal gut (jejunal brake) or extended to the distal gut (ileal brake). In order for the small bowel to respond appropriately to the fat entered, the presence of fat in the lumen must be detected. Afferent nerves that fire specifically in response to luminal fat (fat chemoreceptors) have been found in the lamina propria. Since the terminal ends of these nerves are not in contact with the lumen, a gut endocrine cell in contact with the lumen may serve as a "taste bud" for the small intestine and act on the afferent pathways by releasing a peptide product. Our preliminary data showed that PYY, a peptide that inhibits intestinal transit, is the preabsorptive signal transducer and chylomicron (or its apoprotein component, apo A-IV) is the postabsorptive signal transducer. Since PYY cells are principally found in the distal gut, PYY may be released by fat in the proximal gut via a neurally dependent, CCK-stimulated release mechanism (jejunal brake) but fat in the distal gut may release PYY via a neurally independent, non CCK-stimulated mechanism (ileal brake). In Phase I of the project, we will examine the effect of fat load, the region of fat exposure (proximal vs. distal gut) and the hypothesized mediators on intestinal transit and the release of PYY. In Phase II of the project, we will further examine the conditions for PYY release in a short term culture of ileal PYY cells. This proposal will provide the fundamental physiologic as well as mechanistic information to explain the control of intestinal transit by luminal fat. Such information is needed to develop novel, nutrient-based treatments for patients who are symptomatic from rapid transit including those with dumping syndrome, short bowel syndrome, postvagotomy diarrhea, enteral feeding related diarrhea, gastrectomy, or ileo-anal anastomosis.
Keywords: biological signal transduction, chemoreceptor, dietary lipid, gastrointestinal motility /pressure, gastrointestinal nutrient absorption, cholecystokinin, chylomicron, gastrointestinal hormone, hormone regulation /control mechanism, neural information processing, neuroendocrine system, neuropeptide, dog, nutrition related tag
Project start date: 1996-03-15
Project end date: 2002-02-28
5R29DK046459-05 (2000): $119000
5R29DK046459-04 (1999): $119000
5R29DK046459-03 (1998): $119000
Slowing Of Transit - The Third Enteric Function Of 5-HT
Henry C Lin, Director Gastrointestinal Motility Progr
University Of Southern California Department Of Contracts And Grants Los Angeles, Ca 90033
Grant 5R01DK059983-04 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: ZRG1
Abstract: In order to optimize nutrition, the movement of a meal through the small intestine must be precisely controlled to ensure that there is adequate time to complete the time-demanding steps of digestion and absorption. Abdominal pain, nausea, bloating, diarrhea and malnutrition are the consequences of impaired control of intestinal transit. After a fat-containing meal, inhibitory feedback mechanisms are activated by the proximal and distal small intestine as the jejunal and ileal brake, respectively. In contrast to this focus of the postprandial gut to slow transit, much of the research efforts over the past 100 years have been directed at the peristaltic reflex, which is responsible for the acceleration of intestinal transit and are known to be mediated by 5-HT. Currently, two roles of enteric 5-HT have been established the triggering of the peristaltic and mucosal secretory reflexes via intrinsic primary afferent neurons and gut-to-CNS and gut-to-pancreas communications via extrinsic sensory nerves. We have recently found a third role of enteric 5-HT. Specifically, 5-HT is also involved in the slowing of transit by fat via a 5-HT3 pathway that is dependent on 5-HT transmission via myenteric neurons. In this proposal, we will test our overall hypothesis that slowing of intestinal transit by fat depends on primary afferent nerves, beta-adrenergic pathway and 5-HT transmission via myenteric neurons, which in turn activates opioid neurons, that slow transit. We will test the hypotheses using pharmacologic and physiologic approaches. The results of these studies will help us to refine our hypotheses so that we can test the neuroanatomic components of this pathway using immunohistochemistry. We have developed a collaboration with 2 leading neuroscientists who will provide this project with additional expertise in immunohistochemistry. In addition, to test the role of a novel beta-adrenergic system in the slowing of intestinal transit by fat, we have developed a multi-disciplinary team approach by including a cardiologist experienced in the 13- adrenergic system. The PI has a track record of success in bench-to-bedside translational research in the area of nutrient control of intestinal transit. His experience includes the discovery of a novel, nutrient-based strategy to slow intestinal transit. This application will bring this new treatment back to basic research so that we can understand the neural pathways that underpin the slowing response to fat. The hypotheses to be tested in this project will expand our understanding of a new role for enteric 5-HT which may explain conditions such as irritable bowel syndrome and provide better understanding of the effects of drugs that are directed at 5-HT pathways. In addition, by investigating the mediators of the control of intestinal transit, we will gain knowledge that can be used to control the movement of a meal through the small intestine and, in turn, reduce symptoms and improve nutrition.
