Alterations In Intestinal Motility Research Articles

Duodenal-Jejunal Stenosis as a Manifestation of Eosinophilic Gastroenteritis: A Case Report

Introduction: Eosinophilic gastroenteritis (EGE) is a rare disorder characterized by eosinophilic infiltration of the stomach and small intestine. Its clinical manifestations depend on the extent, location, and depth of the inflammatory infiltrate. The pathogenesis remains unclear, but it may be related to food allergy or other hypersensitivity reactions in some patients. Untreated cases can cause intestinal stricture or perforation, making timely diagnosis and intervention essential. Clinical case: A 13-year-old male adolescent was hospitalized due to symptoms suggesting intestinal obstruction or alterations in intestinal motility. Medical imaging revealed significant gastric distension and delayed gastric emptying. An endoscopic study showed a “snake-skin” pattern, duodenitis due to food stasis, a 2 cm ulcer, and stenosis in the duodenum. The biopsy confirmed EGE with significant irregular eosinophilic infiltration of the lamina propria. A panendoscopy was performed after steroid treatment without being able to assess the site of stenosis and perform pneumatic dilation. After completing the immunomodulatory management, a contrast-enhanced abdominal tomography was performed showed a significant decrease in the intestinal lumen, therefore an exploratory laparotomy with a lateral to lateral jejune-jejunal anastomosis was performed. Discussion: EGE is a rare inflammatory disorder characterized by eosinophilic infiltration of the stomach and small intestine. Symptoms are based on the affected gastrointestinal tract segment. In this case, our patient presented intestinal obstruction symptoms with endoscopic biopsies and a histopathological study confirmed eosinophil infiltration. Treatment typically involves identifying potential triggers and corticosteroids to reduce inflammation and symptoms. However, in this case, a decrease in the intestinal lumen was observed, therefore an elective surgical resection was performed. Conclusion: Eosinophilic gastroenteritis is a rare disorder that requires strong clinical suspicion to be diagnosed, which is why its knowledge is important. In this case, gastrointestinal symptoms, radiological and endoscopic images, in addition to the histopathological report, were key tools for integrating the diagnosis. Although management with steroids and immunomodulators was not successful, surgical management became an appropriate option as definitive treatment.

Sports-Related Gastrointestinal Disorders: From the Microbiota to the Possible Role of Nutraceuticals, a Narrative Analysis.

Intense physical exercise can be related to a significant incidence of gastrointestinal symptoms, with a prevalence documented in the literature above 80%, especially for more intense forms such as running. This is in an initial phase due to the distancing of the flow of blood from the digestive system to the skeletal muscle and thermoregulatory systems, and secondarily to sympathetic nervous activation and hormonal response with alteration of intestinal motility, transit, and nutrient absorption capacity. The sum of these effects results in a localized inflammatory process with disruption of the intestinal microbiota and, in the long term, systemic inflammation. The most frequent early symptoms include abdominal cramps, flatulence, the urge to defecate, rectal bleeding, diarrhea, nausea, vomiting, regurgitation, chest pain, heartburn, and belching. Promoting the stability of the microbiota can contribute to the maintenance of correct intestinal permeability and functionality, with better control of these symptoms. The literature documents various acute and chronic alterations of the microbiota following the practice of different types of activities. Several nutraceuticals can have functional effects on the control of inflammatory dynamics and the stability of the microbiota, exerting both nutraceutical and prebiotic effects. In particular, curcumin, green tea catechins, boswellia, berberine, and cranberry PACs can show functional characteristics in the management of these situations. This narrative review will describe its application potential.

