Changes in intestinal mucosal immune barrier in rats with endotoxemia

AIM： To investigate the dysfunction of the immunological barrier of the intestinal mucosa during endotoxemia and to elucidate the potential mechanism of this dysfunction. METHODS： Male Wistar rats were randomly distributed into two groups： control group and lipopolysaccharide （LPS） group. Endotoxemia was induced by a single caudal venous injection of LPS. Animals were sacrificed in batches 2, 6, 12 and 24 h after LPS infusion. The number of microfold （M）-cells, dendritic cells （DCs）, CD4＋ T cells, CD8＋ T cells, regulatory T （Tr） cells and IgA＋ B cells in the intestinal mucosa were counted after immunohistochemical staining. Apoptotic lymphocytes were counted after TUNEL staining. The levels of interleukin （IL）-4, interferon （IFN）-γ, and forkhead box P3 （Foxp3） in mucosal homogenates were measured by ELISA. The secretory IgA （sIgA） content in the total protein of one milligram of small intestinal mucus was detected using a radioimmunological assay.RESULTS： This research demonstrated that LPS-induced endotoxemia results in small intestinal mucosa injury. The number of M-cells, DCs, CD8~ T cells, and IgA~ B cells were decreased while Tr cell and apoptotic lymphocyte numbers were increased significantly. The number of CD4＋ T cells increased in the early stages and then slightly decreased by 24 h. The level of IL-4 significantly increased in the early stages and then reversed by the end of the study period. The level of IFN-T increased slightly in the early stages and then decreased markedly by the 24 h time point. Level of Foxp3 increased whereas sIgA level decreased.CONCLUSION： Mucosal immune dysfunction forms part of the intestinal barrier injury during endotoxemia. The increased number and function of Tr cells as well as lymphocyte apoptosis result in mucosal immunode- ficiency.

Dynamic changes and mechanism of intestinal endotoxemia in partially hepatectomized rats

AIM： To explore the mechanism of intestinal endotoxemia （IETM） formation and its changes in partially hepatectomized （PH） rats. METHODS： One-hundred and two adult male Wistar rats were randomly divided into three groups： normal control （NC） group, partially hepatectomized （PH） group and a sham-operated （SO） group. To study the dynamic changes, rats were sacrificed before and at different time points after partial hepatectomy or the sham-operation （ 6 h, 12 h, 24 h, 36 h, 48 h, 72 h, 120 h and 168 h）. NC group was used as Oh time point in observation, namely 0 h group. For each time point indicated, six rats were used in parallel. Endotoxin （ET） and diamine oxidase （DAO） levels were determined in serum using Limulus Lysate test with chromogenic substrate and spectrophotometry. Intestinal mucosa barrier was observed under opticcal or electron microscope. The number and functional state of Kupffer cells （KCs） in the remnant regenerating liver were measured by immunohistochemical staining. RESULTS： Serum ET levels significantly increased during 6-72 h period after PH compared with NC and SO groups, and there were two peak values at 12 and 48 h while serum DAO level significantly increased at 12 and 24 h. There was positive correlation （r = 0.757, P 〈 0.05） between the levels of DAO and ET dynamic changes. The optical examination showed neutrophil margination and superficial necrosis of the villi in the intestinal mucosa during 6-24 h period after PH. The penetrated electron microscope examination showed thatthe gaps between intestinal mucosa cells were increased and the Lanthanum （La） particles were observed among the intestinal mucosa cells during 6-48 h period, The numbers of KCs in the remnant regenerating liver were significantly increased during 24-168 h period after PH, However, the activation of KCs was predominantly observed at 48 h after PH. CONCLUSION： The mechanism of IETM in PH rats might be the injury of intestinal mucosa barrier and the decrease of the absolute number of KCs as well as the depression of functional state of KCs, This observation is of potential value in patients undergoing liver resection,

Role of natural products and intestinal flora on type 2 diabetes mellitus treatment

