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Deng FS, Lin MH, Huang CL, Wu CC, Lu CL, Tsai YC. Effects of Lactococcus cremoris PS133 in 5-Hydroxytryptophan-Induced Irritable Bowel Syndrome Model Rats. Int J Mol Sci 2025; 26:2464. [PMID: 40141108 PMCID: PMC11942017 DOI: 10.3390/ijms26062464] [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: 02/05/2025] [Revised: 03/07/2025] [Accepted: 03/08/2025] [Indexed: 03/28/2025] Open
Abstract
Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder marked by abdominal pain and irregular bowel habits. Recently, more and more evidence supports gut microbiota imbalance in IBS and highlights the potential of probiotics in restoring gut health and reducing symptoms. In this study, we explored the effects of Lactococcus cremoris PS133 (PS133) on an IBS-like condition in rats triggered by 5-hydroxytryptophan (5-HTP), a serotonin precursor. Eight-week-old Sprague Dawley rats received either PS133 or saline for 14 days, followed by 5-HTP to induce IBS-like symptoms. Colorectal distension tests showed that PS133 reduced visceral hypersensitivity. PS133 also protected intestinal mucin against 5-HTP-induced degradation, as seen in alcian blue staining, and increased the levels of tight junction proteins (occludin and zonula occludens-1) in the colon, indicating improved gut barrier integrity. Additionally, PS133 normalized the levels of substance P (a neuropeptide) in the spinal cord and altered 5-hydroxyindoleacetic acid (a serotonin metabolite) in the brain. Gut microbiota analysis revealed PS133 regulated specific bacterial groups, including [Eubacterium]_coprostanoligenes_group and Lactococcus. Overall, PS133 improved gut function, reduced IBS-like symptoms, and modulated gut microbiota, neurotransmitters, and intestinal barrier health in this IBS model.
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Affiliation(s)
- Fu-Sheng Deng
- Bened Biomedical Co., Ltd., Taipei 115011, Taiwan; (F.-S.D.); (C.-L.H.)
| | - Miao-Hui Lin
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
| | - Chin-Lin Huang
- Bened Biomedical Co., Ltd., Taipei 115011, Taiwan; (F.-S.D.); (C.-L.H.)
- Biomedical Industry Ph.D. Program, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
| | - Chien-Chen Wu
- Bened Biomedical Co., Ltd., Taipei 115011, Taiwan; (F.-S.D.); (C.-L.H.)
| | - Ching-Liang Lu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
- Institute of Brain Science, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan
- Endoscopy Center of Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei 11221, Taiwan
- Division of Gastroenterology, Taipei Veterans General Hospital, Taipei 11221, Taiwan
| | - Ying-Chieh Tsai
- Institute of Biochemistry and Molecular Biology, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan;
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Zhang Z, Conant CR, El-Baba TJ, Raab SA, Fuller DR, Hales DA, Clemmer DE. Diketopiperazine Formation from FPG nK ( n = 1-9) Peptides: Rates of Structural Rearrangements and Mechanisms. J Phys Chem B 2021; 125:8107-8116. [PMID: 34270248 PMCID: PMC10661757 DOI: 10.1021/acs.jpcb.1c03515] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Peptides with penultimate proline residues undergo trans → cis isomerization of the Phe1-Pro2 peptide bond followed by spontaneous bond cleavage at the Pro2-Xxx3 bond (where Xxx is another amino acid residue), leading to cleavage of the Pro2-Xxx3 bond and formation of a diketopiperazine (DKP). In this paper, ion mobility spectrometry and mass spectrometry techniques were used to study the dissociation kinetics of nine peptides [Phe1-Pro2-Glyn-Lysn+3 (n = 1-9)] in ethanol. Shorter (n = 1-3) peptides are found to be more stable than longer (n = 4-9) peptides. Alanine substitution studies indicate that, when experiments are initiated, the Phe1-Pro2 bond of the n = 9 peptide exists exclusively in the cis configuration, while the n = 1-8 peptides appear to exist initially with both cis- and trans-Phe1-Pro2 configured bonds. Molecular dynamics simulations indicate that intramolecular hydrogen bonding interactions stabilize conformations of shorter peptides, thus inhibiting DKP formation. Similar stabilizing interactions appear less frequently in longer peptides. In addition, in smaller peptides, the N-terminal amino group is more likely to be charged compared to the same group in longer peptides, which would inhibit the dissociation through the DKP formation mechanism. Analysis of temperature-dependent kinetics measurements provides insight about the mechanism of bond cleavage. The analysis gives the following transition state thermochemistry: ΔG⧧ values range from 94.6 ± 0.9 to 101.5 ± 1.9 kJ·mol-1, values of ΔH⧧ range from 89.1 ± 0.9 to 116.7 ± 1.5 kJ·mol-1, and ΔS⧧ values range from -25.4 ± 2.6 to 50.8 ± 4.2 J·mol-1·K-1. Proposed mechanisms and thermochemistry are discussed.
