|
1
|
Lee SH, Han C, Shin C. IUPHAR Review: Microbiota-Gut-Brain Axis and its role in Neuropsychiatric Disorders. Pharmacol Res 2025; 216:107749. [PMID: 40306604 DOI: 10.1016/j.phrs.2025.107749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2025] [Revised: 04/20/2025] [Accepted: 04/25/2025] [Indexed: 05/02/2025]
Abstract
The human gut microbiome, composed of a vast array of microorganisms that have co-evolved with humans, is crucial for the development and function of brain systems. Research has consistently shown bidirectional communication between the gut and the brain through neuronal, endocrine, and immunological, and chemical pathways. Recent neuroscience studies have linked changes in the microbiome and microbial metabolites to various neuropsychiatric disorders such as autism, depression, anxiety, schizophrenia, eating disorders, and neurocognitive disorders. Novel metagenome-wide association studies have confirmed these microbiome variations in large samples and expanded our understanding of the interactions between human genes and the gut microbiome. The causal relationship between gut microbiota and neuropsychiatric disorders is being elucidated through the establishment of large cohort studies incorporating microbiome data and advanced statistical techniques. Ongoing animal and human studies focused on the microbiota-gut-brain axis are promising for developing new prevention and treatment strategies for neuropsychiatric conditions. The scope of these studies has broadened from microbiome-modulating therapies including prebiotics, probiotics, synbiotics and postbiotics to more extensive approaches such as fecal microbiota transplantation. Recent systematic reviews and meta-analyses have strengthened the evidence base for these innovative treatments. Despite extensive research over the past decade, many intriguing aspects still need to be elucidated regarding the role and therapeutic interventions of the microbiota-gut-brain axis in neuropsychiatric disorders.
Collapse
Affiliation(s)
- Seung-Hoon Lee
- Department of Psychiatry, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Changsu Han
- Department of Psychiatry, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Cheolmin Shin
- Department of Psychiatry, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
| |
Collapse
|
|
2
|
Vieira-Neto A, Lean IJ, Santos JEP. Periparturient Mineral Metabolism: Implications to Health and Productivity. Animals (Basel) 2024; 14:1232. [PMID: 38672379 PMCID: PMC11047658 DOI: 10.3390/ani14081232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/02/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Mineral metabolism, in particular Ca, and to a lesser extent phosphorus (P) and magnesium (Mg), is altered with the onset of lactation because of extensive irreversible loss to synthesize colostrum and milk. The transient reduction in the concentration of Ca in blood, particularly when it lasts days, increases the risk of mineral-related disorders such as hypocalcemia and, to a lesser extent, hypophosphatemia. Although the incidence of clinical hypocalcemia can be reduced by prepartum dietary interventions, subclinical hypocalcemia remains prevalent, affecting up to 60% of the dairy cows in the first 3 d postpartum. More importantly, strong associations exist between hypocalcemia and increased susceptibility to other peripartum diseases and impaired reproductive performance. Mechanistic experiments have demonstrated the role of Ca on innate immune response in dairy cows, which presumably predisposes them to other diseases. Hypocalcemia is not related to inadequate Ca intake as prepartum diets marginal to deficient in Ca reduce the risk of the disease. Therefore, the understanding of how Ca homeostasis is regulated, in particular how calciotropic hormones such as parathyroid hormone and 1,25-dihydroxyvitamin D3, affect blood Ca concentrations, gastrointestinal Ca absorption, bone remodeling, and renal excretion of Ca become critical to develop novel strategies to prevent mineral imbalances either by nutritional or pharmacological interventions. A common method to reduce the risk of hypocalcemia is the manipulation of the prepartum dietary cation-anion difference. Feeding acidogenic diets not only improves Ca homeostasis and reduces hypocalcemia, but also reduces the risk of uterine diseases and improves productive performance. Feeding diets that induce a negative Ca balance in the last weeks of gestation also reduce the risk of clinical hypocalcemia, and recent work shows that the incorporation of mineral sequestering agents, presumably by reducing the absorption of P and Ca prepartum, increases blood Ca at calving, although benefits to production and health remain to be shown. Alternative strategies to minimize subclinical hypocalcemia with the use of vitamin D metabolites either fed prepartum or as a pharmacological agent administered immediately after calving have shown promising results in reducing hypocalcemia and altering immune cell function, which might prove efficacious to prevent diseases in early lactation. This review summarizes the current understanding of Ca homeostasis around parturition, the limited knowledge of the exact mechanisms for gastrointestinal Ca absorption in bovine, the implications of hypocalcemia on the health of dairy cows, and discusses the methods to minimize the risk of hypocalcemia and their impacts on productive performance and health in dairy cows.
Collapse
Affiliation(s)
- Achilles Vieira-Neto
- Department of Animal Sciences, University of Florida, Gainesville, FL 32611, USA;
| | - Ian J. Lean
- Scibus, Camden, NSW 2570, Australia;
- Faculty of Veterinary Science, The University of Sydney, Camden, NSW 2570, Australia
| | - José Eduardo P. Santos
- Department of Animal Sciences, University of Florida, Gainesville, FL 32611, USA;
- DH Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, FL 32611, USA
| |
Collapse
|
|
3
|
Opgenorth J, Mayorga EJ, Abeyta MA, Goetz BM, Rodriguez-Jimenez S, Freestone A, Stahl CH, Baumgard LH. Calcium trafficking and gastrointestinal physiology following an acute lipopolysaccharide challenge in pigs. J Anim Sci 2024; 102:skae073. [PMID: 38483214 PMCID: PMC11034434 DOI: 10.1093/jas/skae073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 03/13/2024] [Indexed: 04/23/2024] Open
Abstract
The influence of systemic immune activation on whole-body calcium (Ca) trafficking and gastrointestinal tract (GIT) physiology is not clear. Thus, the study objectives were to characterize the effects of lipopolysaccharide (LPS) on Ca pools and GIT dynamics to increase understanding of immune-induced hypocalcemia, ileus, and stomach hemorrhaging. Twelve crossbred pigs [44 ± 3 kg body weight (BW)] were randomly assigned to 1 of 2 intramuscular treatments: (1) control (CON; 2 mL saline; n = 6) or (2) LPS (40 µg LPS/kg BW; n = 6). Pigs were housed in metabolism stalls to collect total urine and feces for 6 h after treatment administration, at which point they were euthanized, and various tissues, organs, fluids, and digesta were weighed, and analyzed for Ca content. Data were analyzed with the MIXED procedure in SAS 9.4. Rectal temperature and respiration rate increased in LPS relative to CON pigs (1.4 °C and 32%, respectively; P ≤ 0.05). Inflammatory biomarkers such as circulating alkaline phosphatase, aspartate aminotransferase, and total bilirubin increased in LPS compared with CON pigs whereas albumin decreased (P ≤ 0.02). Plasma glucose and urea nitrogen decreased and increased, respectively, after LPS (43% and 80%, respectively; P < 0.01). Pigs administered LPS had reduced circulating ionized calcium (iCa) compared to CON (15%; P < 0.01). Considering estimations of total blood volume, LPS caused an iCa deficit of 23 mg relative to CON (P < 0.01). Adipose tissue and urine from LPS pigs had reduced Ca compared to CON (39% and 77%, respectively; P ≤ 0.05). There did not appear to be increased Ca efflux into GIT contents and no detectable increases in other organ or tissue Ca concentrations were identified. Thus, while LPS caused hypocalcemia, we were unable to determine where circulating Ca was trafficked. LPS administration markedly altered GIT dynamics including stomach hemorrhaging, diarrhea (increased fecal output and moisture), and reduced small intestine and fecal pH (P ≤ 0.06). Taken together, changes in GIT physiology suggested dyshomeostasis and alimentary pathology. Future research is required to fully elucidate the etiology of immune activation-induced hypocalcemia and GIT pathophysiology.
Collapse
Affiliation(s)
- Julie Opgenorth
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - Edith J Mayorga
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - Megan A Abeyta
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - Brady M Goetz
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | | | - Alyssa D Freestone
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| | - Chad H Stahl
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA
| | - Lance H Baumgard
- Department of Animal Science, Iowa State University, Ames, IA 50011, USA
| |
Collapse
|
|
4
|
Gao X, Yang W, Li S, Liu S, Yang W, Song S, Sheng J, Zhao Y, Tian Y. Moringa oleifera leaf alleviates functional constipation via regulating the gut microbiota and the enteric nervous system in mice. Front Microbiol 2023; 14:1315402. [PMID: 38192287 PMCID: PMC10773919 DOI: 10.3389/fmicb.2023.1315402] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/04/2023] [Indexed: 01/10/2024] Open
Abstract
Moringa oleifera Lam. leaf is not only a new food resource in China, but also a traditional medicinal plant. It is commonly used in the folk to alleviate constipation, but its laxative mechanism is not fully understood. Hence we investigated it in loperamide-induced functional constipation (FC) mice. The results showed that MOAE significantly regulated not only gastrointestinal hormones and neurotransmitters in serum but also important gastrointestinal motility factors in the enteric nervous system (ENS)-interstitial cells of Cajal (ICCs)-smooth muscle cell (SMC) network. Meanwhile, MOAE attenuated intestinal inflammation, increased cecal short-chain fatty acid levels and colonic antimicrobial peptide expression, and improved the impaired intestinal barrier function in loperamide-induced FC mice. In addition, MOAE also increased fecal water content by inhibiting the mRNA expression of colonic aquaporins (Aqp3 and Aqp4) in FC mice. Interestingly and importantly, MOAE affected the intestinal microbiota by inhibiting some key "constipation-causing" microbiota, such as Bacteroidaceae, Clostridiaceae, Bacteroides, and Ruminococcus, and promoting the growth of other important "constipation-curing" microbiota, such as Butyricoccus, Tyzzerella, and Desulfovibrio. These important taxa are significantly associated with a variety of indicators of constipation. These findings suggest that MOAE can promote defecation through its rich chemical composition to modulate the ENS-ICCs-SMCs network and the gut microecosystem.