Diabetes mellitus(DM)is a complicated,globally expanding disease that is influenced by hereditary and environmental variables.Changes in modern society’s food choices,physical inactivity,and obesity are significant factors in the development of type 2 DM(T2DM).The association between changes in intestinal flora and numerous disorders,including obesity,diabetes,and cardiovascular diseases,has been studied in recent years.The purpose of this review is to analyze the mechanisms underlying the alteration of the diabetic patients’intestinal flora,as well as their therapeutic choices.Also included is a summary of the antidiabetic benefits of natural compounds demonstrated by studies.The short-chain fatty acids theory,the bile acid theory,and the endotoxin theory are all potential methods by which intestinal flora contributes to the establishment and progression of T2DM.Due to an intestinal flora imbalance,abnormalities in shortchain fatty acids and secondary bile acids have been found in diabetic patients.Additionally,metabolic endotoxemia with altering flora induces a systemic inflammatory response by stimulating the immune system via bacterial translocation.The agenda for diabetes treatment includes the use of short-chain fatty acids,probiotics,prebiotics in the diet,fecal bacteria transplantation,and antibiotics.Animal studies have proven the antidiabetic benefits of numerous bioactive substances,including Flavonoids,Alkaloids,Saponin,and Allicin.However,further research is required to contribute to the treatment of diabetes.

Gut microbiota dysbiosis contributes toα-synuclein-related pathology associated with C/EBPβ/AEP signaling activation in a mouse model of Parkinson’s disease

Parkinson’s disease is a neurodegenerative disease characterized by motor and gastrointestinal dysfunction.Gastrointestinal dysfunction can precede the onset of motor symptoms by several years.Gut microbiota dysbiosis is involved in the pathogenesis of Parkinson’s disease,whether it plays a causal role in motor dysfunction,and the mechanism underlying this potential effect,remain unknown.CCAAT/enhancer binding proteinβ/asparagine endopeptidase(C/EBPβ/AEP)signaling,activated by bacterial endotoxin,can promoteα-synuclein transcription,thereby contributing to Parkinson’s disease pathology.In this study,we aimed to investigate the role of the gut microbiota in C/EBPβ/AEP signaling,α-synuclein-related pathology,and motor symptoms using a rotenone-induced mouse model of Parkinson’s disease combined with antibiotic-induced microbiome depletion and fecal microbiota transplantation.We found that rotenone administration resulted in gut microbiota dysbiosis and perturbation of the intestinal barrier,as well as activation of the C/EBP/AEP pathway,α-synuclein aggregation,and tyrosine hydroxylase-positive neuron loss in the substantia nigra in mice with motor deficits.However,treatment with rotenone did not have any of these adverse effects in mice whose gut microbiota was depleted by pretreatment with antibiotics.Importantly,we found that transplanting gut microbiota derived from mice treated with rotenone induced motor deficits,intestinal inflammation,and endotoxemia.Transplantation of fecal microbiota from healthy control mice alleviated rotenone-induced motor deficits,intestinal inflammation,endotoxemia,and intestinal barrier impairment.These results highlight the vital role that gut microbiota dysbiosis plays in inducing motor deficits,C/EBPβ/AEP signaling activation,andα-synuclein-related pathology in a rotenone-induced mouse model of Parkinson’s disease.Additionally,our findings suggest that supplementing with healthy microbiota may be a safe and effective treatment that could help ameliorate the progression of motor deficits in patients with Parkinson’s disease.