Irritable Bowel Syndrome and the Gut Microbiome: A Comprehensive Review

Irritable Bowel Syndrome (IBS) is a functional disorder of the gastrointestinal tract characterized by abdominal pain and altered bowel habits. It has a prevalence of 10 to 25% in the United States and has a high disease burden, as evidenced by reduced quality of life, decreased work productivity and increased healthcare utilization and costs. IBS has been associated with several intra-intestinal and extra-intestinal conditions, including psychiatric comorbidities. Although the pathophysiology of IBS has not been fully elucidated, it involves dysregulation of communication between the brain and gut (brain-gut axis) which is associated with alterations in intestinal motility, gut permeability, visceral hypersensitivity and gut microbiota composition. The purpose of this article is to review the role the gut microbiota plays in the pathophysiology of IBS, understand factors that affect the gut microbiome and explore the microbiome as a target of treatment.

The Role of Dietary Approach in Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a chronic functional disorder of the gastrointestinal tract and is one of the most frequent gastrointestinal diseases. In IBS multiple pathophysiological mechanisms including alterations in intestinal motility, permeability, nutrient absorption, and intestinal microbiota have been implicated. Foods are commonly reported by patients to be a trigger of symptoms and therefore are likely involved in the generation of symptoms in IBS. Among all possible therapeutic options, a first-line approach to IBS is dietary education and identification of foods potentially responsible for the onset or worsening of symptoms. Dietary approaches include reduction of gas-producing foods (i.e. fermentable oligo-, di-, and monosaccharides and polyols (FODMAPs)), lactose and gluten. Further studies are required to link the ultimate role of diets in different IBS subtypes.

Impact of Intestinal Motility, Mucosal Inflammation and Fecal Microflora on Transplant Intestine Function

Background: Alterations in intestinal motility, fecal microflora and mucosal inflammatory microenvironment may impact allograft intestinal function. Methods: In a cross sectional study, stool samples, intestine biopsies were collected and gastrointestinal scintigraphy using a 6-hour modified gastric emptying test were performed prospectively in adult intestine/multivisceral transplant recipients with (n=10) and without (n=10) excessive diarrhea. Mucosal biopsies were stained for CD163+, CD4+ and CD8+ cells to assess mucosal cellular infiltration. Fecal microorganisms were characterized using shotgun paired-end metagenomic sequencing on the Illumina HiSeq platform. Fecal samples from 6 healthy controls were also compared. Results: Colonic transit time ranged from as short as 1 hour to >6 hours. Overall intestinal motility was within normal limits [1] in 14 (70%) patients, rapid in 5 (25%) patients [Figure 1] and slow in 1(5%) patient, with no correlation between intestinal motility and excessive diarrhea. There were no differences in the mucosal cellular infiltration between the two groups. Overall there were more macrophage infiltration than CD8+ and CD4+ T cells in the mucosal biopsies [Figure 2]. Taxonomic classification of the fecal microflora sequences revealed that, 7 bacterial taxa at the genus level were significantly different in the diarrhea group, including Veillonella (p-value < 0.001), Bifidobacterium (p-value < 0.02), Alistipes (p-value < 0.02), Enterococcus (p-value < 0.02), Odoribacter (p-value < 0.02), Streptococcus (p-value < 0.05), and Lactobacillus (p-value < 0.05) [Figure 3a]. The diversity measured by the Bray-Curtis dissimilarity for the microbial communities in the fecal samples from patients with diarrhea was significantly lower than that in the healthy control samples at the genus level (p-value < 0.05), although the difference between diarrhea and non-diarrhea samples was not statistically significant [Figure 3b]. Conclusions: Excessive diarrhea in intestine transplant recipients without rejection may be a result of less diverse fecal microflora, whereas intestinal motility and mucosal inflammation may not play a significant role. Manipulation of fecal microflora may be useful in controlling chronic diarrhea after intestine transplantation. A study with larger sample size may better define fecal microbial alterations in the setting of intestine transplantation.FigureFigureFigure

Rifaximin for the treatment of irritable bowel syndrome – a drug safety evaluation