Collapse
Affiliation(s)
- Xiaoyu Gao
- Yunnan Key Laboratory of Precision Nutrition and Personalized Food Manufacturing, Yunnan Agricultural University, Kunming, China
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
- Engineering Research Center of Development and Utilization of Food and Drug Homologous Resources, Ministry of Education, Yunnan Agricultural University, Kunming, China
| | - Weiqian Yang
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
- Department of Hotel Management, Chongqing Vocational Institute of Tourism, Chongqing, China
| | - Sijin Li
- College of Pu’er Tea West Yunnan University of Applied Sciences, Puer, China
| | - Shuangfeng Liu
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
- Engineering Research Center of Development and Utilization of Food and Drug Homologous Resources, Ministry of Education, Yunnan Agricultural University, Kunming, China
| | - Weixing Yang
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Shuang Song
- College of Food Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Jun Sheng
- Engineering Research Center of Development and Utilization of Food and Drug Homologous Resources, Ministry of Education, Yunnan Agricultural University, Kunming, China
| | - Yan Zhao
- Division of Science and Technology, Yunnan Agricultural University, Kunming, China
| | - Yang Tian
- Yunnan Key Laboratory of Precision Nutrition and Personalized Food Manufacturing, Yunnan Agricultural University, Kunming, China
- Engineering Research Center of Development and Utilization of Food and Drug Homologous Resources, Ministry of Education, Yunnan Agricultural University, Kunming, China
| |
Collapse
|
|
5
|
Xu Y, Shao M, Fang X, Tang W, Zhou C, Hu X, Zhang X, Su KP. Antipsychotic-induced gastrointestinal hypomotility and the alteration in gut microbiota in patients with schizophrenia. Brain Behav Immun 2022; 99:119-129. [PMID: 34563620 DOI: 10.1016/j.bbi.2021.09.014] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/13/2021] [Accepted: 09/18/2021] [Indexed: 12/18/2022] Open
Abstract
AIM Gut microbiota play an important role in the pathogenesis of gut hypomotility and are critical for the production of the intestinal immune system and the maintenance of the intestinal homeostasis. Patients with psychotic disorders are at a high risk of antipsychotic-induced constipation. However, the mechanisms might be more than neurotransmission properties of antipsychotics. METHODS We recruited a total of 45 patients with constipation according to Rome IV criteria and objective test for colonic motility and the other 45 gender- and age-matching patients without constipation and investigated their differences in composition of gut microbiota. The demographic and serum metabolic indices were collected. The subjective constipation assessment scale (CAS) and the Bristol stool classification (BSS) were also used to evaluate the degree of constipation in both groups. The fecal samples were analysed using the 16S rRNA gene sequencing. RESULTS The constipation group had a significantly increased alpha diversity in Observed species, Chao 1, and ACE as compared to the non-constipation group. At the phylum levels, the relative abundances of Bacteroidetes and Fusobacteria decreased significantly, while those of Firmicutes, Verrucomicrobia, and Synergistetes increased significantly in the constipation group. At the genus level, the relative abundances of Christensenella and Desulfovibrio were higher in the constipation group. The α-diversity indices of gut microbiota were correlated positively with the levels of serum total bile acid and correlated negatively with BSS scores. The BSS scores were positively correlated with the relative abundance of Bacteroidetes but negatively correlated with the relative abundance of Firmicutes. PICRUSt analysis revealed the potential metabolic pathways of lipopolysaccharide, vitamin B6, riboflavin, pyruvate, and propionate functions. CONCLUSIONS The alternation of the gut microbiota in schizophrenia patients with antipsychotic-induced constipation indicates antipsychotic agents might affect gastrointestinal motility via varying microbiome-related metabolites, and the specific bacteria, such as Synergistetes which might act as an anti-inflammatory factor in the healthy human gut, related to colonic transit motility seem inconsistent to the findings from previous literature in gastroenterology. However, the causal effects are still unknown. Our study provides a new possibility to understand the mechanisms of antipsychotic-induced constipation.
Collapse
Affiliation(s)
- Yue Xu
- Department of Geriatric Psychiatry, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, PR China
| | - Miaomiao Shao
- Department of Psychiatry, Jiangning District Second People' s Hospital, Nanjing, PR China
| | - Xinyu Fang
- Department of Geriatric Psychiatry, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, PR China
| | - Wei Tang
- The Affiliated Kangning Hospital of Wenzhou Medical University, Wenzhou Medical University, Wenzhou, PR China
| | - Chao Zhou
- Department of Geriatric Psychiatry, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, PR China
| | - Xiuxiu Hu
- Department of Psychiatry, Jiangning District Second People' s Hospital, Nanjing, PR China
| | - Xiangrong Zhang
- Department of Geriatric Psychiatry, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, PR China.
| | - Kuan-Pin Su
- Department of Psychiatry & Mind-Body Interface Laboratory (MBI-Lab), China Medical University Hospital, Taichung, Taiwan; An-Nan Hospital, China Medical University, Tainan, Taiwan; Institute of Psychiatry, King's College London, London, UK.
| |
Collapse
|
|
6
|
Cao PQ, Li XP, Ou-Yang J, Jiang RG, Huang FF, Wen BB, Zhang XN, Huang JA, Liu ZH. The protective effects of yellow tea extract against loperamide-induced constipation in mice. Food Funct 2021; 12:5621-5636. [PMID: 34018494 DOI: 10.1039/d0fo02969f] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Yellow tea, a rare type tea from China, has a rich breadth of functional ingredients and benefits the gastrointestinal tract. However, it is not clear whether the yellow tea extract can alleviate constipation. Therefore, we used loperamide-induced constipation in mice to evaluate the effects of yellow tea extract. Fifty Kunming mice were randomly divided into five groups: normal, model, low-dose yellow tea extract, low-dose yellow tea extract prevention group, and high-dose yellow tea extract prevention group. Mice were administered yellow tea extract for 5 weeks followed by loperamide-induced constipation for the final 2 weeks. The results showed that yellow tea extract alleviated constipation symptoms by improving the fecal water content, defecation weight, and gastrointestinal transit rate. Yellow tea extract intervention also protected colon tissue, regulated serum neurotransmitters, and decreased the vasoactive intestinal peptide level. Furthermore, qRT-PCR indicated that yellow tea extract regulated genes associated with the constipation state, raised 5-HT3 and 5-HT4 and reduced AQP3 and AQP4 mRNA expression. Moreover, we found that yellow tea extract changed the gut microbiota composition. Community diversity and richness were increased and principal co-ordinate analysis demonstrated that the yellow tea extract prophylaxis groups differed from the model group. Difference analysis indicated that yellow tea extract increased Roseburia, Lachnospiraceae_UCG-006, and Bifidobacterium and decreased norank_f_Clostridiales_vadinBB60_group, unclassified_o_Bacteroidales, and Bacteroides, which are correlated with constipation. Based on these results, we believe that regular yellow tea consumption can effectively alleviate constipation.
Collapse
Affiliation(s)
- Pei-Qin Cao
- Key Laboratory of Ministry of Education for Tea Science, Hunan Agricultural University, Changsha 410128, China.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
7
|
Heeney A, Rogers AC, Mohan H, Mc Dermott F, Baird AW, Winter DC. Prostaglandin E 2 receptors and their role in gastrointestinal motility - Potential therapeutic targets. Prostaglandins Other Lipid Mediat 2021; 152:106499. [PMID: 33035691 DOI: 10.1016/j.prostaglandins.2020.106499] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Revised: 07/20/2020] [Accepted: 10/01/2020] [Indexed: 12/19/2022]
Abstract
Prostaglandin E2 (PGE2) is found throughout the gastrointestinal tract in a diverse variety of functions and roles. The recent discovery of four PGE2 receptor subtypes in intestinal muscle layers as well as in the enteric plexus has led to much interest in the study of their roles in gut motility. Gut dysmotility has been implicated in functional disease processes including irritable bowel syndrome (IBS) and slow transit constipation, and lubiprostone, a PGE2 derivative, has recently been licensed to treat both conditions. The diversity of actions of PGE2 in the intestinal tract is attributed to its differing effects on its downstream receptor types, as well as their varied distribution in the gut, in both health and disease. This review aims to identify the role and distribution of PGE2 receptors in the intestinal tract, and aims to elucidate their distinct role in gut motor function, with a specific focus on functional intestinal pathologies.