肝大部切除大鼠所致的IETM对血浆与肝组织IL-1β的影响

目的探讨肝大部分切除(PH)诱导的肠源性内毒素血症(IETM)对血浆及残余肝组织IL-1β的影响或可能存在的关系。方法 102只健康雄性成年wistar大鼠随机分为正常对照(NC)组、假手术(SO)组和肝大部切除(PH)组,在不同时间点检测血浆内毒素(ET)、IL-1β、ALT的水平以及残余肝组织IL-1β的蛋白表达。结果血浆ET在PH术后6～72h期间升高,在12h、48h呈现峰值,分别与NC组比较(P<0.05,P<0.01);血浆ET在SO组各时间点与NC组比较差异无显著性。血浆IL-1β在PH后6～72h期间升高,与血浆ET动态变化趋势呈显著正相关(r=0.729,P<0.05)。SO组在术后各个时间点与NC组比较差异无显著性。血浆ALT在PH组术后6～72h期间升高,与血浆ALT动态变化趋势呈显著正相关(r=0.767,P<0.05)。PH组残余肝组织IL-1β术后6h于肝细胞质表达,24h IL-1β于肝细胞膜表达。48h～72h IL-1β于肝细胞膜的肝窦面表达且强度明显增加。72h后IL-1β的表达明显减少,至168h IL-1β表达完全消失。NC组肝组织内IL-1β阴性,SO组术后各时间点未见IL-1β特异性染色。结论 PH后诱导的肠源性内毒素直接影响IL-1β的生成变化,两者变化趋势呈显著正相关;IETM可能通过IL-1β的生物学作用影响肝再生。

Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia

A "leaky gut" may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin,activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.

Pathophysiology of increased intestinal permeability in obstructive jaundice

Despite advances in preoperative evaluation and postoperative care, intervention, especially surgery, for relief of obstructive jaundice still carries high morbidity and mortality rates, mainly due to sepsis and renal dysfunction. The key event in the pathophysiology of obstructive jaundice-associated complications is endotoxemia of gut origin because of intestinal barrier failure. This breakage of the gut barrier in obstructive jaundice is multi-factorial, involving disruption of the immunologic, biological and mechanical barrier. Experimental and clinical studies have shown that obstructive jaundice results in increased intestinal permeability. The mechanisms implicated in this phenomenon remain unresolved, but growing research interest during the last decade has shed light in our knowledge in the field. This review summarizes the current concepts in the pathophysiology of obstructive jaundice-induced gut barrier dysfunction, analyzing pivotal factors, such as altered intestinal tight junctions expression, oxidative stress and imbalance of enterocyte proliferation and apoptosis. Clinicians handling patients with obstructive jaundice should not neglect protecting the intestinal barrier function before, during and after intervention for the relief of this condition, which may improve their patients’ outcome.

Pathogenetic effects of platelet activating factor on enterogenic endotoxemia after burn

INTRODUCTION Previous clinical and experimental studies haveindicated that an early endotoxemia occurred after amajor burn.It is unlikely that burn wound sepsis isthe source of circulating endotoxin in less than 12hour after burn.Increasing evidence demonstratesthat the bacteria and endotoxin in thegastrointestinal tract can pass through the gutbarrier into blood circulation to form enterogenicendotoxemia following burn.However。

Liver Cirrhosis and Intestinal Bacterial Translocation

Intestinal barrier dysfunction, facilitating translocation of bacteria and bacterial products, plays an important role in the pathophysiology of liver cirrhosis and its complications. Intestinal defense system including microbial barrier, immunologic barrier, mechanical barrier, chemical barrier, plays an important role in the maintenance of intestinal function. Under normal circumstances, the intestinal barrier can prevent intestinal bacteria through the intestinal wall from spreading to the body. Severe infection, trauma, shock, cirrhosis, malnutrition, immune suppression conditions, intestinal bacteria and endotoxin translocation, can lead to multiple organ dysfunction. The intestinal microflora is not only involved in the digestion of nutrients, but also in local immunity, forming a barrier against pathogenic microorganisms. The derangement of the gut microflora may lead to microbial translocation, defined as the passage of viable microorganisms or bacterial products from the intestinal lumen to the mesenteric lymph nodes and other extraintestinal sites. In patients with cirrhosis, primary and intestinal flora imbalance, intestinal bacterial overgrowth, intestinal mucosal barrier dysfunction, endotoxemia is associated with weakened immunity.

