Effect of amitriptyline on gastrointestinal function and brain-gut peptides: A double-blind trial

AIM: To study the effects of low-dose amitriptyline (AMT) on gastrointestinal function and brain-gut peptides in healthy Chinese volunteers. METHODS: This was a double-blind, randomised, placebo-controlled, two-period cross-over trial. Twentyeight healthy volunteers were randomised and administered 1-wk treatments of AMT (12.5 mg tid) or placebo. Before and during the final two days of treatment, gastric emptying, proximal gastric accommodation and visceral sensitivity were measured by drinkingultrasonography test; the orocecal transit time (OCTT) was measured by lactulose hydrogen breath test, and fasting blood was collected. Plasma levels of ghrelin, motilin and neuropeptide Y (NPY) were measured by enzyme-linked immunosorbent assay kits.RESULTS: AMT slowed the OCTT (109.2 ± 29.68 min vs 96.61 ± 23.9 min, P = 0.004) but did not affect liquid gastric emptying and had no effect on proximal gastric accommodation. AMT resulted in decreases in the visual analogue scale (VAS) for difficulty in drinking 600 and 800 mL of water (3.57 ± 0.94 vs 2.98 ± 0.85, 5.57 ± 0.82 vs 4.57 ± 0.98, P < 0.01 for both), although it had no significant effect on the VAS for difficulty in drinking 200 mL and 400 mL of water. AMT significantly increased the plasma ghrelin level (442.87 ± 176.79 pg/mL vs 526.87 ± 158.44 pg/mL, P = 0.04) and the neuropeptide-Y level (890.15 ± 131.46 pg/mL vs 965.64 ± 165.63 pg/mL, P = 0.03), whereas it had no effect on the MTL level. CONCLUSION: Low-dose AMT could slow OCTT, make the stomach less sensitive and increase the plasma levels of ghrelin and NPY. Thus, we recommend the use of low-dose AMT for functional gastrointestinal disorders.

Brain-gut axis in the pathogenesis of Helicobacter pylori infection

Helicobacter pylori (H. pylori) infection is the main pathogenic factor for upper digestive tract organic diseases. In addition to direct cytotoxic and proinflammatory effects, H. pylori infection may also induce abnormalities indirectly by affecting the brain-gut axis, similar to other microorganisms present in the alimentary tract. The brain-gut axis integrates the central, peripheral, enteric and autonomic nervous systems, as well as the endocrine and immunological systems, with gastrointestinal functions and environmental stimuli, including gastric and intestinal microbiota. The bidirectional relationship between H. pylori infection and the brain-gut axis influences both the contagion process and the host&#x02019;s neuroendocrine-immunological reaction to it, resulting in alterations in cognitive functions, food intake and appetite, immunological response, and modification of symptom sensitivity thresholds. Furthermore, disturbances in the upper and lower digestive tract permeability, motility and secretion can occur, mainly as a form of irritable bowel syndrome. Many of these abnormalities disappear following H. pylori eradication. H. pylori may have direct neurotoxic effects that lead to alteration of the brain-gut axis through the activation of neurogenic inflammatory processes, or by microelement deficiency secondary to functional and morphological changes in the digestive tract. In digestive tissue, H. pylori can alter signaling in the brain-gut axis by mast cells, the main brain-gut axis effector, as H. pylori infection is associated with decreased mast cell infiltration in the digestive tract. Nevertheless, unequivocal data concerning the direct and immediate effect of H. pylori infection on the brain-gut axis are still lacking. Therefore, further studies evaluating the clinical importance of these host-bacteria interactions will improve our understanding of H. pylori infection pathophysiology and suggest new therapeutic approaches.