Collapse
Affiliation(s)
- A Heeney
- Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland; Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland.
| | - A C Rogers
- Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland; Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - H Mohan
- Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland; Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| | - F Mc Dermott
- Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland
| | - A W Baird
- Department of Physiology, College of Life Sciences, University College Dublin, Dublin, Ireland
| | - D C Winter
- Institute for Clinical Outcomes, Research and Education (ICORE), St Vincent's University Hospital, Elm Park, Dublin 4, Ireland; Department of Surgery, St Vincent's University Hospital, Elm Park, Dublin 4, Ireland
| |
Collapse
|
|
8
|
Grasa L, Gonzalo S, De Martino A, Murillo MD. The lipopolysaccharide from Escherichia coli O127:B8 induces inflammation and motility disturbances in rabbit ileum. WORLD RABBIT SCIENCE 2017. [DOI: 10.4995/wrs.2017.5160] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
<p>The aim of this work was to evaluate the effects of lipopolysaccharide (LPS) from <em>Escherichia coli </em>O127:B8 on the expression of toll-like receptor 4 (TLR4), the histology, and motor function in rabbit ileum. Rabbits were injected intravenously with saline or LPS (100 μg/kg, 2 h). The mRNA expression and localization of TLR4 were determined by reverse transcriptase-PCR and immunofluorescence, respectively. Histological damage induced by LPS was evaluated in sections of ileum stained with haematoxylin and eosin. Contractility studies of ileum were performed in an organ bath. The mRNA expression of TLR4 decreased in the muscular but not in the mucosal layer of rabbits treated with LPS. TLR4 was localised in both the mucosal and muscular layers of rabbit ileum. LPS induced intestinal inflammation and altered the spontaneous contractions and the serotonin-, acetylcholine- and KCl-induced contractions. In conclusion, LPS from <em>E. coli </em>O127:B8 induced a decrease in the mRNA expression of TLR4, an inflammatory response, and changes in the contractility of rabbit ileum.</p>
Collapse
|
|
9
|
Dimidi E, Christodoulides S, Scott SM, Whelan K. Mechanisms of Action of Probiotics and the Gastrointestinal Microbiota on Gut Motility and Constipation. Adv Nutr 2017; 8:484-494. [PMID: 28507013 PMCID: PMC5421123 DOI: 10.3945/an.116.014407] [Citation(s) in RCA: 298] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Constipation is a common and burdensome gastrointestinal disorder that may result from altered gastrointestinal motility. The effect of probiotics on constipation has been increasingly investigated in both animal and human studies, showing promising results. However, there is still uncertainty regarding the mechanisms of action of probiotics on gut motility and constipation. Several factors are vital to normal gut motility, including immune and nervous system function, bile acid metabolism and mucus secretion, and the gastrointestinal microbiota and fermentation; an imbalance or dysfunction in any of these components may contribute to aberrant gut motility and, consequently, symptoms of constipation. For example, adults with functional constipation have significantly decreased numbers of bifidobacteria (with one study showing a mean difference of 1 log10/g) and lactobacilli (mean difference, 1.4 log10/g) in stool samples, as well as higher breath methane, compared with control subjects. Modifying the gut luminal environment with certain probiotic strains may affect motility and secretion in the gut and, hence, provide a benefit for patients with constipation. Therefore, this review explores the mechanisms through which probiotics may exert an effect on gut motility and constipation. Nevertheless, the majority of current evidence is derived from animal studies, and therefore, further human studies are needed to determine the mechanisms through specific probiotic strains that might be effective in constipation.
Collapse
Affiliation(s)
- Eirini Dimidi
- Faculty of Life Sciences and Medicine, Diabetes and Nutritional Sciences Division, King’s College London, London, United Kingdom; and,Centre for Neuroscience and Trauma, Neurogastroenterology Group and GI Physiology Unit, Queen Mary University of London, London, United Kingdom
| | - Stephanos Christodoulides
- Faculty of Life Sciences and Medicine, Diabetes and Nutritional Sciences Division, King’s College London, London, United Kingdom; and,Centre for Neuroscience and Trauma, Neurogastroenterology Group and GI Physiology Unit, Queen Mary University of London, London, United Kingdom
| | - S Mark Scott
- Centre for Neuroscience and Trauma, Neurogastroenterology Group and GI Physiology Unit, Queen Mary University of London, London, United Kingdom
| | - Kevin Whelan
- Faculty of Life Sciences and Medicine, Diabetes and Nutritional Sciences Division, King's College London, London, United Kingdom; and
| |
Collapse
|
|
10
|
Guarino MPL, Altomare A, Barera S, Locato V, Cocca S, Franchin C, Arrigoni G, Vannini C, Grossi S, Campomenosi P, Pasqualetti V, Bracale M, Alloni R, De Gara L, Cicala M. Effect of Inulin on Proteome Changes Induced by Pathogenic Lipopolysaccharide in Human Colon. PLoS One 2017; 12:e0169481. [PMID: 28068390 PMCID: PMC5222518 DOI: 10.1371/journal.pone.0169481] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/16/2016] [Indexed: 12/27/2022] Open
Abstract
In the present study, the protective role of inulin against lipopolysaccharide (LPS)-induced oxidative stress was evaluated on human colonic mucosa using a proteomic approach. Human colonic mucosa and submucosa were sealed between two chambers, with the luminal side facing upwards and overlaid with Krebs (control), LPS or LPS+ inulin IQ solution. The solutions on the submucosal side (undernatants) were collected following 30 min of mucosal exposure. iTRAQ based analysis was used to analyze the total soluble proteomes from human colonic mucosa and submucosa treated with different undernatants. Human colonic muscle strips were exposed to the undernatants to evaluate the response to acetylcholine. Inulin exposure was able to counteract, in human colonic mucosa, the LPS-dependent alteration of some proteins involved in the intestinal contraction (myosin light chain kinase (MLCK), myosin regulatory subunit (MYL)), to reduce the up-regulation of two proteins involved in the radical-mediated oxidative stress (the DNA-apurinic or apyrimidinic site) lyase) APEX1 and the T-complex protein 1 subunit eta (CCT7) and to entail a higher level of some detoxification enzymes (the metallothionein-2 MT2A, the glutathione-S-transferase K GSTk, and two UDP- glucuronosyltransferases UGT2B4, UGT2B17). Inulin exposure was also able to prevent the LPS-dependent intestinal muscle strips contraction impairment and the mucosa glutathione level alterations. Exposure of colonic mucosa to inulin seems to prevent LPS-induced alteration in expression of some key proteins, which promote intestinal motility and inflammation, reducing the radical-mediated oxidative stress.
Collapse
Affiliation(s)
| | - Annamaria Altomare
- Gastroenterology Unit, University Campus Bio-Medico di Roma, Rome, Italy
| | - Simone Barera
- Department of Biotechnology and Life Science, University of Insubria, Varese, Italy
| | - Vittoria Locato
- Food Sciences and Human Nutrition Unit, University Campus Bio-Medico di Roma, Rome, Italy
| | - Silvia Cocca
- Gastroenterology Unit, University Campus Bio-Medico di Roma, Rome, Italy
| | - Cinzia Franchin
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- Proteomics Center, University of Padova and Azienda Ospedaliera di Padova, Padova, Italy
| | - Giorgio Arrigoni
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- Proteomics Center, University of Padova and Azienda Ospedaliera di Padova, Padova, Italy
| | - Candida Vannini
- Department of Biotechnology and Life Science, University of Insubria, Varese, Italy
| | - Sarah Grossi
- Department of Biotechnology and Life Science, University of Insubria, Varese, Italy
| | - Paola Campomenosi
- Department of Biotechnology and Life Science, University of Insubria, Varese, Italy
| | - Valentina Pasqualetti
- Food Sciences and Human Nutrition Unit, University Campus Bio-Medico di Roma, Rome, Italy
| | - Marcella Bracale
- Department of Biotechnology and Life Science, University of Insubria, Varese, Italy
| | - Rossana Alloni
- Surgery Unit, University Campus Bio-Medico di Roma, Roma, Italy
| | - Laura De Gara
- Food Sciences and Human Nutrition Unit, University Campus Bio-Medico di Roma, Rome, Italy
| | - Michele Cicala
- Gastroenterology Unit, University Campus Bio-Medico di Roma, Rome, Italy
| |
Collapse
|
|
11
|
Guarino MPL, Cicala M, Putignani L, Severi C. Gastrointestinal neuromuscular apparatus: An underestimated target of gut microbiota. World J Gastroenterol 2016; 22:9871-9879. [PMID: 28018095 PMCID: PMC5143755 DOI: 10.3748/wjg.v22.i45.9871] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 10/13/2016] [Accepted: 11/14/2016] [Indexed: 02/06/2023] Open
Abstract
Over the last few years, the importance of the resident intestinal microbiota in the pathogenesis of several gastro-intestinal diseases has been largely investigated. Growing evidence suggest that microbiota can influence gastro-intestinal motility. The current working hypothesis is that dysbiosis-driven mucosal alterations induce the production of several inflammatory/immune mediators which affect gut neuro-muscular functions. Besides these indirect mucosal-mediated effects, the present review highlights that recent evidence suggests that microbiota can directly affect enteric nerves and smooth muscle cells functions through its metabolic products or bacterial molecular components translocated from the intestinal lumen. Toll-like receptors, the bacterial recognition receptors, are expressed both on enteric nerves and smooth muscle and are emerging as potential mediators between microbiota and the enteric neuromuscular apparatus. Furthermore, the ongoing studies on probiotics support the hypothesis that the neuromuscular apparatus may represent a target of intervention, thus opening new physiopathological and therapeutic scenarios.