Simvastatin Improves Outcomes of Endotoxin-induced Coagulopathy by Regulating Intestinal Microenvironment

Objective:The systemic inflammatory response is regarded as the major cause of endotoxin-induced coagulopathy,which is a strong predictor of mortality in patients with severe sepsis.Simvastatin plays an important role in reducing inflammation.In addition,the gut has long been hypothesized to be the“motor”of critical illness,driving or aggravating sepsis by the increased intestinal permeability and bacterial translocation.

IETM对拟阿尔茨海默病大鼠认知功能及APP、PS1基因表达的影响

目的探讨肠源性内毒素血症(IETM)对拟阿尔茨海默病(AD)大鼠认知功能和β淀粉样前体蛋白(APP)、早老素1(PS1)基因表达的影响。方法选用Wistar大鼠,连续注射D-半乳糖和AlCl390 d制备拟AD动物模型。运用Morris水迷宫实验检测大鼠学习记忆能力,鲎试剂法检测脂多糖(LPS)含量,ELISA法检测肿瘤坏死因子-α(TNF-α)水平,RT-PCR法检测APP、PS1基因的表达。结果拟AD大鼠逃避潜伏期延长(P<0.05),LPS、TNF-α水平增加(P<0.05),且APP、PS1基因表达水平增加(P<0.05)。结论拟AD大鼠模型伴有IETM,其可能是AD发生的危险因素。

Role of intestinal bifidobacteria in the pathogenesis of gut-derived bacteria/endotoxin translocation and the effect of bifidobacterial supplement on gut barrier function following burns

Objective:Early multiple organ dysfunction syndrome appears to be facilitated with bacterial transloca-tion in severely burn injury,yet the mechanisms of bacterial translocation remains in dispute.The aim of this studywas to investigate the potential role of intestinal bifidobacteria in the pathogenesis of gut-derived bacteria/endotoxintranslocation following burns and the effects of bifidohacterial supplement on gut barrier.Methods:Wistar rats wererandomly divided into burn group(Burn,n=60),sham burn g...

清肠祛浊汤治疗肝硬化肠源性内毒素血症的临床效果及机制探讨

目的探讨清肠祛浊汤治疗肝硬化肠源性内毒素血症的效果及潜在机制。方法102例肝硬化肠源性内毒素血症患者,根据随机数字表法分为观察组、对照组1和对照组2,每组34例。三组患者均接受21 d常规临床治疗,对照组2患者加用乳果糖治疗,观察组加用清肠祛浊汤结肠滴注治疗。比较三组患者治疗效果及治疗前后血浆内毒素(ET)、血清炎症因子[白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)]水平。结果观察组患者的治疗总有效率为94.12%,显著高于对照组1的61.76%、对照组2的73.53%,差异具有统计学意义(P<0.05)。治疗后,三组患者血浆内毒素水平均较本组治疗前显著下降,差异具有统计学意义(P<0.05);观察组患者血浆内毒素(0.18±0.06)EU/ml低于对照组1的(0.37±0.09)EU/ml、对照组2的(0.29±0.08)EU/ml,差异具有统计学意义(P<0.05)。治疗后,三组患者血清IL-1β、IL-6和TNF-α水平均较本组治疗前下降,差异具有统计学意义(P<0.05);观察组患者血清IL-1β、IL-6和TNF-α分别为(50.08±15.31)、(79.22±24.76)、(9.89±3.26)pg/ml,显著低于对照组1的(77.80±29.84)、(180.89±50.25)、(24.56±8.76)pg/ml和对照组2的(78.41±25.31)、(147.85±13.80)、(18.79±7.09)pg/ml,差异具有统计学意义(P<0.05)。结论清肠祛浊汤治疗肝硬化肠源性内毒素血症具有明显的临床效果,可以显著降低患者血浆内毒素和血清炎症因子水平,为疾病的治疗提供参考和理论依据。