New technologies to investigate the brain-gut axis

Functional gastrointestinal disorders are commonly encountered in clinical practice, and pain is their commonest presenting symptom. In addition, patients with these disorders often demonstrate a heightened sensitivity to experimental visceral stimulation, termed visceral pain hypersensitivity that is likely to be important in their pathophysiology. Knowledge of how the brain processes sensory information from visceral structures is still in its infancy. However, our understanding has been propelled by technological imaging advances such as functional Magnetic Resonance Imaging, Positron Emission Tomography, Magnetoencephalography, and Electroencephalography （EEG）. Numerous human studies have non-invasively demonstrated the complexity involved in functional pain processing, and highlighted a number of subcortical and cortical regions involved. This review will focus on the neurophysiological pathways （primary afferents, spinal and supraspinal transmission）, brainimaging techniques and the influence of endogenous and psychological processes in healthy controls and patients suffering from functional gastrointestinal disorders. Special attention will be paid to the newer EEG source analysis techniques. Understanding the phenotypic differences that determine an individual＇s response to injurious stimuli could be the key to understanding why some patients develop pain and hyperalgesia in response to inflammation/injury while others do not. For future studies, an integrated approach is required incorporating an individual＇s psychological, autonomic, neuroendocrine, neurophysiological, and genetic profile to define phenotypic traits that may be at greater risk of developing sensitised states in response to gut inflammation or injury.

Neuroimaging the brain-gut axis in patients with irritable bowel syndrome

AIM:To summarize and synthesize current literature on neuroimaging the brain-gut axis in patients with irritable bowel syndrome(IBS).METHODS:A database search for relevant literature was conducted using Pub Med,Scopus and Embase in February 2015.Date filters were applied from the year2009 and onward,and studies were limited to those written in the English language and those performed upon human subjects.The initial search yielded 797articles,out of which 38 were pulled for full text review and 27 were included for study analysis.Investigations were reviewed to determine study design,methodology and results,and data points were placed in tabular format to facilitate analysis of study findings across disparate investigations.RESULTS:Analysis of study data resulted in the abstraction of four key themes:Neurohormonal differences,anatomic measurements of brain structure and connectivity,differences in functional responsiveness of the brain during rectal distention,and confounding/correlating patient factors.Studies in this review noted alterations of glutamate in the left hippocampus(HIPP),commonalities across IBS subjects in terms of brain oscillation patterns,cortical thickness/gray matter volume differences,and neuroanatomical regions withincreased activation in patients with IBS:Anterio cingulate cortex,mid cingulate cortex,amygdala anterior insula,posterior insula and prefrontal cortex.A striking finding among interventions was the substantia influence that patient variables(e.g.,sex,psychologica and disease related factors)had upon the identification of neuroanatomical differences in structure and con nectivity.CONCLUSION:The field of neuroimaging can provide insight into underlying physiological differences that distinguish patients with IBS from a healthy population.

Role of the brain-gut axis in gastrointestinal cancer

Several studies have largely focused on the significant role of the nervous and immune systems in the process of tumorigenesis, including tumor growth, proliferation, apoptosis, and metastasis. The brain-gut-axis is a new paradigm in neuroscience, which describes the biochemical signaling between the gastrointestinal (GI) tract and the central nervous system. This axis may play a critical role in the tumorigenesis and development of GI cancers. Mechanistically, the bidirectional signal transmission of the brain-gut-axis is complex and remains to be elucidated. In this article, we review the current findings concerning the relationship between the brain-gut axis and GI cancer cells, focusing on the significant role of the brain-gut axis in the processes of tumor proliferation, invasion, apoptosis, autophagy, and metastasis. It appears that the brain might modulate GI cancer by two pathways: the anatomical nerve pathway and the neuroendocrine route. The simulation and inactivation of the central nervous, sympathetic, and parasympathetic nervous systems, or changes in the innervation of the GI tract might contribute to a higher incidence of GI cancers. In addition, neurotransmitters and neurotrophic factors can produce stimulatory or inhibitory effects in the progression of GI cancers. Insights into these mechanisms may lead to the discovery of potential prognostic and therapeutic targets.

Study on the regulation of brain-gut peptide by Shenling Baizhu San in functional diarrhea rats