Collapse
|
|
12
|
Lin X, Wang H, Li Y, Chen C, Feng Y, Fichna J. Cannabinoids regulate intestinal motor function and electrophysiological activity of myocytes in rodents. Arch Med Res 2015; 46:439-47. [PMID: 26254701 DOI: 10.1016/j.arcmed.2015.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 07/31/2015] [Indexed: 10/23/2022]
Abstract
BACKGROUND AND AIMS This study aims to investigate the effects of cannabinoid (CB)1 and CB2 receptor ligands on intestinal motor function and muscular electrophysiological activity in rodent gastrointestinal (GI) tract. METHODS Lipopolysaccharide (LPS) was used to induce intestinal hypomotility. The effect of selective CB1 and CB2 agonists and antagonists on contractility of the muscle strips from rat jejunum was measured using organ bath, and the membrane potential of the jejunal smooth muscle cells was recorded with intracellular microelectrodes. The single cell patch clamp technique was applied to record delayed rectifying potassium currents (IKV) and spontaneous transient outward currents (STOC). RESULTS LPS significantly reduced contractility of the smooth muscle strips (p <0.010) and caused hyperpolarization of membrane potential of the smooth muscle cells (p <0.010). This LPS-induced effect was reversed by AM251 and AM630, selective CB1 and CB2 antagonists, respectively, which promoted contractions of smooth muscle strips and triggered cell depolarization (p <0.010). LPS-induced changes were further enhanced in the presence of CB agonists, HU210 and WIN55 (p <0.050 or p <0.010). No effect of HU210 or AM251 on IKV and STOC has been observed. This ex vivo study suggests that CB1 and CB2 receptors are involved in intestinal motor function in normal and LPS-induced pathological states and the regulation of the membrane potential of smooth muscle cells is very likely one of the effective mechanisms. CONCLUSIONS This is one of the first reports on neuronal regulation of intestinal motility through CB-dependent pathways with potential application in the treatment of inflammatory and functional GI disorders.
Collapse
Affiliation(s)
- Xuhong Lin
- Institute of Digestive Disease, Department of Pathophysiology, Tongji University School of Medicine, Siping Road, Shanghai, China; Department of Clinical Laboratory, Huaihe Hospital Affiliated to Henan University, Kaifeng City, Henan Province, China
| | - Huichao Wang
- Department of Nephrology, First Affiliated Hospital of Henan University, Kaifeng City, Henan Province, China
| | - Yongyu Li
- Institute of Digestive Disease, Department of Pathophysiology, Tongji University School of Medicine, Siping Road, Shanghai, China.
| | - Chunqiu Chen
- Institute of Digestive Disease, Department of Pathophysiology, Tongji University School of Medicine, Siping Road, Shanghai, China
| | - Yajing Feng
- Institute of Digestive Disease, Department of Pathophysiology, Tongji University School of Medicine, Siping Road, Shanghai, China
| | - Jakub Fichna
- Department of Biochemistry, Medical University of Lodz, Lodz, Poland
| |
Collapse
|
|
13
|
Mikawa S, Ohta Y, Kaji N, Islam MS, Murata T, Ozaki H, Hori M. Time-dependent changes in inhibitory action of lipopolysaccharide on intestinal motility in rat. J Vet Med Sci 2015; 77:1443-9. [PMID: 26051129 PMCID: PMC4667662 DOI: 10.1292/jvms.15-0198] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Endotoxin causes gastrointestinal motility disorder. Aim of this study is to clarify
inhibitory mechanisms of lipopolysaccharide (LPS) on smooth muscle contraction in rat
ileum. Ileal tissues were isolated from control rat or from LPS-induced peritonitis model
rat. Treatment with LPS inhibited carbachol (CCh)-mediated contraction in a time-dependent
manner. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes were
also upregulated, but iNOS expression was preceded by a rising of COX-2. All subtypes of
prostaglandin E2 (PGE2) receptors (EP1-EP4) were expressed in ileum,
and PGE2 and selective EP2 or EP4 agonist inhibited CCh-mediated contraction.
Selective iNOS inhibitor did not reverse LPS-induced inhibition of contraction by CCh at 1
and 2 hr, but reduced the inhibitory action at 4 hr after the LPS treatment. COX-2
inhibitor reversed the inhibitory action by LPS in all exposure time. Finally, in ileal
tissues isolated from peritonitis model rat, iNOS expression was upregulated only at 4 hr
after LPS administration, resulting in enhanced inhibitory action of LPS against
CCh-induced contraction. In conclusion, LPS induces COX-2 to produce PGE2,
which initially activates EP2 and/or EP4 on smooth muscle cells to inhibit the
contractility in early phase of LPS exposure. Moreover, in late phase of LPS treatment,
iNOS is expressed to produce NO, which in turn inhibited the contraction by CCh. The
inhibitory cascade is similar in the ileum isolated from peritonitis model rat, indicating
time-dependent changes of inhibitory action by LPS on intestinal motility in
peritonitis.
Collapse
Affiliation(s)
- Shoma Mikawa
- Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan
| | | | | | | | | | | | | |
Collapse
|
|
14
|
Pasqualetti V, Altomare A, Guarino MPL, Locato V, Cocca S, Cimini S, Palma R, Alloni R, De Gara L, Cicala M. Antioxidant activity of inulin and its role in the prevention of human colonic muscle cell impairment induced by lipopolysaccharide mucosal exposure. PLoS One 2014; 9:e98031. [PMID: 24837182 PMCID: PMC4024047 DOI: 10.1371/journal.pone.0098031] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 04/28/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Fructans, such as inulin, are dietary fibers which stimulate gastro-intestinal (GI) function acting as prebiotics. Lipopolysaccharide (LPS) impairs GI motility, through production of reactive oxygen species. The antioxidant activity of various fructans was tested and the protective effect of inulin on colonic smooth muscle cell (SMC) impairment, induced by exposure of human mucosa to LPS, was assessed in an ex vivo experimental model. METHODS The antioxidant capacity of fructans was measured in an in vitro system that simulates cooking and digestion processes. Human colonic mucosa and submucosa, obtained from disease-free margins of resected segments for cancer, were sealed between two chambers, with the mucosal side facing upwards with Krebs solution with or without purified LPS from a pathogenic strain of Escherichia coli (O111:B4) and inulin (Frutafit IQ), and the submucosal side facing downwards into Krebs solution. The solutions on the submucosal side were collected following mucosal exposure to Krebs in the absence (N-undernatant) or presence of LPS (LPS-undernatant) or LPS+inulin (LPS+INU-undernatant). Undernatants were tested for their antioxidant activity and the effects on SMCs contractility. Inulin protective effects on mucosa and submucosa layers were assessed measuring the protein oxidation level in the experimental conditions analyzed. RESULTS Antioxidant activity of inulin, which was significantly higher compared to simple sugars, remained unaltered despite cooking and digestion processes. Inulin protected the mucosal and submucosal layers against protein oxidation. Following exposure to LPS-undernatant, a significant decrease in maximal acetylcholine (Ach)-induced contraction was observed when compared to the contraction induced in cells incubated with the N-undernatant (4±1% vs 25±5% respectively, P<0.005) and this effect was completely prevented by pre-incubation of LPS with Inulin (35±5%). CONCLUSIONS Inulin protects the human colon mucosa from LPS-induced damage and this effect appears to be related to the protective effect of inulin against LPS-induced oxidative stress.
Collapse
Affiliation(s)
- Valentina Pasqualetti
- Food Sciences and Human Nutrition Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Annamaria Altomare
- Gastroenterology Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | | | - Vittoria Locato
- Food Sciences and Human Nutrition Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Silvia Cocca
- Gastroenterology Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Sara Cimini
- Food Sciences and Human Nutrition Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Rossella Palma
- Gastroenterology Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Rossana Alloni
- Surgery Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Laura De Gara
- Food Sciences and Human Nutrition Unit, University Campus Bio-Medico of Rome, Rome, Italy
| | - Michele Cicala
- Gastroenterology Unit, University Campus Bio-Medico of Rome, Rome, Italy
| |
Collapse
|
|
15
|
Guarino MPL, Sessa R, Altomare A, Cocca S, Di Pietro M, Carotti S, Schiavoni G, Alloni R, Emerenziani S, Morini S, Severi C, Cicala M. Human colonic myogenic dysfunction induced by mucosal lipopolysaccharide translocation and oxidative stress. Dig Liver Dis 2013; 45:1011-1016. [PMID: 23891549 DOI: 10.1016/j.dld.2013.06.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Revised: 05/03/2013] [Accepted: 06/08/2013] [Indexed: 02/08/2023]
Abstract
BACKGROUND Impairment of gastrointestinal motility is frequently observed in patients with severe infection. AIM To assess whether exposure of human colonic mucosa to pathogenic lipopolysaccharide affects smooth muscle contractility. METHODS Human colonic mucosa and submucosa were sealed between two chambers, with the luminal side facing upwards and covered with Krebs solution, with or without lipopolysaccharide from a pathogenic strain of Escherichia coli (O111:B4; 1,000 ng/mL), and with the submucosal side facing downwards into Krebs. The solution on the submucosal side was collected following 30-min mucosal exposure to Krebs without (N-undernatant) or with lipopolysaccharide (lipopolysaccharide undernatant). Undernatants were tested for lipopolysaccharide and hydrogen peroxide levels and for their effects on smooth muscle cells in the presence of catalase, indomethacin or MG132. RESULTS Smooth muscle cells incubated with N-undernatant had a maximal contraction of 32 ± 5% that was reduced by 62.9 ± 12% when exposed to lipopolysaccharide undernatant. Inhibition of contraction was reversed by catalase, indomethacin and MG132. Lipopolysaccharide levels were higher in the lipopolysaccharide undernatant (2.7 ± 0.7 ng/mL) than in N-undernatant (0.45 ± 0.06 ng/mL) as well as hydrogen peroxide levels (133.75 ± 15.9 vs 82 ± 7.5 nM respectively). CONCLUSIONS Acute exposure of colonic mucosa to pathogenic lipopolysaccharide impairs muscle cell contractility owing to both lipopolysaccharide mucosal translocation and production of free radicals.
