Dietary Carbohydrates and Lipids in the Pathogenesis of Leaky Gut Syndrome: An Overview

This review summarizes the recent knowledge on the effects of dietary carbohydrates and lipids on the pathophysiology of leaky gut syndrome (LGS). Alterations in intestinal barrier permeability may lead to serious gastrointestinal (GI) disorders. LGS is caused by intestinal hyperpermeability due to changes in the expression levels and functioning of tight junctions. The influence of dietary habits on intestinal physiology is clearly visible in incidence rates of intestinal diseases in industrial and developing countries. Diseases which are linked to intestinal hyperpermeability tend to localize to Westernized countries, where a diet rich in fats and refined carbohydrates predominates. Several studies suggest that fructose is one of the key carbohydrates involved in the regulation of the intestinal permeability and its overuse may cause harmful effects, such as tight junction protein dysfunction. On the other hand, short chain fatty acids (mainly butyrate) at appropriate concentrations may lead to the reduction of intestinal permeability, which is beneficial in LGS. However, long chain fatty acids, including n-3 and n-6 polyunsaturated fatty acids have unclear properties. Some of those behave as components untightening and tightening the intestinal membrane

Preventing Bacterial Translocation in Patients with Leaky Gut Syndrome: Nutrition and Pharmacological Treatment Options

Leaky gut syndrome is a medical condition characterized by intestinal hyperpermeability. Since the intestinal barrier is one of the essential components maintaining homeostasis along the gastrointestinal tract, loss of its integrity due to changes in bacterial composition, decreased expression levels of tight junction proteins, and increased concentration of pro-inflammatory cytokines may lead to intestinal hyperpermeability followed by the development of gastrointestinal and non-gastrointestinal diseases. Translocation of microorganisms and their toxic metabolites beyond the gastrointestinal tract is one of the fallouts of the leaky gut syndrome. The presence of intestinal bacteria in sterile tissues and distant organs may cause damage due to chronic inflammation and progression of disorders, including inflammatory bowel diseases, liver cirrhosis, and acute pancreatitis. Currently, there are no medical guidelines for the treatment or prevention of bacterial translocation in patients with the leaky gut syndrome; however, several studies suggest that dietary intervention can improve barrier function and restrict bacteria invasion. This review contains current literature data concerning the influence of diet, dietary supplements, probiotics, and drugs on intestinal permeability and bacterial translocation

AdipoRon, an Orally Active, Synthetic Agonist of AdipoR1 and AdipoR2 Receptors Has Gastroprotective Effect in Experimentally Induced Gastric Ulcers in Mice

Introduction: Adiponectin is a hormone secreted by adipocytes, which exhibits insulin-sensitizing and anti-inflammatory properties and acts through adiponectin receptors: AdipoR1 and AdipoR2. The aim of the study was to evaluate whether activation of adiponectin receptors AdipoR1 and AdipoR2 with an orally active agonist AdipoRon has gastroprotective effect and to investigate the possible underlying mechanism. Methods: We used two well-established mouse models of gastric ulcer (GU) induced by oral administration of EtOH (80% solution in water) or diclofenac (30 mg/kg, p.o.). Gastroprotective effect of AdipoRon (dose 5 and 50 mg /kg p.o) was compared to omeprazole (20 mg/kg p.o.) or 5% DMSO solution (control). Clinical parameters of gastroprotection were assessed using macroscopic (gastric lesion area) and microscopic (evaluation of the gastric mucosa damage) scoring. To establish the molecular mechanism, we measured: myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) activities; glutathione (GSH) level; and IL-1β, adenosine monophosphate-activated protein kinase (AMPK), and phosphorylated AMPK expression in gastric tissue. Results: AdipoRon produced a gastroprotective effect in both GU mouse models as evidenced by significantly lower macroscopic and microscopic damage scores. AdipoRon exhibited anti-inflammatory effect by reduction in MPO activity and IL-1β expression in the gastric tissue. Moreover, AdipoRon induced antioxidative action, as demonstrated with higher GSH levels, and increased SOD and GPX activity. Conclusions: Activation of AdipoR1 and AdipoR2 using AdipoRon reduced gastric lesions and enhanced cell response to oxidative stress. Our data suggest that AdipoR1 and AdipoR2 activation may be an attractive therapeutic strategy to inhibit development of gastric ulcers

Activation of Free Fatty Acid Receptor 4 Affects Intestinal Inflammation and Improves Colon Permeability in Mice