Keywords: afferent nerve, dietary lipid, gastrointestinal absorption /transport, neuroregulation, neurotransmitter transport, serotonin, beta adrenergic receptor, interdisciplinary collaboration, myenteric plexus, neural transmission, neuropharmacology, neurophysiology, neurotoxin, phentolamine, propanol, dog, immunocytochemistry, immunofluorescence technique, nutrition related tag
Project start date: 2003-09-01
Project end date: 2007-08-31
5R01DK059983-04 (2005): $244688
5R01DK059983-03 (2004): $244563
IS SMALL INTESTINAL BACTERIAL OVERGROWTH ASSOCIATED WITH FUNCTIONAL DYSPEPSIA?
Henry C Lin
Biomedical Research Institute Of New Mex, Albuquerque, Nm 87108
Grant 5R21DK078101-02 from National Institute Of Diabetes And Digestive And Kidney Diseases
Abstract: Functional dyspepsia (FD) affects ~15% of the population. While numerous findings have been associated with these patients including reduced volume of tolerance to nutritive drinks, the pathophysiology and treatment of this condition remain unclear. Postprandial bloating is a key symptom of FD with patients noting abdominal distension after meals. Bloating is a symptom shared with irritable bowel syndrome (IBS), another functional bowel disorder with a prevalence of ~15%. Recently, we have shown that up to 84% of patients with IBS have an abnormal pattern of bacterial gas excretion on lactulose breath test (LBT) to suggest small intestinal bacterial overgrowth (SIBO). SIBO is the abnormal expansion of the indigenous gut bacterial flora proximally into the small intestine. SIBO is associated with leaky gut, bacterial translocation and immune activation to represent a shift in host-gut bacterial relationship. In this setting, bacterial fermentation takes place in both the small and large intestine resulting in excessive production of bacterial gases leading to bloating and distension. In a randomized, placebo- controlled antibiotic treatment of IBS, successful treatment of SIBO results in a significant improvement of both gastrointestinal symptoms such as bloating and extraintestinal symptoms such as fatigue. Objective We will determine the prevalence and association of SIBO, abnormal interdigestive motility, and hypersensitivity in FD. We will also determine the relationship between SIBO and hypersensitivity of FD using randomized antibiotic treatment. Research design We will compare in a cohort of FD patients and healthy controls breath testing, interdigestive motility and hypersensitivity. A nonabsorbable, small-bowel targeting antibiotic treatment will be administered in a randomized, double, blind, placebo-controlled manner. Methodology We will recruit patients with negative upper gastrointestinal endoscopy and negative 24h pH study who meet the inclusion criteria for FD along with healthy controls. We will compare symptom scores recorded on questionnaires, LBT results, small bowel manometry, and volume of tolerance of a nutritive drink before and after treatment of SIBO. Clinical relationships FD has been a perplexing and disabling disorder affecting ~15% of population. Current treatment is directed at symptom reduction but is characterized by poor efficacy. The identification of a gut bacterial explanation for FD will lead to the development of novel diagnostic and treatment approaches targeting SIBO. This will represent a major advance in the clinical care of FD patients. Public Health Relevance Functional dyspepsia with a prevalence of up to ~15% of the population is a common but poorly understood disorder without effective treatment. Bloating is a key complaint of these patients. In this proposal, we will test the hypothesis that excessive bacterial fermentation may play a role in the bloating and other dyspeptic symptoms of functional dyspepsia
Project start date: 2008-04-15
Project end date: 2011-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2011
PFA/PA: PA-06-301
5R21DK078101-02 (2010): $163536
Slowing Of Transit - The Third Enteric Function Of 5-HT
Henry C Lin
Cedars-sinai Medical Center
1R01DK059983-01A2 (2003): $292230