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Affiliation(s)
- Zhichao Zhang
- Department of Chemistry, Indiana University, Bloomington, Indiana, United States
| | - Christopher R Conant
- Department of Chemistry, Indiana University, Bloomington, Indiana, United States
| | - Tarick J El-Baba
- Department of Chemistry, Indiana University, Bloomington, Indiana, United States
| | - Shannon A Raab
- Department of Chemistry, Indiana University, Bloomington, Indiana, United States
| | - Daniel R Fuller
- Department of Chemistry, Indiana University, Bloomington, Indiana, United States
| | - David A Hales
- Department of Chemistry, Hendrix College, Conway, Arkansas, United States
| | - David E Clemmer
- Department of Chemistry, Indiana University, Bloomington, Indiana, United States
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Liu YW, Wang YP, Yen HF, Liu PY, Tzeng WJ, Tsai CF, Lin HC, Lee FY, Jeng OJ, Lu CL, Tsai YC. Lactobacillus plantarum PS128 Ameliorated Visceral Hypersensitivity in Rats Through the Gut-Brain Axis. Probiotics Antimicrob Proteins 2021; 12:980-993. [PMID: 31691208 DOI: 10.1007/s12602-019-09595-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder characterized by abdominal pain and alterations in bowel habits. Current treatments for IBS are unsatisfactory due to its multifactorial pathogenesis involving the microbiota-gut-brain axis. Lactobacillus plantarum PS128 (PS128) was reported to exhibit neuromodulatory activity which may be beneficial for improving IBS. This study aimed to investigate the effect of PS128 on visceral hypersensitivity (VH) and the gut-brain axis using a 5-hydroxytryptophan (5-HTP)-induced VH rat model without colonic inflammation induction, mimicking the characteristics of IBS. Male Sprague-Dawley rats were administered with PS128 (109 CFU in 0.2 mL saline/rat/day) or saline (0.2 mL saline/rat/day) for 14 days. Colorectal distension (CRD) with simultaneous electromyography recording was performed 30 min before and 30 min after the 5-HTP injection. Levels of neuropeptides and neurotrophins were analyzed. PS128 significantly reduced VH induced by the 5-HTP injection and CRD. Neurotransmitter protein levels, substance P, CGRP, BDNF, and NGF, were decreased in the dorsal root ganglion but increased in the spinal cord in response to the 5-HTP injection; PS128 reversed these changes. The hypothalamic-pituitary-adrenal axis was modulated by PS128 with decreased corticosterone concentration in serum and the expression of mineralocorticoid receptors in the amygdala. Oral administration of PS128 inhibited 5-HTP-induced VH during CRD. The ameliorative effect on VH suggests the potential application of PS128 for IBS.
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Affiliation(s)
- Yen-Wenn Liu
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.,Microbiome Research Center, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan
| | - Yen-Po Wang
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan.,Institute of Brain Science, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.,School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan
| | - Hsu-Fang Yen
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan
| | - Pei-Yi Liu
- Institute of Brain Science, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan
| | - Wen-Jian Tzeng
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan
| | - Chia-Fen Tsai
- School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.,Department of Psychiatry, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan
| | - Han-Chieh Lin
- School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan
| | - Fa-Yauh Lee
- School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.,Division of Gastroenterology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan
| | | | - Ching-Liang Lu
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan. .,Institute of Brain Science, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan. .,School of Medicine, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan. .,Division of Gastroenterology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Rd., Beitou Dist., Taipei, 11217, Taiwan.
| | - Ying-Chieh Tsai
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan. .,Microbiome Research Center, National Yang-Ming University, No. 155, Sec. 2, Linong St., Beitou Dist., Taipei, 11221, Taiwan.