ABSTRACTIntroduction: Irritable bowel syndrome is a functional gastrointestinal disorder with a multifactorial etiology. Alterations of intestinal motility and immunity, gut-brain interactions, as well as gut microbiota dysbiosis contribute to the development of irritable bowel syndrome. Therefore, gut microbiota modulation by non-absorbable antibiotics is a therapeutic option in patients with IBS.Areas covered: Published articles including patients with irritable bowel syndrome reporting data about rifaximin activity and safety have been searched throughout the literature and selected.Expert opinion: The optimal antibiotic molecule should be local-acting, long-acting and safe-acting. Rifaximin is a non-absorbable antibiotic with additional anti-inflammatory and gut microbiota-modulating activity. It is effective in inducing symptoms relief in patients with IBS, even after repeated treatment courses. Rifaximin-related side effects in patients with IBS are reported to be mild and infrequent; microbial resistance is rare and transient, due to the high local concentration of the drug and to the absence of horizontal transmission. Clostridium difficile infection is not usual in patients receiving rifaximin in absence of predisposing conditions such as hospitalization and immunosuppression, which are uncommon in patients affected by irritable bowel syndrome. Nevertheless rifaximin is an antibiotic active against Clostridium difficile infection. Rifaximin has limited metabolic interactions and is not expected to interfere with drug metabolism in patients with normal hepatic function. These properties make rifaximin a safe antibiotic for gut microbiota modulation in patients with IBS.

Su1943 Alterations in Intestinal Motility and Gut Microbiota Composition by Maternal Separation Stress in Rats

Su1943 Alterations in Intestinal Motility and Gut Microbiota Composition by Maternal Separation Stress in Rats

Small Bowel Bacterial Overgrowth in Children.

The aim of study was to perform a comprehensive review of the pathogenesis, available diagnostic procedures, prevalence, clinical manifestations, and consequences of small bowel bacterial overgrowth (SBBO) as well as treatment options in the pediatric population. A literature search including MEDLINE, PubMed, and Web of Science databases was performed. SBBO is found in a variety of childhood conditions in which the normal homeostatic mechanisms restricting bacterial colonization in the small bowel are disturbed by congenital or acquired anatomical abnormalities, diminished gastric acid secretion, congenital alteration of intestinal motility or acquired small bowel diseases, or other chronic disorders including primary or acquired immunodeficiency. Data show that SBBO may be an underrecognized cause of pediatric morbidity. Although several diagnostic tests for SBBO determination are available, each has its drawbacks and limitations. Indeed, there is still no "criterion standard" for SBBO diagnosis in the pediatric population. Owing to lack of established guidelines and few published interventional studies that assess the effectiveness of SBBO therapy, treatment of children with SBBO remains empiric and comprises antibiotic or probiotic therapy. Further research is needed to determine the clinical impact of SBBO and to establish diagnostic and therapeutic guidelines applicable to children.

The zebrafish mutant lessen: an experimental model for congenital enteric neuropathies.

Congenital enteric neuropathies of the distal intestine (CEN) are characterized by the partial or complete absence of enteric neurons. Over the last decade, zebrafish has emerged as a leading model organism in experimental research. Our aim was to demonstrate that the mutant zebrafish, lessen, expressing CEN characteristics, is an equally valuable animal model alongside mammalian models for CEN, by studying its enteric phenotype. The effect of the lessen mutation on the development of the enteric nervous system (ENS), interstitial cells of Cajal (ICC), and intestinal motility in each intestinal region of mutant and wild-type (wt) zebrafish embryos at 3-6 dpf, was analyzed by immunofluorescent detection of neurochemical markers and motility assays. Development of intestinal motility in the mutant was delayed and the majority of the observed contractions were disturbed. A significant disturbance in ENS development resulted in a distal intestine that was almost free of neuronal elements, in reduced neuronal density in the proximal and mid-intestine, and in a defect in the expression of neurochemical markers. Furthermore, markedly disturbed development of ICC gave rise to a less dense network of ICC. The observed alterations in intestinal motility, intrinsic innervation and ICC network of the mutant in comparison with the wt zebrafish, are similar to those seen in the oligo- and aganglionic regions of the intestine of CEN patients. It is concluded that the zebrafish mutant lessen is an appropriate animal model to investigate CEN.