Objective:To explore the therapeutic mechanism of Shenling Baizhu San (SLBZS) on functional diarrhea (FDr) by studying the brain-gut axis and related neuropeptides.Methods:Sixty male Wistar rats were randomly divided into the control group,model group,SLBZS-treated group and Montmorillonite Powder-treated group (MP-treated group) (n =15/group).Rats received gavage after the establishment of functional diarrhea.An equal volume of SLBZS solution and Montmorillonite Powder (MP) solution was administered to the SLBZS-treated group and MP-treated group,respectively,and an equal volume of distilled water was administered to the control group and the model group.The chemical components and targets related to SLBZS were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and Traditional Chinese Medicine Integrated Database (TCMID).The effective chemical components were screened based on oral bioavailability (OB) and drug like-index (DL),and their biological functions were analyzed by GlueGO.Based on this screening,the expression of Cholecystokinin (CCK) and Ghrelin in the hypothalamus of rats was detected by real-time PCR (RT-PCR) and western blotting.Results:In this study,72 effective components and 190 core targets of SLBZS were screened.SLBZS may regulate smooth muscle contraction,energy metabolism and other biological processes.The results of RT-PCR showed that in the model group,the expression of CCK mRNA (P =.001) and Ghrelin mRNA (P =.000) increased significantly.Compared with the model group,CCK mRNA (P =.007) and Ghrelin mRNA (P =.001) levels in SLBZS-treated rats were decreased significantly.The results of western blotting showed that in the model group,the protein expression of CCK (P =.001) and Ghrelin (P =.000) increased significantly.The protein levels of CCK (P =.001) and Ghrelin (P =.005) in the SLBZS-treated group were decreased significantly compared with the model group.Conclusion:SLBZS improved functional diarrhea by regulating the brain-gut axis.Changes in the expressions of brain-gut peptide,CCK and Ghrelin might explain the pathogenesis of functional diarrhea related to brain-gut peptide and gastrointestinal hormone.

Application progress of Chinese medicine in the treatment of irritable bowel syndrome based on the brain-gut axis theory

Irritable bowel syndrome is one of the most common functional gastrointestinal diseases,with a global prevalence of about 12%[1].Modern studies have shown that the abnormality of brain-gut peptides is closely related to the occurrence of irritable bowel syndrome.This article starts with vasoactive intestinal peptide,substance P,serotonin,neuropeptide Y,corticotropin releasing factor,calcitonin gene-related peptide,cholecystokinin and other brain-gut peptides and their correlation with intestinal flora,to summarize the treatment of irritable bowel syndrome with traditional Chinese medicine in recent years.

Therapeutic effect of zhuodu theory on ulcerative colitis and its effect on brain-gut peptide in serum and inflammatory factor

Objective:To investigate the therapeutic effect of traditional Chinese medicine xiezhuojiedu decoction on ulcerative colitis(UC)based on zhuodu theory and its effect on serum brain-gut peptide and inflammatory factors.Methods:110 cases of UC patients were divided into 2 groups according to the random number table method,with 55 cases in each group.The control group was treated with mesalazine,and the treatment group was given oral administration of Chinese medicine xiezhuojiedu decoction on the basis of the control group.Both groups received continuous treatment for 8 weeks.Integral of TCM syndromes,serum inflammatory factor and brain-gut peptide before and after treatment were compared between the two groups.The clinical efficiency,mucosal healing rate and endoscopic response rate of the two groups were compared.Results:After treatment,Integral of the main TCM syndromes abdominal pain,diarrhea,abdominal distention,mucous hematochezia,tenesmus of the treatment group were lower than the control group(P<0.01),the levels of serum(Tumor necrosis factor-α,(TNF-α),Interleukin(IL)-33,Substance P(SP)were lower than the control group(P<0.01),the levels of IL-10,vasoactive intestinal peptide(VIP),Somatostatin(SS)were higher than the control group(P<0.01),the clinical efficiency and mucosal healing rate were higher than control group(P<0.05),The difference was statistically significant.Conclusion:Based on the zhuodu theory,the xiezhuojiedu decoction can effectively regulate the levels of inflammatory factor and brain-gut peptide in the treatment of UC,improve the symptoms of patients,and promote the repair of intestinal mucosa.It's effective in treatment.

Clinical Application and Mechanism of Acupuncture in the Brain-Gut Interaction

Acupuncture and moxibustion is an important part of traditional medicine.Acupuncture and moxibustion can affect the digestive function of human body by interfering with the interaction between the brain and the intestines,while simultaneously having a benign adjustment effect on the mental state.In recent years,a large number of clinical studies at home and abroad have further proved the importance of acupuncture and moxibustion in the treatment of physical and mental diseases,and related mechanism studies have provided modern scientific evidence for the intervention of acupuncture and moxibustion in the brain-gut interaction from the perspectives of intestinal flora and brain functional imaging.On this basis,we integrate relevant viewpoints to provide ideas and methods for future research.