肥胖相关代谢性内毒素血症对精子畸形率的影响因素分析

目的探讨肥胖人群的代谢性内毒素血症对精子畸形率影响的高危因素分析。方法选取2021年1~12月就诊的畸形精子症患者453例作为观察组,选取同期精子畸形率正常人员231例作为对照组。检测身高、体重、血清人连蛋白(Zonulin)、血清脂多糖结合蛋白(LBP)、人精液弹性蛋白酶(Elastase)、精液8-羟基脱氧鸟苷(8OHdG)、精子畸形率。采用多因素Logistic回归分析法、Pearson相关分析法探究肥胖人群相关的代谢性内毒素血症对精子畸形率影响的高危因素。结果观察组肥胖率显著高于对照组(72.4%∶25.1%,χ^(2)=8.231,P=0.009);观察组8OHdG异常率高于对照组(73.5%∶19.9%,χ^(2)=5.964,P=0.018);观察组Zonulin异常率显著高于对照组(79.7%∶8.2%,χ^(2)=9.635,P=0.002);观察组LBP异常率高于对照组(69.3%∶29.4%,χ^(2)=7.524,P=0.013);观察组雌二醇(E2)异常率高于对照组(43.5%∶10%,χ^(2)=6.954,P=0.019);在年龄、Elastase、FSH、LH、TT等观察指标方面,2组差异无统计学意义。多因素Logistic回归分析结果显示,BMI(OR=5.984,P=0.004)、8OhdG(OR=3.521,P=0.001)、Zonulin(OR=3.241,P=0.017)、LBP(OR=5.511,P=0.001)、E2(OR=4.671,P=0.026)是影响精子畸形率的高危因素。BMI与Zonulin、LBP、8OhdG、E2存在相关关系(P<0.05)。结论肥胖可诱发代谢性内毒素血症,肠道通透性的增加以及内毒素水平的升高可造成全身炎性反应,诱导氧化应激的出现。由氧化应激造成白细胞释放的活性氧将会造成精子畸形率升高。因此,肥胖诱导的代谢性内毒素血症可引起Zonulin、LBP、8OHdG、E2升高,它们是影响精子畸形率的高危因素。

肥胖相关的内毒素血症对男性性腺功能影响的研究进展

肥胖是影响人口健康的重大公共卫生问题,其可造成包括性腺功能低下等的男性生殖健康疾病。通过收集近期的一些研究资料,我们发现造成男性性腺功能受损的发生机制除了雌激素代谢异常、瘦素抵抗及炎症细胞因子对下丘脑-垂体轴的直接抑制作用,还包括肠道因素对性腺功能及生育力造成的损害。究其成因,主要是肠黏膜通透性增加而出现肠内细菌易位侵入循环系统,诱发代谢性内毒素血症,并引起氧化应激,损害睾丸Leydig细胞与生殖细胞功能。益生菌可减少肠道细菌易位,从而减轻或消除代谢性内毒素血症对睾丸组织的损害,提升性腺功能。但益生菌的疗效尚未被广泛认可,针对肥胖男性这一群体,开展更为具体的临床用药研究将是未来研究的新方向。