Antibiotic-Induced Depletion of Murine Microbiota Induces Mild Inflammation and Changes in Toll-Like Receptor Patterns and Intestinal Motility

We examine the impact of changes in microbiota induced by antibiotics on intestinal motility, gut inflammatory response, and the function and expression of toll-like receptors (TLRs). Alterations in mice intestinal microbiota were induced by antibiotics and evaluated by q-PCR and DGGE analysis. Macroscopic and microscopic assessments of the intestine were performed in control and antibiotic-treated mice. TLR expression was determined in the intestine by q-RT-PCR. Fecal parameter measurements, intestinal transit, and muscle contractility studies were performed to evaluate alterations in intestinal motility. Antibiotics reduced the total bacterial quantity 1000-fold, and diversity was highly affected by treatment. Mice with microbiota depletion had less Peyer's patches, enlarged ceca, and mild gut inflammation. Treatment with antibiotics increased the expression of TLR4, TLR5, and TLR9 in the ileum and TLR3, TLR4, TLR6, TLR7, and TLR8 in the colon, and it reduced the expression of TLR2, TLR3, and TLR6 in the ileum and TLR2 and TLR9 in the colon. Antibiotics decreased fecal output, delayed the whole gut and colonic transit, and reduced the spontaneous contractions and the response to acetylcholine (ACh) in the ileum and colon. Activation of TLR4 by lipopolysaccharide (LPS) reverted the reduction of the spontaneous contractions induced by antibiotics in the ileum. Activation of TLR4 by LPS and TLR5 by flagellin reduced the response to ACh in the ileum in control mice. Our results confirm the role of the microbiota in the regulation of TLRs expression and shed light on the microbiota connection to motor intestinal alterations.

Role of innate immunity and altered intestinal motility in LPS- and MnCl2-induced intestinal intussusception in mice

Intestinal intussusception (ISS) commonly causes intestinal obstruction in children. One mechanism that has been proposed to cause ISS is inflammation-induced alteration of intestinal motility. We investigated whether innate inflammatory factors or altered motility is required for induction of ISS by LPS. We compared rates of ISS among BALB/c and C57BL/6 mice, mice lacking lymphocytes or depleted of phagocytes, or mice with defects in the Toll-like receptor 4 (TLR4) signaling pathway following administration of LPS or the Ca(2+) analog MnCl2. At 6 or 2 h after administration of LPS or MnCl2, respectively, mice underwent image analysis to assess intestinal contraction rate or laparotomy to identify ISS. LPS-induced ISS (LPS-ISS) was observed in BALB/c mice, but not in C57BL/6 mice or any BALB/c mice with disruptions of TLR4 signaling. LPS-induced serum TNF-α, IL-6, and nitric oxide (NO) and intestinal NO levels were similar in BALB/c and C57BL/6 mice. The rate of LPS-ISS was significantly reduced in phagocyte-depleted, but not lymphocyte-deficient, mice. Intestinal contraction rates were reduced in LPS-ISS-susceptible BALB/c mice, but not in LPS-ISS-resistant C57BL/6 or TLR4 mutant mice, suggesting a role for reduced intestinal contraction rate in LPS-ISS susceptibility. This was tested with MnCl2, a Ca(2+) antagonist that reduced intestinal contraction rates and induced ISS, irrespective of mouse strain. Therefore, LPS-ISS is initiated by innate immune signaling that requires TLR4 and phagocytes but may be independent of TNF-α, IL-6, and NO levels. Furthermore, alteration of intestinal motility, specifically, reduced intestinal contraction rate, is a key factor in the development of ISS.

¿Antimicrobianos para el síndrome de intestino irritable?