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Yaklai K, Pattanakuhar S, Chattipakorn N, Chattipakorn SC. The Role of Acupuncture on the Gut-Brain-Microbiota Axis in Irritable Bowel Syndrome. THE AMERICAN JOURNAL OF CHINESE MEDICINE 2021; 49:285-314. [PMID: 33622207 DOI: 10.1142/s0192415x21500154] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Irritable bowel syndrome (IBS) is a chronic dysfunction of the gastrointestinal tract, commonly characterized by abdominal pain or abdominal discomfort. These symptoms can substantially reduce the quality of life and work productivity of the patients. The exact pathogenesis of IBS remains unclear, as it has become apparent that multiple pathways are activated in the condition, including inflammation, immunology, neurology and psychology. Recent evidence has shown that symptoms in IBS are related to the dysfunction of the nervous system, particularly the viscerosomatic pathway, through immune-to-brain communication. The potential link between brain-gut relationships is gut microbiota. The management of IBS mostly focuses on symptomatically treating the patients. There are a wide range of standard treatments, including pharmacological to psychological interventions which are effective in some patients. Therefore, a combination of therapies including both standard and complimentary treatments, including Traditional Chinese Medicine (TCM) such as acupuncture, have been used in treating IBS patients. Several in vivo and clinical studies have demonstrated the efficacy of acupuncture in treating IBS. Increasing attention has been paid to research regarding the action mechanisms of acupuncture for IBS. This paper summarizes and discusses the possible mechanisms associated with acupuncture on the pathophysiology of IBS, including gastrointestinal (GI) motility, visceral hypersensitivity, the immune system, neurotransmitters, and the brain-gut axis. The results fromin vivo and clinical studies have been included. In addition, the effects of acupuncture on gut microbiota in IBS are included and any contradictory findings are deliberated.
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Affiliation(s)
- Kiangyada Yaklai
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai, Thailand.,Sriphat Medical Center, Chiang Mai University, Chiang Mai, Thailand
| | - Sintip Pattanakuhar
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai, Thailand.,Department of Rehabilitation Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai, Thailand.,Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C Chattipakorn
- Neurophysiology Unit, Cardiac Electrophysiology Research and Training Center, Chiang Mai University, Chiang Mai, Thailand.,Department of Oral Biology and Diagnostic Sciences, Faculty of Dentistry, Chiang Mai University, Chiang Mai, Thailand
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Tadalafil versus linaclotide in gastrointestinal dysfunction and depressive behavior in constipation-predominant irritable bowel syndrome. Life Sci 2020; 256:117960. [PMID: 32534033 DOI: 10.1016/j.lfs.2020.117960] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 05/30/2020] [Accepted: 06/08/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Intestinal GC-C/cGMP pathway may be involved in visceral hypersensitivity and fluid secretion in irritable bowel syndrome (IBS). The guanylcyclase C agonist linaclotide, approved for IBS- constipation, is contraindicated in children as it may cause severe diarrhea. In contrast, drugs increasing cGMP by inhibiting phosphodiesterase 5 (PDE-5) are well tolerated in children with pulmonary hypertension. Accordingly, we investigated whether beneficial effects of linaclotide in IBS might be shared by PDE-5inhibitor tadalafil without the severe diarrhea reported for linaclotide. Since depression is commonly comorbid with IBS and is implicated in its pathophysiology; and since tadalafil is absorbed systemically and crosses blood brain barrier, whereas linaclotide does not, impact of both drugs on behavioral changes in IBS was also investigated. METHODS 72 rats were divided into 6groups (control naive, control tadalafil, control linaclotide, untreated IBS, IBS tadalafil, and IBS linaclotide-treated). IBS was induced by 0 to 4 °C intragastric saline for 14 days. RESULTS Both drugs reduced visceral hypersensitivity and colonic C fos. Tadalafil, and to a greater extent, linaclotide increased colonic cGMP, fecal pellets (8.66 ± 4.6 (IBS),versus14.8 ± 3.3(tadalafil), 20 ± 1.2(linaclotide), fecal water content (29.8 ± 5.5 (IBS), versus 47.83 ± 12.6 (tadalafil), 63.58 ± 11.6 (linaclotide) and reduced intestinal transit time (% distance travelled: 29 ± 6.1(IBS), versus 40.58 + 7.5(tadalafil), 51.83 ± 8.3(linaclotide). Tadalafil, but not linaclotide, increased hippocampal cGMP, and improved behavioral tests scores compared to linaclotide (immobility time: 97.3 ± 12.5 s (IBS) versus 68 ± 12.8(tadalafil), 80 ± 17.06 (linaclotide). CONCLUSION Systemic PDE-5 inhibitors might be alternatives to locally acting guanyl cyclase agonists in IBS, inducing less severe diarrhea and more beneficial effects on the associated behavioral changes.