基于文献研究的肝衰竭肠源性内毒素血症中医治法及用药规律分析

目的:总结分析肝衰竭肠源性内毒素血症(Intestinal Endotoxemia,IETM)的中医治法及用药规律,为临床治疗提供参考。方法:在中国知网、万方数据库、维普数据库中检索中医或中西医结合治疗肝衰竭IETM的临床研究,文献发表时间范围为2000年-2021年。提取中医治法和用药信息并建立数据库,进行中医治法、用药频次及频率、主药剂量的统计和聚类分析。结果:共纳入文献154篇,其中中药口服91篇、中药灌肠69篇。在口服中药方剂中,中医治法频次在前5位的依次是活血化瘀、清热解毒、益气健脾、通腑泻下、利湿退黄;在灌肠中药方剂中,中医治法频次在前5位的依次是活血化瘀、通腑泻下、清热解毒、益气健脾、利湿退黄。口服中药方剂共91首,涉及中药148味,频次在前10位的中药依次是大黄、丹参、赤芍、茵陈、白术、茯苓、栀子、黄芪、郁金、枳实;灌肠中药方剂共69首,涉及中药77味,频次在前10位的中药依次是大黄、赤芍、枳实、厚朴、茯苓、乌梅、薏苡仁、蒲公英、黄芩、丹参。对高频药物进行聚类分析,得到口服中药方剂10组药对聚类组合、4组3味药聚类组合、2组多味药聚类组合。灌肠中药方剂得到7组药对聚类组合、3组3味药聚类组合、2组多味药聚类组合。口服中药方剂主药大黄、丹参、赤芍常用剂量依次为1~10 g、11~20 g、11~20 g;灌肠中药方剂主药大黄、赤芍、枳实常用剂量依次为11~20 g、21~30 g、11~20 g。结论:治疗肝衰竭IETM的口服和灌肠中药方剂均以活血化瘀、清热解毒、通腑泻下、益气健脾为主要治法,口服中药侧重于益气健脾,灌肠中药侧重于通腑泻下;常重用赤芍、大黄以加强凉血化瘀之力。

肠道菌群及内毒素在多器官功能不全综合征时的变化

目的 探讨肠道菌群及内毒素在多器官功能不全综合征( MODS)时的变化。方法 取SD大鼠,腹腔注射无菌酵母多糖A制备MODS模型,检测大鼠肠道菌群、外周血和门静脉血中的内毒素以及肠道游离内毒素含量,并进行定量分析。结果 模型组大鼠肠道专性厌氧菌的数量明显减少,革兰阴性杆菌和双歧杆菌的比例倒置,内毒素含量明显增加,与对照组比差异有显著性( P<0 .0 5 )。结论 MODS时肠道细菌微生态发生明显改变。

酒精性肝病发病机制研究的新进展

随着酒精性肝病(ALD)发病率逐年增长,对人类健康和社会发展构成严重威胁,因此,在全世界范围内受到普遍关注。ALD的发病机制非常复杂,以往主要集中在乙醇代谢过程引起氧化应激和谷胱甘肽耗竭、营养不良、内毒素激活枯否细胞而引起相关炎症上。最新研究发现,脂代谢、肝再生和凋亡、肝脏抗氧化等多种信号转导通路、肠道菌群紊乱、细胞因子、免疫反应等多种因素参与ALD的发生发展。因此,本文将目前有关ALD最新研究进展结合国内外自然病程研究、流行现状和其它影响因素,对ALD发病机制作一综述。

肝硬化大鼠小肠微绒毛形态和超微结构的改变与肠源性内毒素血症的关系

目的观察肝硬化大鼠小肠黏膜形态及超微结构的改变与肠源性内毒素血症的关系。方法CCl4诱导的肝硬化大鼠分为2组:肝硬化伴内毒素血症组(n=22)和肝硬化不伴内毒素血症组(n=18),另取20只健康大鼠作为正常对照组,分别观察小肠黏膜在光镜和电镜下的形态。结果光镜下观察到肝硬化伴内毒素血症的大鼠小肠绒毛明显缩短,炎症细胞浸润明显;电镜下观察到肝硬化伴内毒素血症的大鼠小肠壁超微结构明显受损,紧密连接缺失,细胞间隙扩大,肝硬化不伴内毒素血症大鼠的小肠绒毛形态以及超微结构与正常大鼠相比没有明显改变。结论肝硬化大鼠小肠黏膜损伤与肠源性内毒素血症的发生密切相关。