The Irritable Bowel Syndrome (ibs) is a chronic functional disorder of the digestive tract which courses with discomfort or abdominal pain, diarrhea or constipation, bloating and other intestinal symptoms. Although a unique cause of ibs is unknown, recently it has been emphasized the participation of the bacteria in its pathophysiology, especially by the presentation of the ibs after gastrointestinal infections. The presence of bacterial overgrowth in the small intestine and changes of the intestinal micro-biota may cause intestinal micro-inflammation, alterations of intestinal motility, visceral hypersensitivity and excessive production of gas, which would be the cause of the symptoms. A longer clinical response after the use of non absorbable antibiotics of wide spectrum, especially rifaximina, supports the concept and provides an additional treatment for many patients.

Papel Da Ultrassonografia No Abdome Agudo Obstrutivo

Acute intestinal obstruction represents an intestinal obstruction syndrome caused by the presence of an obstacle or mechanical alteration of intestinal motility that prevents the normal progression of the bolus. Approximately 20% of hospital admissions for abdominal pain are due to intestinal obstruction, and of these, 80% occur in the small bowel and 20% in the large bowel.

Use of duodenal ultrasonography to detect alterations in intestinal motility of endurance horses

Colic is a common cause of morbidity and mortality in the endurance horse. Detection of ileus may promote earlier intervention, preventing progression to colic. The purpose of this study was to evaluate the effect of a 50 mile (80.46 km) endurance ride on duodenal motility in endurance horses using trans-abdominal (duodenal) ultrasonography, and compare duodenal motility to gastrointestinal motility as assessed by gastrointestinal auscultation. 29 horses competing in five different 50 mile rides were included in this prospective study. Signalment, experience level, and ride performance data were recorded. Physical examination findings were recorded before and at completion of the ride. Trans-abdominal ultrasonography was performed before and within 90 min of completion of the ride to assess duodenal contractility. Duodenal motility assessed via ultrasonography decreased from before to after the race in horses undergoing ultrasound evaluation within 60 min of completion (P=0.03). Gastrointestinal motility assessed via auscultation decreased significantly after the race (P=0.03). Duodenal motility was negatively correlated with physical examination findings of dehydration and altered metabolic status. These findings indicate that gastrointestinal motility in horses is decreased by endurance exercise. Ultrasonography appears to be a useful method for objective assessment of motility in endurance horses.

Antiulcerogenic Activity of the Hydroalcoholic Extract of Leaves ofCroton campestrisA. St.-Hill in Rodents

Croton campestris A. St.-Hill., popularly known as “velame do campo,” is a species native to the savannah area of Northeast Brazil, which is used by traditional communities in folk medicine for variety of health problems, especially detoxification, inflammation, and gastritis. The hydroalcoholic extract of C. campestris leaves (HELCC) was assessed for its antiulcerogenic effect in gastric lesion models and effect on intestinal motility in mice, and possible mechanisms of action were examined. HELCC showed significant gastroprotective action in all models of gastric ulcer evaluated; the results suggest that this action probably involves the nitric oxide pathway. HELCC did not show alteration of intestinal motility in mice. It was also found that C. campestris represents a promising natural source with important biological potential, justifying some of its uses in folk medicine.

Effect of Oroxylum indicum on intestinal motility in rodents

Oroxylum indicum is traditional herbal medicine in India, China and Japan used for its anti-diarrhoeal/anti-dysenteric activity, also found to be active against experimentally induced (DNBS induced) inflammatory bowel disease in rats with potential reduction in diarrhoea. It promotes us to evaluate effects of Oroxylum indicum on intestinal motility, both in vitro and in vivo, in rodents. Flavonoids rich fraction of O. indicum was obtained and the effect of extract on contraction of acetylcholine, barium chloride and electrical field stimulation was studied on isolated rabbit ileum. Anti-diarrhoeal activities were investigated using castor oil and magnesium sulphate-induced diarrhoeal models in mice. Effect on intestinal motility was studied using gastrointestinal motility and antienteropooling assay methods. Antimicrobial activity of extract was evaluated using disc diffusion assay method. Extract inhibited the contractions induced by acetylcholine, barium chloride and electrical field stimulation. Verapamil potentiates inhibitory effect of extract. Extract showed significant and dose-dependent anti-diarrhoeal effect devoid of altering gastrointestinal motility in normal animals. It also inhibited the microbial growth in disc diffusion assay method. Extract normalized intestinal motility altered by inflammatory stimulus and possesses antidiarrhoeal activity. Alteration of intestinal motility may involve modification in L-type Ca2+ channels.