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Lei WY, Chang CY, Wu JH, Lin FH, Hsu Chen C, Chang CF, Lin YR, Wu HP. An Initial Attack of Urinary Stone Disease Is Associated with an Increased Risk of Developing New-Onset Irritable Bowel Syndrome: Nationwide Population-Based Study. PLoS One 2016; 11:e0157701. [PMID: 27337114 PMCID: PMC4919104 DOI: 10.1371/journal.pone.0157701] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2015] [Accepted: 04/19/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The neurotransmitter pathways in irritable bowel syndrome (IBS) and urinary stone attacks are both related to serotonin, and each disease may be influenced by viscero-visceral hyperalgesia. However, the relationship between urinary tract stone disease and IBS has never been addressed. We aimed to investigate the risk of suffering new-onset IBS after an initial urinary stone attack using a nationwide database. METHODS A study group enrolled a total of 13,254 patients who were diagnosed with an initial urinary stone attack; a comparison group recruited 39,762 matched non-urinary stone participants during 2003 and 2007. We followed each patient for 3 years to determine new-onset IBS. We also used Cox proportional hazards models to analyze the risk of IBS between the study and comparison groups after modified by demographics, residence, patient characteristics and personal histories. RESULTS The occurrence rates of IBS were 3.3% (n = 440) and 2.6% (n = 1,034) respectively in the study and comparison groups. A covariate-adjusted hazard ratio (HR) of IBS in the study group that was 1.28 times greater (HR = 1.29, 95% CI, 1.15-1.44) than that in the comparison group was showed in the stratified Cox proportional analysis. The adjusted HRs of IBS did not decrease after considering demographics and past histories. The majority of IBS (30.5%) occurred within the first 6 months after the stone attack. CONCLUSION Patients with an initial urinary stone attack are at increased risk of developing new-onset IBS. The HRs of IBS did not decrease even after adjusting for patient demographics and past histories. Most importantly, 30.5% of IBS occurred within the first 6 months after the urinary stone attack.
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Affiliation(s)
- Wei-Yuan Lei
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Chih-Yu Chang
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
- Department of Biological Science and Technology of Biochemical Engineering, National Chiao Tung University, Hsinchu, Taiwan
| | - Jr-Hau Wu
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Fei-Hung Lin
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Cheng Hsu Chen
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Chin-Fu Chang
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Yan-Ren Lin
- Department of Emergency Medicine, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Han-Ping Wu
- Division of Pediatric General Medicine, Department of Pediatrics, Chang Gung Memorial Hospital at Linko, Kweishan, Taoyuan, Taiwan
- College of Medicine, Chang Gung University, Taoyuan, Taiwan
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Yin Y, Zhong L, Wang JW, Zhao XY, Zhao WJ, Kuang HX. Tong Xie Yao Fang relieves irritable bowel syndrome in rats via mechanisms involving regulation of 5-hydroxytryptamine and substance P. World J Gastroenterol 2015; 21:4536-4546. [PMID: 25914462 PMCID: PMC4402300 DOI: 10.3748/wjg.v21.i15.4536] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2014] [Revised: 12/09/2014] [Accepted: 01/30/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether the Chinese medicine Tong Xie Yao Fang (TXYF) improves dysfunction in an irritable bowel syndrome (IBS) rat model.
METHODS: Thirty baby rats for IBS modeling were separated from mother rats (1 h per day) from days 8 to 21, and the rectum was expanded by angioplasty from days 8 to 12. Ten normal rats were used as normal controls. We examined the effects of TXYF on defection frequency, colonic transit function and smooth muscle contraction, and the expression of 5-hydroxytryptamine (5-HT) and substance P (SP) in colonic and hypothalamus tissues by Western blot and RT-PCT techniques in both normal rats and IBS model rats with characterized visceral hypersensitivity.