Effect of Xiaoyao San on the brain-gut axis in rats after chronic immobilization stress

Objective:To investigate the effect of Xiaoyao San on the brain-gut axis in rats exposed to chronic immobilization stress (ClS).Methods:Rats were divided into control,model,and treatment groups.The rats belonging to the model and treatment groups were subjected to CIS for 21 consecutive days,during which they were administered Xiaoyao San decoction [3.854 g/(kg· d)] or vehicle by gavage,and their body weight gain,food intake and water intake were monitored.The rats were subsequently subjected to the open field test (OFT) and D-XyloSe absorption test,and the expression levels of neuropeptides secreted by the hypothalamus and stomach were determined by enzyme-linked immunosorbent assay (ELISA),radioimmune analysis,or real-time fluorescence quantitative polymerase chain reaction.Gastric mucosal morphology was also assessed.Results:The model rats exhibited complex brain-gut axis abnormalities following exposure to CIS,abnormalities signified by decreases in food intake,reductions in digestive absorption,decreases in body weight,decreases in the total distances traveled and increases in the time in the central zone during the OFT,gastric mucosal lesion development and decreases in gastrointestinal hormone secretion.These changes were reversed after treatment with Xiaoyao San,which also regulated the secretion of both peripheral (serum and stomach) and central (hypothalamus) brain-gut peptides.Specifically,the levels of neuropeptide Y (NPY) and neuropeptide Y receptor Y5,which are secreted by the hypothalamus and promote digestive function,were increased in the Xiaoyao San-treated group compared with the model group.Furthermore,the levels of pro-opiomelanocortin (POMC) and its receptor,melanocortin-4 receptor (MC4R),which are secreted by the hypothalamus and inhibit digestive function,were significantly decreased in the treatment group compared with the model group.However,the levels of ghrelin (GHRL),gastrin (GAS) and motilin (MTL),which are secreted by the stomach,were significantly increased in the serum and stomach of the treatment group compared with the serum and stomach of the model group following Xiaoyao San treatment (P <.05 vs.the model group).Conclusion:Xiaoyao San attenuates CIS-induced gastrointestinal dysregulation by regulating the peptides secreted by both the hypothalamus and the gastrointestinal tract (GIT),suggesting that its effects are associated with the brain-gut axis.

Immune cell signatures and causal association with irritable bowel syndrome:A mendelian randomization study

BACKGROUND The mucosal barrier's immune-brain interactions,pivotal for neural development and function,are increasingly recognized for their potential causal and therapeutic relevance to irritable bowel syndrome(IBS).Prior studies linking immune inflammation with IBS have been inconsistent.To further elucidate this relationship,we conducted a Mendelian randomization(MR)analysis of 731 immune cell markers to dissect the influence of various immune phenotypes on IBS.Our goal was to deepen our understanding of the disrupted brain-gut axis in IBS and to identify novel therapeutic targets.AIM To leverage publicly available data to perform MR analysis on 731 immune cell markers and explore their impact on IBS.We aimed to uncover immunophenotypic associations with IBS that could inform future drug development and therapeutic strategies.METHODS We performed a comprehensive two-sample MR analysis to evaluate the causal relationship between immune cell markers and IBS.By utilizing genetic data from public databases,we examined the causal associations between 731 immune cell markers,encompassing median fluorescence intensity,relative cell abundance,absolute cell count,and morphological parameters,with IBS susceptibility.Sensitivity analyses were conducted to validate our findings and address potential heterogeneity and pleiotropy.RESULTS Bidirectional false discovery rate correction indicated no significant influence of IBS on immunophenotypes.However,our analysis revealed a causal impact of IBS on 30 out of 731 immune phenotypes(P<0.05).Nine immune phenotypes demonstrated a protective effect against IBS[inverse variance weighting(IVW)<0.05,odd ratio(OR)<1],while 21 others were associated with an increased risk of IBS onset(IVW≥0.05,OR≥1).CONCLUSION Our findings underscore a substantial genetic correlation between immune cell phenotypes and IBS,providing valuable insights into the pathophysiology of the condition.These results pave the way for the development of more precise biomarkers and targeted therapies for IBS.Furthermore,this research enriches our comprehension of immune cell roles in IBS pathogenesis,offering a foundation for more effective,personalized treatment approaches.These advancements hold promise for improving IBS patient quality of life and reducing the disease burden on individuals and their families.