Tu1439 Fecal Cysteine Protease Activity in Patients With Irritable Bowel Syndrome -Clinical and Physiological Aspects.

Increased activity of fecal proteases has been reported in patients with irritable bowel syndrome (IBS). Animal studies demonstrated that fecal proteases induce physiological alterations in intestinal motility, sensation and permeability, similar to those found in patients with IBS. Fecal cysteine-protease has been suggested to have a role in the pathogenesis of C-IBS. However, fecal cysteine-protease has not been investigated in other subtypes of IBS and its relationship with IBS symptoms and intestinal physiology is unknown. Aims: To measure and compare the level of fecal cysteine-protease activity (FCPA) between patients with IBS, subtypes of IBS, and healthy controls and to investigate the relationship between FCPA, abdominal pain, IBS severity and gastrointestinal transit. Methods: We studied a total of 60 patients who met the Rome III criteria for IBS (C-IBS, n=14; D-IBS, n=28; MIBS, n=18) and 34 healthy controls. FCPA was measured in homogenized fecal samples of all subjects using an enzymatic-based method with specific substrates and inhibitors, and expressed as Δfluo/mg protein. Abdominal pain was assessed using a 0-10 scale and IBS severity scores was assessed by IBS-Symptom Severity Scale. Wireless Motility Capsule (SmartPillTM) was used to measure small bowel (SBTT), colonic (CTT), and whole gut (WGTT) transit times. Comparisons of FCPA between the groups of interest were done using student t-tests. Pearson correlation analysis was used to assess the association between FCPA and clinical and physiological variables. Results: Compared to HC, subjects with IBS, and all subtypes of IBS, had significantly higher levels of FCPA (HC: 128.0±334.4; all IBS: 595.9±853.1, p=0.03; D-IBS: 447.4±635.2, p=0.014; M-IBS: 749.9±748.5, p<0.0001; CIBS: 694.8±1281.2, p=0.02 respectively). Subjects with C-IBS had significantly higher FCPA levels than D-IBS (p<0.0001). FCPA levels showed a significant positive correlation with abdominal pain (r=0.37, p=0.006) and a trend of a positive correlation with IBS symptom severity (r=0.24, p=0.08). No correlation was found between FCPA levels and the transit time variables of interest. Demographic characteristics were similar between the groups. Conclusions: We provide evidence for significant differences in FCPA between patients with IBS, subtypes of IBS and healthy controls. FCPA is strongly correlated with abdominal pain, a hallmark symptom of IBS. These findings suggest a role for luminal cysteine protease in the pathogenesis of IBS.

Nuclear factor κB is a key transcription factor in the duodenal contractility alterations induced by lipopolysaccharide