RESULTS: Defecation frequency was 1.8 ± 1.03 in normal rats and 4.5 ± 1.58 in IBS model rats (P < 0.001). However, the defecation frequency was significantly decreased (3.0 ± 1.25 vs 4.5 ± 1.58, P < 0.05), while the time (in seconds) of colon transit function was significantly increased (256.88 ± 20.32 vs 93.36 ± 17.28, P < 0.001) in IBS + TXYF group rats than in IBS group rats. Increased colonic smooth muscle tension and contract frequency in IBS model rats were significantly decreased by administration of TXYF. Exogenous agonist stimulants increased spontaneous activity and elicited contractions of colon smooth muscle in IBS model rats, and all of these actions were significantly reduced by TXYF involving 5-HT and SP down-regulation.
CONCLUSION: TXYF can modulate the activity of the enteric nervous system and alter 5-HT and SP activities, which may contribute to the symptoms of IBS.
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Neural plasticity in the gastrointestinal tract: chronic inflammation, neurotrophic signals, and hypersensitivity. Acta Neuropathol 2013; 125:491-509. [PMID: 23417735 DOI: 10.1007/s00401-013-1099-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2012] [Revised: 01/31/2013] [Accepted: 02/07/2013] [Indexed: 12/28/2022]
Abstract
Neural plasticity is not only the adaptive response of the central nervous system to learning, structural damage or sensory deprivation, but also an increasingly recognized common feature of the gastrointestinal (GI) nervous system during pathological states. Indeed, nearly all chronic GI disorders exhibit a disease-stage-dependent, structural and functional neuroplasticity. At structural level, GI neuroplasticity usually comprises local tissue hyperinnervation (neural sprouting, neural, and ganglionic hypertrophy) next to hypoinnervated areas, a switch in the neurochemical (neurotransmitter/neuropeptide) code toward preferential expression of neuropeptides which are frequently present in nociceptive neurons (e.g., substance P/SP, calcitonin-gene-related-peptide/CGRP) and of ion channels (TRPV1, TRPA1, PAR2), and concomitant activation of peripheral neural glia. The functional counterpart of these structural alterations is altered neuronal electric activity, leading to organ dysfunction (e.g., impaired motility and secretion), together with reduced sensory thresholds, resulting in hypersensitivity and pain. The present review underlines that neural plasticity in all GI organs, starting from esophagus, stomach, small and large intestine to liver, gallbladder, and pancreas, actually exhibits common phenotypes and mechanisms. Careful appraisal of these GI neuroplastic alterations reveals that--no matter which etiology, i.e., inflammatory, infectious, neoplastic/malignant, or degenerative--neural plasticity in the GI tract primarily occurs in the presence of chronic tissue- and neuro-inflammation. It seems that studying the abundant trophic and activating signals which are generated during this neuro-immune-crosstalk represents the key to understand the remarkable neuroplasticity of the GI tract.
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Feng B, La JH, Schwartz ES, Gebhart GF. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. Neural and neuro-immune mechanisms of visceral hypersensitivity in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 2012; 302:G1085-98. [PMID: 22403791 PMCID: PMC3362095 DOI: 10.1152/ajpgi.00542.2011] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Irritable bowel syndrome (IBS) is characterized as functional because a pathobiological cause is not readily apparent. Considerable evidence, however, documents that sensitizing proinflammatory and lipotoxic lipids, mast cells and their products, tryptases, enteroendocrine cells, and mononuclear phagocytes and their receptors are increased in tissues of IBS patients with colorectal hypersensitivity. It is also clear from recordings in animals of the colorectal afferent innervation that afferents exhibit long-term changes in models of persistent colorectal hypersensitivity. Such changes in afferent excitability and responses to mechanical stimuli are consistent with relief of discomfort and pain in IBS patients, including relief of referred abdominal hypersensitivity, upon intra-rectal instillation of local anesthetic. In the aggregate, these experimental outcomes establish the importance of afferent drive in IBS, consistent with a larger literature with respect to other chronic conditions in which pain is a principal complaint (e.g., neuropathic pain, painful bladder syndrome, fibromyalgia). Accordingly, colorectal afferents and the environment in which these receptive endings reside constitute the focus of this review. That environment includes understudied and incompletely understood contributions from immune-competent cells resident in and recruited into the colorectum. We close this review by highlighting deficiencies in existing knowledge and identifying several areas for further investigation, resolution of which we anticipate would significantly advance our understanding of neural and neuro-immune contributions to IBS pain and hypersensitivity.