Collapse
|
|
16
|
Guarino MPL, Cocca S, Altomare A, Emerenziani S, Cicala M. Ursodeoxycholic acid therapy in gallbladder disease, a story not yet completed. World J Gastroenterol 2013; 19:5029-5034. [PMID: 23964136 PMCID: PMC3746374 DOI: 10.3748/wjg.v19.i31.5029] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Revised: 07/12/2013] [Accepted: 07/18/2013] [Indexed: 02/06/2023] Open
Abstract
Gallstone disease represents an important issue in the healthcare system. The principal non-invasive non-surgical medical treatment for cholesterol gallstones is still represented by oral litholysis with bile acids. The first successful and documented dissolution of cholesterol gallstones was achieved in 1972. Since then a large number of investigators all over the world, have been dedicated in biochemical and clinical studies on ursodeoxycholic acid (UDCA), demonstrating its extreme versatility. This editorial is aimed to provide a brief review of recent developments in UDCA use, current indications for its use and, the more recent advances in understanding its effects in terms of an anti-inflammatory drug.
Collapse
|
|
17
|
Ruan YC, Zhou W, Chan HC. Regulation of smooth muscle contraction by the epithelium: role of prostaglandins. Physiology (Bethesda) 2011; 26:156-70. [PMID: 21670162 DOI: 10.1152/physiol.00036.2010] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
As an analog to the endothelium situated next to the vascular smooth muscle, the epithelium is emerging as an important regulator of smooth muscle contraction in many vital organs/tissues by interacting with other cell types and releasing epithelium-derived factors, among which prostaglandins have been demonstrated to play a versatile role in governing smooth muscle contraction essential to the physiological and pathophysiological processes in a wide range of organ systems.
Collapse
Affiliation(s)
- Ye Chun Ruan
- School of Life Science, Sun Yat-sen University, China
| | | | | |
Collapse
|
|
18
|
Hernández LV, Gonzalo S, Castro M, Arruebo MP, Plaza MA, Murillo MD, Grasa L. Nuclear factor κB is a key transcription factor in the duodenal contractility alterations induced by lipopolysaccharide. Exp Physiol 2011; 96:1151-62. [PMID: 21890516 DOI: 10.1113/expphysiol.2011.060830] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
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.
Collapse
Affiliation(s)
- Ligia Verónica Hernández
- Department of Pharmacology and Physiology, Faculty of Veterinary Medicine, University of Zaragoza, 50013 Zaragoza, Spain.
| | | | | | | | | | | | | |
Collapse
|
|
19
|
Lin XH, Yuece B, Li YY, Feng YJ, Feng JY, Yu LY, Li K, Li YN, Storr M. A novel CB receptor GPR55 and its ligands are involved in regulation of gut movement in rodents. Neurogastroenterol Motil 2011; 23:862-e342. [PMID: 21726355 DOI: 10.1111/j.1365-2982.2011.01742.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND This study was to investigate the effects of the novel cannabinoid receptor - G protein-coupled receptor 55 (GPR55) - and its ligands O-1602 and cannabidiol (CBD) on gastrointestinal (GI) motility in rodents. METHODS Lipopolysaccharide (LPS) was used in vivo to produce the model of septic ileus. The intestinal motility was measured by recording myoelectrical activity of jejunum in rats, and by measuring GI transit with a charcoal marker in mice, in presence of O-1602 or CBD. Inflammatory response was assessed serologically and histologically. The expression and distribution of GPR55 in the different parts of rat intestine were investigated by real-time PCR and immunohistochemistry. In vitro, the effects of the drugs on the GI movement were investigated by measuring the contraction of the intestinal muscle strips in organ bath, and the intracellular responses of the muscle cells with microelectrode technique. KEY RESULTS G protein-coupled receptor 55 was expressed in different parts of rat intestine. Lipopolysaccharide significantly inhibited the intestinal motility, increased inflammatory cytokines and GPR55 expression. Pretreatment with CBD normalized LPS-induced hypomotility and improved the inflammatory responses serologically and histologically. Both O-1602 and CBD counteracted LPS-induced disturbances of the gut contraction, but had no effect on the membrane potential of the muscle cells, while cannabinoid type 1 receptor antagonist AM251 and cannabinoid type 2 receptor antagonist AM630 increased the potential. CONCLUSIONS & INFERENCES G protein-coupled receptor 55 existed throughout the whole intestine of rats. O-1602 or CBD selectively normalized the motility disturbances. Possible mechanisms involved systemic anti-inflammation and the regulation of myoelectrical activity of the intestine.
Collapse
Affiliation(s)
- X-H Lin
- Department of Pathophysiology, Institute of Digestive Disease, Tongji University School of Medicine, Shanghai, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Lipopolysaccharide-induced intestinal motility disturbances are mediated by c-Jun NH2-terminal kinases. Dig Liver Dis 2011; 43:277-85. [PMID: 21168375 DOI: 10.1016/j.dld.2010.10.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2010] [Revised: 09/09/2010] [Accepted: 10/17/2010] [Indexed: 12/11/2022]
Abstract
BACKGROUND Lipopolysaccharide (LPS) is a causative agent of sepsis. Many alterations, such as intestinal motility disturbances, have been attributed to LPS. AIMS Here we investigated the role of c-Jun NH(2)-terminal kinases (JNK) in the effect of LPS on intestinal motility, the oxidative stress status and the cyclooxygenese-2 (COX-2) expression. METHODS Rabbits were injected with either (1) saline, (2) LPS, (3) SP600125, a specific JNK inhibitor, or (4) SP600125+LPS. Duodenal contractility was studied in an organ bath. The formation of products of oxidative damage to proteins (carbonyls) and lipids [malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)] was quantified by spectrophotometry in the intestine and plasma. The protein expression of p-JNK, total JNK, and COX-2 was measured by Western blot, and p-JNK was localized by immunohistochemistry. RESULTS LPS decreased the contractions evoked by acetylcholine and prostaglandin E(2) and KCl-induced contractions. LPS increased phospho-JNK and COX-2 expressions and the levels of carbonyls and MDA+4-HDA. SP600125 blocked the effect of LPS on the acetylcholine, prostaglandin E(2), and KCl-induced contractions, the levels of carbonyls and MDA+4-HDA, and the p-JNK and COX-2 expressions. p-JNK was detected in the smooth muscle cells of duodenum. CONCLUSION Our results suggest that JNK is involved in the mechanism of action of LPS in the intestine.
Collapse
|
|
21
|
Barona I, Fagundes DS, Gonzalo S, Grasa L, Arruebo MP, Plaza MÁ, Murillo MD. Role of TLR4 and MAPK in the local effect of LPS on intestinal contractility. J Pharm Pharmacol 2011; 63:657-62. [PMID: 21492167 DOI: 10.1111/j.2042-7158.2011.01253.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVES Lipopolysaccharide (LPS) has been shown to alter intestinal contractility. Toll-like receptor 4 (TLR4), K(+) channels and mitogen-activated protein kinases (MAPKs) have been proposed to be involved in the mechanism of action of LPS. The aim of this study was to determine the role of TLR4, K(+) channels and MAPKs (p38, JNK and MEK1/2) in the local effect of LPS on the acetylcholine (ACh)-induced contractions in rabbit small intestine in vitro. METHODS Segments of rabbit duodenum were suspended in the direction of longitudinal or circular smooth muscle fibres in a thermostatically controlled organ bath. KEY FINDINGS LPS (0.3 µg/ml) reduced the contractions induced by ACh (100 µm) in the longitudinal and circular smooth muscle of the duodenum after 90 min of incubation. Polymyxin (TLR4 inhibitor), SB203580 (p38 MAPK inhibitor), SP600125 (JNK1/2 inhibitor) and U0126 (MEK1/2 inhibitor) antagonized the effects of the LPS on ACh-induced contractions in duodenal smooth muscle. Incubation with the blockers of K(+) channels, TEA, apamin, charybdotoxin, iberiotoxin, glibenclamide or quinine, did not reverse the effect of LPS on ACh-induced contractions. CONCLUSIONS These results suggest that the effect of LPS on ACh-induced contractions in the rabbit duodenum might be mediated by TLR4 and p38, JNK1/2 and MEK1/2 MAPKs.