Alterations in intestinal motility are one of the features of sepsis induced by lipopolysaccharide (LPS). This study investigated the role of the nuclear transcription factor κB (NF-κB) in the LPS-induced duodenal contractility alterations, generation of reactive oxygen species (ROS) and production of cytokines in rabbit duodenum. Rabbits were treated with saline, LPS, sulfasalazine + LPS, pyrrolidinedithiocarbamate (PDTC) + LPS or RO 106-9920 + LPS. Contractility studies were performed in an organ bath. The formation of products of oxidative damage to proteins (carbonyls) and lipids (malondialdehyde and 4-hydroxyalkenals) was quantified in intestinal tissue and plasma. The protein expression of NF-κB was measured by Western blot. The DNA binding activity of NF-κB was evaluated by transcription factor activity assay. The expression of interleukin-1β, tumour necrosis factor α (TNF-α), interleukin-6, interleukin-10 and interleukin-8 mRNA was determined by RT-PCR. Sulfasalazine, PDTC and RO 106-9920 blocked the inhibitory effect of LPS on contractions induced by ACh in the longitudinal smooth muscle of rabbit duodenum. Sulfasalazine, PDTC and RO 106-9920 reduced the increased levels of malondialdehyde and 4-hydroxyalkenals and the carbonyls induced by LPS in plasma. Lipopolysaccharide induced the activation, translocation to the nucleus and DNA binding of NF-κB. Lipopolysaccharide increased the mRNA expression of interleukin-6 and TNF-α in duodenal tissue, and this effect was partly reversed by PDTC, sulfasalazine and RO 106-9920. In conclusion, NF-κB mediates duodenal contractility disturbances, the generation of ROS and the increase in the expression of interleukin-6 and TNF-α induced by LPS. Sulfasalazine, PDTC and RO 106-9920 may be therapeutic drugs to reduce these effects.

Gastrointestinal infections and the development of irritable bowel syndrome

Approximately 10% of the millions of persons with functional gastrointestinal disorders (FGDs) including irritable bowel syndrome (IBS) had their illness onset following an acute bout of infectious diarrhea and are referred to as having postinfectious (PI) FGD or PI-IBS. Recent studies have helped to identify the pathogenesis and natural history of these disorders. Groups of patients with acute diarrhea or dysentery (passage of grossly bloody stools) are being followed for development of PI-IBS. Persistent mucosal inflammation, air trapping in the gut, and alteration of intestinal motility contribute to the disease symptoms in genetically susceptible persons. The prognosis of postinfectious forms of IBS is more favorable compared with people with idiopathic forms of the disorder. With full characterization of postdiarrhea forms of FGDs, we should be able to define the mechanisms of disease early in the course of chronic illness and to better understand the more common idiopathic forms of the disease. We are likely to identify specific alteration of gut pathophysiology in postinfectious FGDs and to then classify them not as a poorly characterized group of functional disorders but as specific gastrointestinal disorders.

Serotonin Receptor Type 3 Antagonists Improve Obesity-Associated Fatty Liver Disease in Mice

Obesity is a major cause for nonalcoholic fatty liver disease (NAFLD). Previous studies suggested that alterations in intestinal motility and permeability contribute to the development of NAFLD. Serotonin and serotonin receptor type 3 (5-HT(3)R) are key factors in the regulation of intestinal motility and permeability. Therefore, we studied the effect of the 5-HT(3)R antagonists tropisetron and palonosetron on the development of NAFLD in leptin-deficient obese mice. Four-week-old ob/ob mice and lean controls were treated for 6 weeks orally with tropisetron or palonosetron at 0.2 mg/kg per day. We determined markers of liver damage and inflammation, portal endotoxin levels, and duodenal concentrations of serotonin, serotonin-reuptake transporter (SERT), occludin, and claudin-1. Tropisetron treatment significantly reduced liver fat content (-29%), liver inflammation (-56%), and liver cell necrosis (-59%) in ob/ob mice. The beneficial effects of tropisetron were accompanied by a decrease in plasma alanine aminotransferase and portal vein plasma endotoxin levels, an attenuation of enhanced MyD88 and tumor necrosis factor-α mRNA expression in the liver, and an increase of tight junction proteins in the duodenum. Tropisetron treatment also caused a reduction of elevated serotonin levels and an increase of SERT in the duodenum of ob/ob mice. Palonosetron had similar effects as tropisetron with regard to the reduction of liver fat and other parameters. Tropisetron and palonosetron are effective in attenuating NAFLD in a genetic mouse model of obesity. The effect involves the intestinal nervous system, resulting in a reduction of endotoxin influx into the liver and subsequently of liver inflammation and fat accumulation.