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Affiliation(s)
- Bin Feng
- Center for Pain Research, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Jun Ho La
- Center for Pain Research, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Erica S. Schwartz
- Center for Pain Research, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - G. F. Gebhart
- Center for Pain Research, Department of Anesthesiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
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Kalafatakis K, Triantafyllou K. Contribution of neurotensin in the immune and neuroendocrine modulation of normal and abnormal enteric function. ACTA ACUST UNITED AC 2011; 170:7-17. [PMID: 21549161 DOI: 10.1016/j.regpep.2011.04.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2010] [Revised: 03/22/2011] [Accepted: 04/16/2011] [Indexed: 12/19/2022]
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Dandagi PM, Mastiholimath VS, Gadad AP, Kulkarni AR, Konnur BK. pH-Sensitive Mebeverine Microspheres for Colon Delivery. Indian J Pharm Sci 2011; 71:464-8. [PMID: 20502560 PMCID: PMC2865826 DOI: 10.4103/0250-474x.57303] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2008] [Revised: 04/23/2009] [Accepted: 08/11/2009] [Indexed: 11/23/2022] Open
Abstract
Mebeverine hydrochloride is known to suffer from extensive first pass effect. In an attempt to improve its oral bioavailability and possibility to restrict its absorption only to the colon, mebeverine microspheres were prepared by emulsion solvent evaporation method. Four formulations were prepared with varying drug and polymer ratio. These formulations were subjected to various evaluation parameters like percent practical yield, entrapment efficiency, particle size, in vitro drug release, in vivo activity. Practical yield of the microspheres was up to 89.59% with encapsulation efficiency up to 79.4%. Scanning electron microscopy confirmed that the microsphere structures were smooth, spherical, and discrete and the particles were of the size range 200 to 300 μm. In vitro release of the drug showed biphasic release pattern with non-Fickian diffusion release in 12 h. On the basis of drug content, particle size, in vitro release and in vivo studies, formulation F-3 was found to be optimal. Antiirritable bowel syndrome activity was performed in colorectal distention in rat, which is a model for constipation-induced irritable bowel syndrome. The formulations F-2 and F-3 showed significant effect in fecal output when compared to the control as well as the marketed preparation in the constipation-induced irritable bowel syndrome in rats.
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Affiliation(s)
- P M Dandagi
- Department of Pharmaceutics, K. L. E. S's College of Pharmacy, J. N. M. C. Campus, Nehru Nagar, Belgaum-590 010, India
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Hong Y, Liang WM, Xia BJ, Hu Y, Han J, Li YX, Xie L. Expression of 5-HT and SP in the rectum of rats during heroin abstinence, detoxification or relapse. Shijie Huaren Xiaohua Zazhi 2011; 19:477-482. [DOI: 10.11569/wcjd.v19.i5.477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of 5-hydroxytryptamine (5-HT) and substance P (SP) in the rectum of rats during heroin abstinence, detoxication, and relapse.
METHODS: Male Sprague-Dawley rats were divided into normal control group (NCG), saline control group (SCG), and experiment group (EG). The EG group was further divided into heroin abstinence group (HAG), methadone detoxication group (MDG), and heroin relapse group (HRG). Rectum tissue samples were taken from each group to perform immunohistochemistry to detect the expression of 5-HT and SP.
RESULTS: Compared with the NCG and SCG groups, the immunostaining density of 5-HT- and SP-positive cells was greater, the numbers of 5-HT- and SP-positive cells increased (5-HT: 10 d: 5.09 ± 3.39 vs 3.16 ± 2.05, 2.80 ± 2.13; 24 d: 5.05 ± 3.04 vs 3.16 ± 2.05, 2.81 ± 1.85; SP: 10 d: 2.55 ± 1.35 vs 1.29 ± 0.86, 1.37 ± 0.93; 24 d: 2.57 ± 1.27 vs 1.29 ± 0.86, 1.39 ± 0.79, all P < 0.05), and the mean grey degree of 5-HT- and SP-positive cells decreased (F = 36.642, 4.583, P < 0.05) in the HAG and HRG groups. Compared with the NCG and SCG groups, there were no statistical significances in the immunostaining density, numbers, and mean grey degree of 5-HT- and SP- positive cells in the MDG group (all P > 0.05).
CONCLUSION: Altered expression of 5-HT and SP in the tunica mucosa recti of rats during heroin abstinence or relapse suggests that 5-HT and SP can regulate the recovery of digestive function during heroin abstinence, detoxification, and relapse.