Diet and physical activity influence the composition of gut microbiota,benefit on Alzheimer's disease

Alzheimer's disease is a neurodegenerative disease with complex etiology.Gut microbiota influences the gutbrain axis,which may affect pathways related to the pathogenesis of Alzheimer's disease.Additionally,diet and physical activity are likely to affect the pathology of Alzheimer's disease as well as the gut microbiota.This demonstrates that it may be possible to prevent or halt the progression of Alzheimer's disease by regulating the gut microbiota using diet and physical activity strategies.Therefore,the present study reviews the association between these two interventions and gut microbiota in the human body.It also summarizes how these two interventions benefit Alzheimer's disease.Furthermore,the primary limitations of these two interventions are discussed and promising strategies are proposed,which may be beneficial to further study and develop the intervening measure for the progression of Alzheimer's disease.

玉米多肽抗氧化作用的研究

用K3[Fe（CN）6]测定了玉米多肽的还原力；采用脱氧核糖一铁体系、超氧阴离子自由基体系、二苯代苦味肼基自由基（DPPH·）体系对玉米多肽的抗氧化活性进行了研究，并同VC进行了比较。结果表明：玉米多肽具有还原力。玉米多肽对这几种自由基均有不同程度的清除作用，其中在20～50mg／mE清除羟基自由基能力与VC相差不大；玉米多肽清除DPPH·和O^2-·的能力均低于Vc，玉米多肽5mg／mL时，DPPH·清除率接近57．59％，10mg／mL时，O^2-·清除率为46．05％。

真鲷鳃组织cDNA文库的构建与hepcidin抗菌肽基因序列的扩增

以细菌攻毒的真鲷鳃组织为材料，分离出mRNA，合成双链后，回收500～4000bp cDNA片段，构建了λZAP表达型cDNA文库。初级文库的容量为1．75×10^5个重组子，扩增文库的滴度达到1×10^9pfu·mL^-1，随机挑选噬菌斑的插入片断在500～2000bp之间。以hepcidin特异性引物做PCR扩增文库，获得了hepcidin抗菌肽基因cDNA序列，证明所建立的文库可用于免疫相关基因的筛选。本文库可作为筛选真鲷免疫相关基因的重要资源。

玉米蛋白粉制备玉米肽脱脂及水解工艺研究

利用碳酸钠对玉米蛋白粉进行预处理,以脱脂率为判断标准,确定玉米蛋白粉最佳预处理工艺参数为碳酸钠质量浓度为40 g/L,添加量为16 mL/g,40℃下浸泡10 min。以处理后的玉米蛋白粉为原料,用邻苯三酚自氧化法比较不同水解度玉米肽抗氧化性强弱,确定每克玉米蛋白粉最佳水解条件为50℃,pH 8.0条件下以0.06 mL碱性蛋白酶催化水解4 h,可获得30%水解度的玉米肽液体产品。

大豆低聚肽的膜分离研究

本研究选用分子量1000的超滤膜来分离大豆低聚肽,分别研究了料液原始浓度、时间、压力、膜阻力、膜效能等对超滤的影响,确定在料液浓度0.2%、ΔP=0.32MPa的条件下,超滤效果最佳,低聚肽的得率为55.6%。

热休克蛋白gp96-肽复合物的提取及纯化

目的:建立从H22肝癌细胞中提取、纯化热休克蛋白gp96肽复合物的方法。方法:①制备H22肝癌细胞蛋白:将H22肝癌细胞裂解、离心、过滤及透析后获得。②gp96肽复合物的纯化:上述可溶性H22肝癌细胞蛋白经分级硫酸铵盐析后,依次用ConASepharose亲和层析、SephadexG25更换缓冲液及DEAESephacel离子交换层析分离纯化。③gp96肽复合物的鉴定和浓度测定:所得蛋白经SDS聚丙烯酰胺凝胶电泳和Westernblot进行蛋白分子量及性质鉴定,Lowry法测定蛋白浓度。结果:分离、纯化得到的蛋白经SDS聚丙烯酰胺凝胶电泳、银染鉴定为单一带,分子量为96kD;Westernblot结果证实为HSPgp96。每20ml压积H22细胞最终获得1mg的HSPgp96。结论:使用本分离纯化方法可获得高纯度HSPgp96肽复合物。