Diet is considered an important trigger in inflammatory bowel diseases (IBD), as feeding habits can affect intestinal permeability and clearance of bacterial antigens, consequently influencing the immune system. Free fatty acid receptors (FFARs), expressed on the intestinal epithelial cells, belong to the family of luminal-facing receptors that are responsive to nutrients. The objective of this study was to characterize the anti-inflammatory activity and the effect on intestinal barrier function of synthetic FFAR agonists in mouse models of colitis. Therapeutic activity of GW9508 (FFAR1 agonist), 4-CMTB (FFAR2 agonist), AR420626 (FFAR3 agonist), and GSK137647 (FFAR4 agonist) was investigated in two models of semi-chronic colitis: induced by trinitrobenzenesulfonic acid (TNBS), mimicking Crohn’s disease, as well as induced by dextran sulfate sodium (DSS), which recapitulates ulcerative colitis in humans. Moreover, we assessed the influence of FFARs agonists on epithelial ion transport and measured the ion flow stimulated by forskolin and veratridine. Administration of FFAR4 agonist GSK137647 attenuated both TNBS-induced and DSS-induced colitis in mice, as indicated by macroscopic parameters and myeloperoxidase activity. The action of FFAR4 agonist GSK137647 was significantly blocked by pretreatment with selective FFAR4 antagonist AH7614. Moreover, FFAR1 and FFAR4 agonists reversed the increase in the colon permeability caused by inflammation. FFAR4 restored the tight junction genes expression in mouse colon. This is the first evaluation of the anti-inflammatory activity of selective FFAR agonists, showing that pharmacological intervention targeting FFAR4, which is a sensor of medium and long chain fatty acids, attenuates intestinal inflammation

Characterization of the Synergistic Effect between Ligands of Opioid and Free Fatty Acid Receptors in the Mouse Model of Colitis

Background: Recent studies suggest that lipids, including free fatty acids (FFAs), are necessary for proper μ opioid receptor (MOR) binding and that activation of opioid receptors (ORs) improves intestinal inflammation. The objective of the study was to investigate a possible interaction between the ORs and FFA receptors (FFARs) ligands in the colitis. Methods: The potential synergistic effect of ORs and FFARs ligands was evaluated using mouse model of acute colitis induced by dextran sulfate sodium (DSS, 4%). Compounds were injected intraperitoneally (i.p.) once or twice daily at the doses of 0.01 or 0.02 mg/kg body weight (BW) (DAMGO—an MOR agonist), 0.3 mg/kg BW (DPDPE—a δ OR (DOR) agonist) and 1 mg/kg BW (naloxone—a non-selective OR antagonist, GLPG 0974—a FFAR2 antagonist, GSK 137647—a FFAR4 agonist and AH 7614—a FFAR4 antagonist) for 4 days. Results: Myeloperoxidase (MPO) activity was significantly decreased after DAMGO (0.02 mg/kg BW) and GSK 137647 (1 mg/kg BW) administration and co-administration as compared to DSS group. Conclusions: Treatment with ligands of ORs and FFARs may affect the immune cells in the inflammation; however, no significant influence on the severity of colitis and no synergistic effect were observed

Expression of FFAR3 and FFAR4 Is Increased in Gastroesophageal Reflux Disease

Background: The negative impact of a high-fat diet on the course of gastroesophageal reflux disease (GERD) has been previously reported. Free fatty acid receptors (FFARs) may be mediators of this phenomenon. The aim of this study was to characterize the role of FFARs in the course of nonerosive (NERD) and erosive (ERD) reflux disease. Methods: Collectively, 73 patients (62 with GERD and 11 healthy controls (HCs)) were recruited to the study. Esophageal biopsies were drawn from the lower third of the esophagus and kept for further experiments. Quantitative, real-time polymerase chain reaction was used to assess the expression of FFAR1, FFAR2, FFAR3, and FFAR4 in biopsies. Histological evaluation of dilated intracellular spaces (DISs) was also performed. Results: FFAR3 exhibited the highest expression, and FFAR4 exhibited the lowest expression in all esophageal samples. Higher relative expression of FFAR1 and FFAR2 and significantly higher expression of FFAR3 (p = 0.04) was noted in patients with GERD compared to respective HCs. Patients with nonerosive GERD (NERD) presented higher expression of all FFARs compared to patients with erosive GERD (ERD) and respective HCs. Interestingly, in patients with ERD, the expression of FFAR3 was lower than in HCs. Significant, weak, positive correlation was found for FFAR3 and FFAR4 expression and DIS scores (r = 0.36, p < 0.05 for FFAR 3, and r = 0.39, p < 0.05 for FFAR4). Conclusions: In this study, we show that FFARs may play a role in GERD pathogenesis, particularly in the NERD type. It may be assumed that FFARs, in particular FFAR3 and FFAR4, may have diagnostic and therapeutic potential in GERD