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Ma XP, Tan LY, Yang Y, Wu HG, Jiang B, Liu HR, Yang L. Effect of electro-acupuncture on substance P, its receptor and corticotropin-releasing hormone in rats with irritable bowel syndrome. World J Gastroenterol 2009; 15:5211-7. [PMID: 19891022 PMCID: PMC2773902 DOI: 10.3748/wjg.15.5211] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effect and mechanism of electro-acupuncture (EA) at ST25 and ST37 on irritable bowel syndrome (IBS) of rats.
METHODS: A total of 21 male Sprague-Dawley rats were randomly divided into normal group, model group and EA group. A rat model of IBS was established by constraining the limbs and distending the colorectum of rats. Rats in EA group received bilateral EA at ST25 and ST37 with a sparse and intense waveform at a frequency of 2/50 Hz for 15 min, once a day for 7 d as a course. Rats in normal and model groups were stimulated by distending colorectum (CR). An abdominal withdrawal reflex (AWR) scoring system was used to evaluate improvements in visceral hypersensitivity. Toluidine blue-improved method, immunohistochemistry and radioimmunoassay were used to observe mucosal mast cells (MC), changes of substance P (SP) and substance P receptor (SPR) in colon and change of corticotropin-releasing hormone (CRH) in hypothalamus.
RESULTS: The threshold of visceral sense was significantly lower in model group than in normal group, and significantly higher in EA group than in model group. The number of mucosal MC was greater in model group than in normal group and significantly smaller in EA group than in model group. The CRH level in hypothalamus of rats was significantly higher in model group than in normal group, which was remarkably decreased after electro-acupuncture treatment. The SP and SPR expression in colon of rats in model group was decreased after electro-acupuncture treatment.
CONCLUSION: EA at ST25 and ST37 can decrease the number of mucosal MC and down-regulate the expression of CRH in hypothalamus, and the expression of SP and SPR in colon of rats with IBS.
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Hu J, Hu TM, He WQ, Huang YD. Effects of Huangshu Enema on the levels of serum IL-1β and IL-10 in rats with diarrhea-predominant irritable bowel syndrome. Shijie Huaren Xiaohua Zazhi 2009; 17:2188-2191. [DOI: 10.11569/wcjd.v17.i21.2188] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the effects of Huangshu Enema (HSE) on the levels of IL-1β and IL-10 in the serum of rats with diarrhea-predominant irritable bowel syndrome (D-IBS).
METHODS: A rat model of D-IBS was created by intracolonic instillation of acetic acid and restraint stress. Sixty healthy female Sprague-Dawley rats were randomly divided into normal control group (n = 15), model control group (n = 15), HSE treatment group (n = 15) and dicetel treatment group (n = 15). The changes in serum IL-1β and IL-10 levels in rats were observed.
RESULTS: The level of serum IL-1β was significantly higher in the model control group than the normal control group, while the level of serum IL-10 was significantly lower in the model control group than in the normal control group (t = 21.9998 and 27.0556, respectively; both P < 0.01). The level of serum IL-1β in the two treatment groups significantly decreased when compared to the model control group (t = 12.0599 and 6.1647, respectively; both P < 0.01), while the level of serum IL-10 in the two treatment groups significantly increased when compared to the model control group (t = 17.3802 and 6.8408, respectively; both P < 0.01). HSE was superior to dicetel in decreasing serum IL-1β level and increasing serum IL-10 level (t = 9.7410, P < 0.01).
CONCLUSION: HSE may be able to reduce the number of activated immune cells, increase anti-inflammatory cytokines and enhance the anti-inflammatory activity, and adjust the imbalance between anti-inflammatory and pro-inflammatory cytokines, thereby exerting therapeutic effects on D-IBS.