C肽对糖尿病大鼠肾脏的影响

比较C肽和胰岛素对大鼠糖尿病肾病的治疗作用。方法:选取Wistar大鼠40只,分为正常对照组(NG组)和糖尿病组(DM组),糖尿病组链脲佐菌素诱发大鼠成模后,随机分为三组:糖尿病组(DM组)、胰岛素组(IG组)和C肽组(ICG组)。治疗8周后测定各组大鼠24小时尿白蛋白排泄率(UAER)、肾重/体重,并观察糖尿病大鼠肾脏超微结构变化。结果:24小时尿白蛋白排泄率:糖尿病组明显增加,C肽组明显低于糖尿病组和胰岛素组,差异具有显著性。大鼠肾脏超微结构变化:各组大鼠肾小球截面积、肾小球平均体积(MGV)、细胞外基质/肾小球截面积比值、细胞外基质截面积、肾小球基底膜厚度相比,糖尿病组明显升高,C肽组较胰岛素组和糖尿病组明显下降,差异具有显著性。结论:C肽治疗可以降低24小时尿白蛋白排泄率,改善糖尿病大鼠肾脏超微结构病变。

重组人促性腺激素释放激素及导肽的分离纯化与活性分析

对含重组人促性腺激素释放激素(GnRH)及导肽(LEP)的工程菌株进行诱导表达,分离纯化GnRH/LEP并进行生物学活性分析。工程菌IPTG诱导,收获的菌体经超声破碎后,裂解液用Glutathione-Sepharose 4B亲和层析纯化GST-GnRH/LEP融合蛋白,经CNBr裂解、Sephadex G-25柱脱盐、QAE-Sepharose FF阴离子交换柱层析和RP-C18柱脱盐,得到纯度大于98%的重组GnRH/LEP。Western blot表明表达产物均具有GnRH抗原特异性。生物学活性分析表明:该表达产物可促进小鼠次级卵泡向成熟卵泡发育,可提高其血清中E2含量。

戊己丸对炎症后肠易激综合征大鼠脑肠肽的调控作用

目的寻找诊断和治疗肠易激综合征(IBS)的生物学指标。方法采用乙酸加束缚应激法建立炎症后肠易激综合征(PI-IBS)动物模型;采用大鼠结肠运动指数(MI)、2 h内排出的粪粒数以及玻璃小球排出时间评价大鼠结肠的运动能力;观察PI-IBS模型大鼠的形成以及戊己丸对其的治疗作用;采用ELISA法检测PI-IBS大鼠脑和结肠组织中的降钙素基因相关肽(CGRP)、胃动素(MTL)、神经肽Y(NPY)、P物质(SP)、生长抑素(SS)、血管活性肠肽(VIP)、胆囊收缩素(CCK)水平。结果成功建立PI-IBS大鼠模型。模型大鼠体重降低;摄食量减少;排便量增多;出现稀便和无定形软便;自主运动量减少;结肠MI显著增加(P<0.05);大鼠排出的粪粒数显著增加(P<0.05);玻璃小球排出时间显著缩短(P<0.05)。戊己丸治疗7 d后能够明显改善以上症状。与正常对照组相比,PI-IBS大鼠脑组织中的CGRP、SS和VIP水平显著增加(P<0.05),NPY浓度显著降低(P<0.05);而戊己丸给药可以显著降低CGRP、SS和VIP浓度水平(P<0.05),显著升高NPY浓度水平(P<0.05)。与正常对照组相比,PI-IBS大鼠结肠组织中的CCK、NPY、MTL、SS和VIP均显著降低(P<0.05);戊己丸给药能够显著升高CCK和VIP水平(P<0.05)。结论戊己丸可通过调节IBS大鼠脑和结肠组织内多种脑肠肽的水平用来治疗IBS,这些可被调节的异常变化的脑肠肽可以成为潜在的诊断和治疗IBS的生物学指标。