Collapse
Affiliation(s)
- Inés Barona
- Farmacologia y Fisiologia, Universidad de Zaragoza, Facultad de Veterinaria, Miguel Servet, Zaragoza, Spain
| | | | | | | | | | | | | |
Collapse
|
|
22
|
Gonzalo S, Grasa L, Arruebo MP, Plaza MÁ, Murillo MD. Extracellular signal-regulated kinase (ERK) is involved in LPS-induced disturbances in intestinal motility. Neurogastroenterol Motil 2011; 23:e80-90. [PMID: 21087357 DOI: 10.1111/j.1365-2982.2010.01632.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Lipopolysaccharide (LPS) is a causative agent of sepsis. A relationship has been described between LPS, free radicals, and cyclooxygenase-2 (COX-2). Here, we investigate the role of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinases (MAPK) in the effect of LPS on intestinal motility, oxidative stress status, and COX-2 expression. METHODS Rabbits were injected with (i) saline, (ii) LPS, (iii) U0126, an ERK MAPK inhibitor, or (iv) U0126+LPS. Duodenal contractility was studied in an organ bath with acetylcholine, prostaglandin E(2), and KCl added. Neuromuscular function was assessed by electrical field stimulation (EFS). Neurotransmitter blockers were used to study the EFS-elicited contractile response. The formation of products of oxidative damage to proteins (carbonyls), lipids, [malondialdehyde (MDA), and 4-hydroxyalkenals (4-HDA)] was quantified in plasma and intestine. The protein expression of phospho-ERK (p-ERK), total ERK, and COX-2 in the intestine was measured by western blot, and p-ERK was localized by immunohistochemistry. KEY RESULTS Acetylcholine, prostaglandin E(2), and KCl-induced contractions decreased with LPS. Electrical field stimulation induced a neurogenic contraction that was reduced by LPS. Lipopolysaccharide increased p-ERK and COX-2 expression and the levels of carbonyls and MDA+4-HDA. U0126 blocked the effect of LPS on acetylcholine, prostaglandin E(2), KCl, and EFS-induced contractions, the levels of carbonyls and MDA+4-HDA and p-ERK and COX-2 expression. Phospho-ERK was detected mostly in the neurons of the myenteric and submucosal ganglia. CONCLUSIONS & INFERENCES We can suggest that ERK is involved in the mechanism of action of LPS in the intestine.
Collapse
Affiliation(s)
- S Gonzalo
- Departamento de Farmacología y Fisiología, Unidad de Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
| | | | | | | | | |
Collapse
|
|
23
|
Gonzalo S, Grasa L, Fagundes DS, Arruebo MP, Plaza MÁ, Murillo MD. Intestinal effects of lipopolysaccharide in rabbit are mediated by cyclooxygenase-2 through p38 mitogen activated protein kinase. Eur J Pharmacol 2010; 648:171-8. [PMID: 20832398 DOI: 10.1016/j.ejphar.2010.08.041] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2010] [Revised: 07/21/2010] [Accepted: 08/25/2010] [Indexed: 01/19/2023]
Abstract
The mediators of the pathophysiological symptoms of septic shock are not completely understood. The intracellular signalling mechanisms of lipopolysaccharide (LPS)-induced effects need further investigation. This study investigates (1) the role of COX-2 in the effect of LPS on (a) the KCl, acetylcholine and prostaglandin E₂-induced contractions of rabbit duodenum and (b) the oxidative stress status in plasma and intestine and (2) the relationship between p38 MAPK and COX-2 expression in rabbit duodenum. Rabbits were injected i.v. with either (1) saline, (2) LPS, (3) SB203580, a p38 MAPK inhibitor, (4) SB203580+LPS, (5) NS-398, a COX-2 inhibitor or (6) NS-398+LPS. Contractility studies were performed by suspending pieces of duodenum in an organ bath in the direction of longitudinal and circular smooth muscle fibres. The formation of products of oxidative damage to proteins (carbonyls) and lipids [malondialdehyde (MDA) and 4-hydroxyalkenals (4-HDA)] was quantified in intestinal tissue and plasma. The protein expression of COX-2 was measured by western blot. The KCl, acetylcholine and prostaglandin E₂-induced contractions decreased with LPS. In addition, LPS increased the levels of carbonyls and MDA+4-HDA in plasma and duodenum as well as COX-2 expression in duodenal tissue. All these effects were blocked by NS-398. The p38 MAPK inhibitor SB203580 blocked the effect of LPS on COX-2 expression. These results suggest that the effect of LPS on KCl, acetylcholine and prostaglandin E₂-induced contractions in the rabbit duodenum and oxidative stress might be mediated by an increase in COX-2 expression through the p38 MAPK pathway.
Collapse
Affiliation(s)
- Sergio Gonzalo
- Departamento de Farmacología y Fisiología, Unidad de Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, 50013 Zaragoza, Spain
| | | | | | | | | | | |
Collapse
|
|
24
|
Carotti S, Guarino MPL, Cicala M, Perrone G, Alloni R, Segreto F, Rabitti C, Morini S. Effect of ursodeoxycholic acid on inflammatory infiltrate in gallbladder muscle of cholesterol gallstone patients. Neurogastroenterol Motil 2010; 22:866-e232. [PMID: 20426797 DOI: 10.1111/j.1365-2982.2010.01510.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Reduced gallbladder (GB) contractility and chronic inflammatory changes in the mucosa have been reported in patients with cholesterol gallstones (GS). Ursodeoxycholic acid (UDCA) restores GB contractility and antagonises liver macrophage activation. In the colon, hydrophobic bile acid, not hydrophilic UDCA, induces mast cell degranulation. We studied the presence of monocyte/macrophage infiltrate, cyclooxygenase (COX)-2, inducible nitric oxide synthase (iNOS) expression, the number of total and degranulated mast cells in the GB muscle layer of cholesterol GS patients, and the effect of UDCA administration. METHODS Gallbladder tissue was obtained from cholesterol GS patients, either treated or untreated with UDCA (10 mg kg(-1) day(-1)) for 30 days prior to surgery. Gallbladders removed for neoplastic diseases, not involving GB, were evaluated for control purposes. The presence of monocytes/macrophages (CD68 positive), granulocytes, and mast cells, and the COX-2 and iNOS expression, was determined immunohistochemically. KEY RESULTS The number of CD68, granulocytes, mast cells, COX-2 and iNOS positive cells was significantly higher in the muscle layer of GS patients than in controls. Compared to untreated patients, those treated with UDCA showed significantly lower levels of CD68, COX-2 positive cells and degranulated mast cells and a lesser number of iNOS positive cells and granulocytes. CONCLUSIONS & INFERENCES An inflammatory monocyte/macrophage, mast cell and granulocyte infiltrate is present in the GB muscle layer of GS patients. Ursodeoxycholic acid decreases macrophages, degranulated mast cells and COX-2 expression. These results suggest that monocytes/macrophages and degranulating mast cells contribute to muscle cell dysfunction in cholesterol GS patients and support the anti-inflammatory effect of UDCA.
Collapse
Affiliation(s)
- S Carotti
- Department of Biomedical Research (CIR), University Campus Bio-Medico, Rome, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Scirocco A, Matarrese P, Petitta C, Cicenia A, Ascione B, Mannironi C, Ammoscato F, Cardi M, Fanello G, Guarino MPL, Malorni W, Severi C. Exposure of Toll-like receptors 4 to bacterial lipopolysaccharide (LPS) impairs human colonic smooth muscle cell function. J Cell Physiol 2010; 223:442-50. [PMID: 20112289 DOI: 10.1002/jcp.22053] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Endotoxemia by bacterial lipopolysaccharide (LPS) has been reported to affect gut motility specifically depending on Toll-like receptor 4 activation (TLR4). However, the direct impact of LPS ligation to TLR4 on human smooth muscle cells (HSMC) activity still remains to be elucidated. The present study shows that TLR4, its associated molecule MD2, and TLR2 are constitutively expressed on cultured HSMC and that, once activated, they impair HSMC function. The stimulation of TLR4 by LPS induced a time- and dose-dependent contractile dysfunction, which was associated with a decrease of TLR2 messenger, a rearrangement of microfilament cytoskeleton and an oxidative imbalance, i.e., the formation of reactive oxygen species (ROS) together with the depletion of GSH content. An alteration of mitochondria, namely a hyperpolarization of their membrane potential, was also detected. Most of these effects were partially prevented by the NADPH oxidase inhibitor apocynin or the NFkappaB inhibitor MG132. Finally, a 24 h washout in LPS-free medium almost completely restored morphofunctional and biochemical HSMC resting parameters, even if GSH levels remained significantly lower and no recovery was observed in TLR2 expression. Thus, the exposure to bacterial endotoxin directly and persistently impaired gastrointestinal smooth muscle activity indicating that HSMC actively participate to dysmotility during infective burst. The knowledge of these interactions might provide novel information on the pathogenesis of infection-associated gut dysmotility and further clues for the development of new therapeutic strategies.
Collapse
|
|
26
|
Gonzalo S, Grasa L, Arruebo MP, Plaza MA, Murillo MD. Inhibition of p38 MAPK improves intestinal disturbances and oxidative stress induced in a rabbit endotoxemia model. Neurogastroenterol Motil 2010; 22:564-72, e123. [PMID: 20003078 DOI: 10.1111/j.1365-2982.2009.01439.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Lipopolysaccharide (LPS) decreases intestinal contractility and induces the release of reactive oxygen species, which play an important role in the pathogenesis of sepsis. p38 mitogen-activated protein kinase (MAPK) can be activated by a variety of stimuli such as LPS. The aims of this study were: (i) to investigate the role of p38 MAPK in the effect of LPS on (a) the acetylcholine, prostaglandin E(2) and KCl-induced contractions of rabbit duodenum and (b) the oxidative stress status; (ii) to localize the active form of p38 in the intestine. METHODS Rabbits were injected with (i) saline, (ii) LPS, (iii) SB203580, a specific p38 MAPK inhibitor or (iv) SB203580 + LPS. Duodenal contractility was studied in an organ bath. SB203580 was also tested in vitro. The protein expression of p-p38 and total p38 was measured by Western blot and p-p38 was localized by immunohistochemistry. The formation of products of oxidative damage to proteins (carbonyls) and lipids (MDA+4-HDA) was quantified in intestine and plasma. KEY RESULTS ACh, PGE(2) and KCl-induced contractions decreased with LPS. LPS increased phospho-p38 expression and the levels of carbonyls and MDA+4-HDA. SB203580 blocked the effect of LPS on the ACh, PGE(2) and KCl-induced contractions in vivo and in vitro and the levels of carbonyls and MDA+4-HDA. P-p38 was detected in neurons of the myenteric plexus and smooth muscle cells of duodenum. CONCLUSIONS & INFERENCES Lipopolysaccharide decreases the duodenal contractility in rabbits and increases the production of free radicals. p38 MAPK is a mediator of these effects.