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Li J, Micevych P, McDonald J, Rapkin A, Chaban V. Inflammation in the uterus induces phosphorylated extracellular signal-regulated kinase and substance P immunoreactivity in dorsal root ganglia neurons innervating both uterus and colon in rats. J Neurosci Res 2009; 86:2746-52. [PMID: 18478547 DOI: 10.1002/jnr.21714] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
In women, clinical studies suggest that pain syndromes such as irritable bowel syndrome and interstitial cystitis, which are associated with visceral hyperalgesia, are often comorbid with endometriosis and chronic pelvic pain. One of the possible explanations for this phenomenon is viscerovisceral cross-sensitization, in which increased nociceptive input from an inflamed pelvic organ sensitizes neurons that receive convergent input to the same dorsal root ganglion (DRG) from an unaffected visceral organ. Nociception induces up-regulation of cellular mechanisms such as phosphorylated extracellular signal-regulated kinase (pERK) and substance P (SP), neurotransmitters associated with induced pain sensation. The purpose of this study was to determine, in a rodent model, whether uterine inflammation increased the number of pERK- and SP-positive neurons that received input from both the uterus and the colon. Cell bodies of colonic and uterine DRG were retrogradely labeled with fluorescent tracer dyes microinjected into the colon/rectum and into the uterus. Ganglia were harvested for fluorescent microscopy to identify positively stained neurons. Approximately 6% of neurons were colon specific and 10% uterus specific. Among these uterus- or colon-specific neurons, up to 3-5% of DRG neurons in the lumbosacral neurons (L1-S3 levels) received input from both visceral organs. Uterine inflammation increased the number of pERK- and SP-immunoreactive DRG neurons innervating specifically colon, or innervating specifically uterus, and those innervating both organs. These results suggest that a localized inflammation activates primary visceral afferents, regardless of whether they innervate the affected organ. This visceral sensory integration in the DRG may underlie the observed comorbidity of female pelvic pain syndromes.
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Affiliation(s)
- Jichang Li
- Department of Anesthesiology, Harbor-UCLA Medical Center, Los Angeles, California, USA
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Kraneveld AD, Rijnierse A, Nijkamp FP, Garssen J. Neuro-immune interactions in inflammatory bowel disease and irritable bowel syndrome: future therapeutic targets. Eur J Pharmacol 2008; 585:361-74. [PMID: 18417115 DOI: 10.1016/j.ejphar.2008.02.095] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2008] [Revised: 02/11/2008] [Accepted: 02/20/2008] [Indexed: 12/22/2022]
Abstract
The gastro-intestinal tract is well known for its largest neural network outside the central nervous system and for the most extensive immune system in the body. Research in neurogastroenterology implicates the involvement of both enteric nervous system and immune system in symptoms of inflammatory bowel disease and irritable bowel syndrome. Since both disorders are associated with increased immune cell numbers, nerve growth and activation of both immune cells and nerves, we focus in this review on the involvement of immune cell-nerve interactions in inflammatory bowel disease and irritable bowel syndrome. Firstly, the possible effects of enteric nerves, especially of the nonadrenergic and noncholinergic nerves, on the intestinal immune system and their possible role in the pathogenesis of chronic intestinal inflammatory diseases are described. Secondly, the possible effects of immunological factors, from the innate (chemokines and Toll-like receptors) as well as the adaptive (cytokines and immunoglobulins) immune system, on gastro-intestinal nerves and its potential role in the development of inflammatory bowel disease and irritable bowel syndrome are reviewed. Investigations of receptor-mediated and intracellular signal pathways in neuro-immune interactions might help to develop more effective therapeutic approaches for chronic inflammatory intestinal diseases.
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Affiliation(s)
- Aletta D Kraneveld
- Division Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences, Utrecht University, PO box 80082, 3508 TB Utrecht, The Netherlands.
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Rijnierse A, Nijkamp FP, Kraneveld AD. Mast cells and nerves tickle in the tummy: implications for inflammatory bowel disease and irritable bowel syndrome. Pharmacol Ther 2007; 116:207-35. [PMID: 17719089 DOI: 10.1016/j.pharmthera.2007.06.008] [Citation(s) in RCA: 85] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2007] [Accepted: 06/20/2007] [Indexed: 12/12/2022]
Abstract
Mast cells are well known as versatile cells capable of releasing and producing a variety of inflammatory mediators upon activation and are often found in close proximity of neurons. In addition, inflammation leads to local activation of neurons resulting in the release neuropeptides, which also play an important immune modulatory role by stimulation of immune cells. In intestinal disorders like inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), the number of mast cells is known to be much higher than in the normal intestine. Moreover, both these disorders are also reported to be associated with alterations in neuropeptide content and in neural innervation. Mutual association between mast cells and enteric nerves has been demonstrated to be increased in pathophysiological conditions and contribute to spreading and amplification of the response in IBD and IBS. In this review the focus lies on studies appointed to the direct interaction between mast cells and nerves in IBD, IBS, and animal models for these disorders so far.
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Affiliation(s)
- Anneke Rijnierse
- Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
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