Collapse
Affiliation(s)
- S Gonzalo
- Departamento de Farmacología y Fisiología, Unidad de Fisiología, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
| | | | | | | | | |
Collapse
|
|
27
|
Fornai M, Antonioli L, Colucci R, Bernardini N, Ghisu N, Tuccori M, De Giorgio R, Del Tacca M, Blandizzi C. Emerging role of cyclooxygenase isoforms in the control of gastrointestinal neuromuscular functions. Pharmacol Ther 2010; 125:62-78. [DOI: 10.1016/j.pharmthera.2009.09.007] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2009] [Accepted: 09/16/2009] [Indexed: 02/06/2023]
|
|
28
|
Fagundes DS, Gonzalo S, Arruebo MP, Plaza MA, Murillo MD. Melatonin and Trolox ameliorate duodenal LPS-induced disturbances and oxidative stress. Dig Liver Dis 2010; 42:40-4. [PMID: 19501031 DOI: 10.1016/j.dld.2009.04.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2008] [Revised: 03/19/2009] [Accepted: 04/14/2009] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Lipopolysaccharide evokes gastrointestinal motility disturbances and oxidative stress. The aims of the present study were to investigate the effect of melatonin and Trolox in the actions of lipopolysaccharide on duodenal contractility and on lipid peroxidation in rabbit duodenum. METHODS The in vitro duodenal contractility studies were carried out in organ bath and the levels of malondialdehyde were assayed by spectrophotometry. Duodenal segments were incubated with lipopolysaccharide (0.3 microg mL(-1)). RESULTS Lipopolysaccharide decreased acetylcholine-induced contractions and increased malondialdehyde and 4-hydroxyalkenals concentrations in homogenates of duodenum. Melatonin reduced the amplitude of spontaneous contractions in duodenal muscle. Acetylcholine-induced contractions were not altered by melatonin in longitudinal and circular muscles. Trolox decreased the amplitude of spontaneous contractions of duodenal muscle. Trolox (1.2 or 4 mM) did not alter acetylcholine-induced contractions in duodenal muscle, but the concentration of 12 mM diminished the frequency of contractions and acetylcholine-induced contractions. Melatonin (0.3 mM) or Trolox (4 mM) diminished malondialdehyde and 4-hydroxyalkenals levels induced by lipopolysaccharide in the duodenum. CONCLUSIONS Melatonin and Trolox reduce oxidative stress induced by lipopolysaccharide and ameliorate the effect of lipopolysaccharide on duodenal contractility.
Collapse
Affiliation(s)
- D S Fagundes
- Pharmacology and Physiology Department (Physiology), Veterinary Faculty, Zaragoza University, Miguel Servet 177, 50013 Zaragoza, Spain
| | | | | | | | | |
Collapse
|
|
29
|
Guarino MPL, Altomare A, Stasi E, Marignani M, Severi C, Alloni R, Dicuonzo G, Morelli L, Coppola R, Cicala M. Effect of acute mucosal exposure to Lactobacillus rhamnosus GG on human colonic smooth muscle cells. J Clin Gastroenterol 2008; 42 Suppl 3 Pt 2:S185-S190. [PMID: 18685510 DOI: 10.1097/mcg.0b013e31817e1cac] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
AIM To define whether human colonic mucosa exposure to Lactobacillus rhamnosus GG (LGG), American Type Culture Collection (ATCC) 53103, may influence intestinal muscle cell contractility. METHODS Human colon specimens were obtained from disease-free margins of resected segments for cancer. The mucosa and submucosa, after dissection, were sealed between 2 chambers, with the luminal side of the mucosa facing upward and covered with 5 mL of Krebs solution and the submucosal side facing downward into 20 mL of Krebs solution. LGG or normal undernatant (N-undernatant) were added to the luminal side of the mucosa for 30 minutes. Smooth muscle cells (SMCs), isolated from the circular muscle layer, were exposed to undernatant for 30 minutes from the submucosal chamber of mucosa that was either preexposed to N-undernatant or to LGG (36 x 10(-9) colony forming units/mL) (LGG-undernatant). Acetylcholine (Ach) dose-response was obtained for SMCs. RESULTS SMCs exposed to N-undernatant presented a dose-response to Ach (maximal contraction: 32%+/-5% with 1-muM Ach) that is similar to unstimulated SMCs. Exposure to LGG-undernatant resulted both in an 18%+/-3% cell shortening and a 78%+/-7% inhibition of maximal Ach-induced contraction. When SMCs were directly exposed to LGG, a significant impairment of contraction (70%+/-5%, compared with control cells) and a dose-dependent and time-dependent shortening were observed. CONCLUSIONS After acute exposure of colonic mucosa to LGG, a significant shortening of SMCs is observed that possibly contributes to the reduced contractile response to Ach. Further studies are needed to establish the mechanisms of this effect that could account for the clinical efficacy of probiotics in intestinal disorders.
Collapse
Affiliation(s)
- Michele Pier Luca Guarino
- Department of Digestive Diseases, Campus Biomedico University, Via Alvaro del Portillo, Rome, Italy.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Lamarca V, Grasa L, Fagundes DS, Arruebo MP, Plaza MA, Murillo MD. K+ channels involved in contractility of rabbit small intestine. J Physiol Biochem 2006; 62:227-36. [PMID: 17615948 DOI: 10.1007/bf03165751] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Most excitable cells, including gastrointestinal smooth muscle cells, express several types of K+ channels. The aim of this study was to examine the types of K' channels involved in the contractility of longitudinal smooth muscle of rabbit small intestine in vitro. Spontaneous contractions and KCl-stimulated contractions were reduced by atropine, phentolamine, propranolol, suramin, tetrodotoxin and indomethacin. The amplitude and tone of spontaneous contractions were increased by apamin, charybdotoxin, iberiotoxin, E4031, tetraetylammonium (TEA) and BaCl2. The frequency of contractions was reduced in the presence of apamin and TEA and increased by charybdotoxin. It was found that 4-aminopyridine increased the tone of spontaneous contractions and reduced the amplitude and frequency of contractions. Glibenclamide did not modify the amplitude, frequency or tone of contractions. KCl-stimulated contractions were increased by E4031, were not modified by apamin, glibenclamide, NS1619 or diazoxide, and were reduced by charybdotoxin, TEA, 4-aminopyridine or BaCl2. These results suggest that both Ca2+-activated K+ channels of small and high conductance, and HERG K+ channels and inward rectifier K+ channels participate in spontaneous contractions of small intestine. On the other hand, voltage-dependent K+ channels, HERG K+ channels, inward rectifier K+ channels and high conductance Ca2+-activated K+ channels are involved in KCl-stimulated contractions.
Collapse
Affiliation(s)
- V Lamarca
- Departamento de Farmacología y Fisiologia (Fisiologia), Facultad de Veterinaria, Universidad de Zaragoza, Miguel Servet 177, 50013 Zaragoza, Spain
| | | | | | | | | | | |
Collapse
|
|
31
|
Barbara G, Stanghellini V, Brandi G, Cremon C, Di Nardo G, De Giorgio R, Corinaldesi R. Interactions between commensal bacteria and gut sensorimotor function in health and disease. Am J Gastroenterol 2005; 100:2560-2568. [PMID: 16279914 DOI: 10.1111/j.1572-0241.2005.00230.x] [Citation(s) in RCA: 216] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Commensal bacteria inhabiting the human intestine (i.e., intestinal microflora) participate in the development and maintenance of gut sensory and motor functions, including the promotion of intestinal propulsive activity. On the other hand, intestinal motility represents one of the major control systems of gut microflora, through the sweeping of excessive bacteria from the lumen. There is emerging evidence indicating that changes in this bidirectional interplay contribute to the pathogenesis of gut diseases, such as small intestinal bacterial overgrowth and intestinal pseudo-obstruction. Recent interest has also been directed to the potential role of intestinal microflora in the pathogenesis of the irritable bowel syndrome. Although the status of intestinal microflora in the irritable bowel syndrome remains unsettled, small intestinal bacterial overgrowth (as detected with breath testing) and increased fermentation of foods with gas production, provide indirect evidence that microflora may contribute to symptom generation in irritable bowel syndrome. The potential benefit of antibiotic and probiotic therapy is currently under investigation and opens new perspectives in irritable bowel syndrome treatment.
Collapse
Affiliation(s)
- Giovanni Barbara
- Department of Internal Medicine and Gastroenterology, Univeristy of Bologna, Bologna, Italy
| | | | | | | | | | | | | |
Collapse
|
|
32
|
Wang B, Glatzle J, Mueller MH, Kreis M, Enck P, Grundy D. Lipopolysaccharide-induced changes in mesenteric afferent sensitivity of rat jejunum in vitro: role of prostaglandins. Am J Physiol Gastrointest Liver Physiol 2005; 289:G254-60. [PMID: 15790760 DOI: 10.1152/ajpgi.00329.2004] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Bacterial translocation across the intestinal mucosal barrier leads to a macrophage-mediated inflammatory response, visceral hyperalgesia, and ileus. Our aim was to examine how mediators released into mesenteric lymph following LPS treatment influence intestinal afferent sensitivity and the role played by prostanoids in any sensitization. Intestinal lymph was collected from awake rats following treatment with either saline or LPS (5 mg/kg ip). Extracellular multiunit afferent recordings were made from paravascular mesenteric nerve bundles supplying the rat jejunum in vitro following arterial administration of control lymph, LPS lymph, and LPS. Mesenteric afferent discharge increased significantly after LPS lymph compared with control lymph. Peak discharge occurred within 2 min and remained elevated for 5 to 8 min. This response was attenuated by pretreatment with naproxen (10 microM), and restored upon addition of prostaglandin E(2) (5 microM) in the presence of naproxen, but AH6809 (5 microM), an EP(1)/EP(2) receptor(s) antagonist, failed to decrease the magnitude of LPS lymph-induced response. LPS itself also stimulated mesenteric afferent discharge but was unaffected by naproxen. TNF-alpha was significantly increased in LPS lymph compared with control lymph (1,583 +/- 197 vs. 169 +/- 38 pg/ml, P < 0.01) but exogenous TNF-alpha failed to evoke any afferent nerve discharge. We concluded that inflammatory mediators released from the gut into mesenteric lymph during endotoxemia have a profound effect on afferent discharge. These mediators influence afferent firing via the release of local prostaglandins.
Collapse
Affiliation(s)
- B Wang
- Dept. of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK
| | | | | | | | | | | |
Collapse
|
|
33
|
Liang YC, Liu HJ, Chen SH, Chen CC, Chou LS, Tsai LH. Effect of lipopolysaccharide on diarrhea and gastrointestinal transit in mice: Roles of nitric oxide and prostaglandin E 2. World J Gastroenterol 2005; 11:357-61. [PMID: 15637744 PMCID: PMC4205337 DOI: 10.3748/wjg.v11.i3.357] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect of lipopolysaccharide (LPS) on the diarrheogenic activity, gastrointestinal transit (GIT), and intestinal fluid content and the possible role of nitric oxide (NO) and prostaglandin E2 (PGE2) in gastrointestinal functions of endotoxin-treated mice.
METHODS: Diarrheogic activity, GIT, and intestinal fluid content as well as nitric oxide and PGE2 products were measured after intraperitoneal administration of LPS in mice.
RESULTS: LPS dose-dependently accumulated abundant fluid into the small intestine, induced diarrhea, but decreased the GIT. Both nitric oxide and PGE2 were found to increase in LPS-treated mice. Western blot analysis indicated that LPS significantly induced the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 in mice intestines. Pretreatment with NG-nitro-L-arginine-methyl ester (L-NAME, a non-selective NOS inhibitor) or indomethacin (an inhibitor of prostaglandin synthesis) significantly attenuated the effects of LPS on the diarrheogenic activity and intestine content, but reversed the GIT.
CONCLUSION: The present study suggests that the pathogenesis of LPS treatment may mediate the stimulatory effect of LPS on nitric oxide and PGE2 production and NO/prostaglandin pathway may play an important role on gastrointestinal function.
Collapse
Affiliation(s)
- Yu-Chih Liang
- Graduate Institute of Biomedical Technology, Taipei Medical University, Taipei, Taiwan, China
| | | | | | | | | | | |
Collapse
|
|
34
|
Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA. Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br J Pharmacol 2004; 142:1247-54. [PMID: 15249429 PMCID: PMC1575196 DOI: 10.1038/sj.bjp.0705889] [Citation(s) in RCA: 110] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The biological effects of cannabinoids (CB) are mediated by CB(1) and CB(2) receptors. The role of CB(2) receptors in the gastrointestinal tract is uncertain. In this study, we examined whether CB(2) receptor activation is involved in the regulation of gastrointestinal transit in rats. Basal and lipopolysaccharide (LPS)-stimulated gastrointestinal transit was measured after instillation of an Evans blue-gum Arabic suspension into the stomach, in the presence of specific CB(1) and CB(2) agonists and antagonists, or after treatment with inhibitors of mediators implicated in the transit process. In control rats a CB(1) (ACEA; 1 mg kg(-1)), but not a CB(2) (JWH-133; 1 mg kg(-1)), receptor agonist inhibited basal gastrointestinal transit. The effects of the CB(1) agonist were reversed by the CB(1) antagonist AM-251, which alone increased basal transit. LPS treatment increased gastrointestinal transit. This increased transit was reduced to control values by the CB(2), but not the CB(1), agonist. This inhibition by the CB(2) agonist was dose dependent and prevented by a selective CB(2) antagonist (AM-630; 1 mg kg(-1)). By evaluating the inhibition of LPS-enhanced gastrointestinal transit by different antagonists, the effects of the CB(2) agonist (JWH-133; 1 mg kg(-1)) were found to act via cyclooxygenase, and to act independently of inducible nitric oxide synthase (NOS) and platelet-activating factor. Interleukin-1 beta and constitutive NOS isoforms may be involved in the accelerated LPS transit. The activation of CB(2) receptors in response to LPS is a mechanism for the re-establishment of normal gastrointestinal transit after an inflammatory stimulus.
Collapse
Affiliation(s)
- Ronald Mathison
- Gastrointestinal Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Mucosal Inflammation Research Groups, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Winnie Ho
- Gastrointestinal Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Mucosal Inflammation Research Groups, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Quentin J Pittman
- Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Mucosal Inflammation Research Groups, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Joseph S Davison
- Gastrointestinal Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Keith A Sharkey
- Gastrointestinal Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Neuroscience Research Group, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Mucosal Inflammation Research Groups, Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
- Author for correspondence:
| |
Collapse
|
|
35
|
Rebollar E, Guerrero-Lindner E, Arruebo MP, Plaza MA, Murillo MD. Role of prostaglandins in lipopolysaccharide effects on K+-induced contractions in rabbit small intestine. ACTA PHYSIOLOGICA SCANDINAVICA 2003; 179:299-307. [PMID: 14616246 DOI: 10.1046/j.0001-6772.2003.01189.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIM The mediators of the pathophysiologcal symptoms of septic shock are not completely understood. The aim of this work was to investigate the effect of lipopolysaccharide (LPS) on the K+-induced response of longitudinal segments of rabbit small intestine in vitro and the possible role of prostaglandins. METHODS AND RESULTS Rabbits were treated with intravenously injected LPS. After 90 min animals were killed and intestinal segments were mounted in an organ bath. Lipopolysaccharide (0.2 microg kg-1) inhibited K+-induced contractions (60 mm) by 68% in duodenum, 58% in jejunum and 52% in ileum. Indomethacin antagonized LPS actions when injected 15 min before LPS. PGE2 reduced K+-induced contractions, imitating LPS effects. In contrast, contractions induced by K+ increased when intestinal segments were incubated in vitro with LPS for 90 min. The LPS (0.3 microg mL-1) increased K+-induced contractions (60 mm) by 46% in duodenum, 63% in jejunum and 85% in ileum. The LPS effect was antagonized by indomethacin at 10-6 m in duodenum and jejunum and at 10-8 m in ileum. PGE2 evoked dose-dependent contractions when added to the bath in duodenum, jejunum and ileum. CONCLUSION These results suggest that effect of LPS on K+-induced contractions in the rabbit small bowel may be mediated by prostaglandin E2.
Collapse
Affiliation(s)
- E Rebollar
- Departamento de Farmacología y Fisiología (Fisiología), Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain
| | | | | | | | | |
Collapse
|
|
36
|
Guerrero-Lindner E, Castro M, Muñoz JM, Arruebo MP, Murillo MD, Buéno L, Plaza MA. Central tumour necrosis factor-alpha mediates the early gastrointestinal motor disturbances induced by lipopolysaccharide in sheep. Neurogastroenterol Motil 2003; 15:307-16. [PMID: 12787340 DOI: 10.1046/j.1365-2982.2003.00402.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Cytokines are involved in fever and other symptoms of the acute phase response induced by endotoxins. The aim of this work was to study the involvement of central tumour necrosis factor-alpha (TNF-alpha) in the changes induced by lipopolysaccharide (LPS) on gastrointestinal (GI) motility in sheep. Body temperature and myoelectric activity of the antrum, duodenum and jejunum was recorded continuously. Intravenous (i.v.) administration of LPS (0.1 micro g kg-1)-induced hyperthermia, decreased gastrointestinal myoelectric activity and increased the frequency of the migrating motor complex (MMC). These effects started 40-50 min after LPS and lasted for 6-7 h. TNF-alpha (50 and 100 ng kg-1) mimicked these effects when injected intracerebroventricularly (i.c.v.) but not i.v. Pretreatment with soluble recombinant TNF receptor (TNFR:Fc, 10 micro g kg-1, i.c.v.) abolished the TNF-induced actions and reduced those evoked by LPS. Furthermore, the effects induced by either LPS or TNF were suppressed by prior i.c.v. injection of indomethacin (100 micro g kg-1). In contrast, the i.v. injections of TNFR:Fc or indomethacin were ineffective. Our data suggest that LPS disturbs GI motility in sheep through a central pathway that involves TNF-alpha and prostaglandins sequentially.
Collapse
Affiliation(s)
- E Guerrero-Lindner
- Department of Pharmacology and Physiology, Veterinary Faculty, University of Zaragoza, Zaragoza, Spain
| | | | | | | | | | | | | |
Collapse
|