代谢相关脂肪性肝病的发病机制及其与肠道真菌群关系的研究进展

［摘要］　代谢相关脂肪性肝病(MAFLD)对人类健康所构成的威胁不容忽视,现代医学关于MAFLD的发病机制的探讨较多,该文回顾了MAFLD的发病机制及其与肠道真菌群的关系,并讨论了肠道真菌群可能影响疾病进展的机制。控制肠道真菌群的策略可能被开发用于治疗或预防肝脏疾病。     

慢性肝脏疾病肠道真菌的特点及其研究进展

目前已有大量研究揭示肠道细菌在肝脏良性疾病中发挥着十分复杂的作用, 而对肠道真菌的研究却相对较少。作为肠道微生物的一部分, 肠道真菌的数量相比于肠道细菌可以忽略, 但肠道真菌对人体健康与疾病存在的影响却不容忽视。现总结目前酒精性肝病、非酒精性脂肪性肝病、病毒性肝炎和肝硬化患者肠道真菌的特点及其研究进展, 为肠道真菌在肝脏良性疾病诊断和治疗方面的进一步研究提供参考依据与思路。     

SARS-CoV-2感染肠道微生态研究进展

肠道微生物群位于人体肠道内，是一个呈多元化微生态体系。其通过影响膳食消化、营养物质吸收，维护肠黏膜屏障，调控机体炎症反应，免疫应答等在维护宿主健康方面发挥着重要作用。而菌群的失调则影响了诸多炎性、免疫性疾病的发生发展。“肠-肺轴”概念的提出，揭示了肠道微生物与肺部疾病的关系，使其在SARS-CoV-2感染的作用中受到广泛关注。高通量多组学研究发现肠道微生物群-SARS-CoV-2-宿主免疫三者之间相互作用。COVID-19患者中存在肠道微生物群(细菌、真菌、病毒等)组成及结构紊乱，以机会性致病细菌、真菌和真核病毒富集为特征，与疾病的严重程度和临床症状密切相关，并且这种肠道微生物特征在COVID-19治愈后仍持续存在。因此，探究肠道微生态在SARS-CoV-2感染中的作用机制，明确益生菌在疾病治疗及COVID-19疫苗效应方面的作用，为COVID-19的预防、治疗及预后提供新的潜在靶点，具有重要意义。     

非酒精性脂肪性肝病患者肠道微生态差异性及其与糖脂代谢相关指标的关系

目的分析非酒精性脂肪性肝病(NAFLD)患者肠道微生态差异性及其与糖脂代谢相关指标的关系。方法选择2017年6月至2019年4月三二〇一医院收治的NAFLD患者121例为观察组,同期选择100例健康体检患者为对照组,将观察组患者根据临床分型分为单纯性脂肪肝组(n=50)、非酒精性脂肪性肝炎(NASH)组(n=40)和肝硬化组(n=31)。观察各组肠道微生物、糖脂代谢相关指标水平,并分析肠道微生物与糖脂代谢相关指标相关性。结果观察组肠杆菌、肠球菌、酵母样真菌数量高于对照组,且双歧杆菌、乳酸杆菌数量低于对照组(P<0.05);观察组FBG、FINS、TG、TC、LDL-C指标高于对照组,且HDL-C低于对照组(P<0.05);肝硬化组肠杆菌、肠球菌、酵母样真菌数量高于单纯性脂肪肝组、NASH组,且双歧杆菌、乳酸杆菌数量低于单纯性脂肪肝组、NASH组(P<0.05);NASH组肠杆菌、肠球菌、酵母样真菌数量高于单纯性脂肪肝组,且双歧杆菌、乳酸杆菌数量低于单纯性脂肪肝组(P<0.05);肝硬化组FBG、FINS、TG、LDL-C指标高于单纯性脂肪肝组、NASH组,且TC、HDL-C低于单纯性脂肪肝组、NASH组(P<0.05);NASH组FBG、FINS、TG、LDL-C指标高于单纯性脂肪肝组,且TC、HDL-C低于单纯性脂肪肝组(P<0.05);糖脂代谢指标与肠球菌、肠杆菌、酵母样真菌数量呈正相关,与乳酸杆菌、双岐杆菌数量呈负相关(P<0.05)。结论NAFLD患者较单纯性脂肪肝患者肠道微生态、糖脂代谢具有显著差异,且两者有一定相关性。     

非酒精性脂肪性肝炎患者肠道菌群的变化及意义

目的探讨非酒精性脂肪性肝炎肠道菌群的变化及意义。方法选择肠道菌群中具有代表性的细菌共5种进行培养和计数。选择健康正常成人、单纯性非酒精性脂肪肝和非酒精性脂肪性肝炎(NASH)患者各30例,计数各组肠道菌群中5种细菌的数量,比较各组细菌数量的变化。结果 NASH组患者存在不同程度的肠道菌群失调,主要表现为厌氧菌减少(P<0.05),而需氧菌显著增多(P<0.05),而兼性厌氧菌酵母样真菌没有显著变化(P>0.05)。结论 NASH患者存在肠道菌群失调、革兰阴性杆菌过度生长的现象,提示肠道微生态失衡可能参与了NASH的发生发展。     

新型益生菌与肠道疾病防治

益生菌指在足量条件下能对宿主产生确切有益健康功效的微生物。在肠道疾病防治中, 传统益生菌如乳杆菌属(Lactobacillus)、双歧杆菌属(Bifidobacteria)、链球菌属(Streptococcus)经过长期的研究已被证实安全、有效, 但使用二代测序技术和生物信息学工具鉴定出的新型益生菌的具体作用和机制亟待阐明。本文重点回顾脆弱拟杆菌(Bacteroides fragilis)、嗜黏蛋白阿克曼菌(Akkermansia muciniphila)、普氏栖粪杆菌(Faecalibacterium prausnitzii)3种新型益生菌与肠道疾病防治的研究进展, 其通过改善肠道炎症, 维护肠黏膜屏障结构和功能完整, 抑制肠道肿瘤的进程, 辅助诊断, 以及预测疗效等多种作用促进肠道疾病的防治。虽然现阶段仍面临安全性、准确性和可利用性的挑战, 但相关研究与转化的不断改进将使新型益生菌更好地服务于肠道疾病防治。     

蠕虫及肠道原虫感染与肠道菌群关系研究进展

肠道菌群是人体最大最复杂的生态系统,与肠道病毒和寄生虫等共同栖息在人或动物肠道内。已有研究表明,肠道菌群紊乱与多种疾病的发生、发展及预后密切相关。定植在宿主体内的寄生虫可直接或间接影响肠道菌群及其与机体的相对稳态,而肠道菌群结构及多样性的改变也会影响寄生虫感染及疾病的发生、发展和预后。本文就蠕虫及肠道原虫与肠道菌群相互关系研究进展作一综述。     

芳香烃受体在肠道功能及疾病中的研究进展

芳香烃受体(AHR)在肠道的免疫和非免疫细胞中广泛表达。AHR介导的相关效应参与肠道炎症、肠道黏膜屏障、肠道免疫、肠道动力等肠道功能。AHR的内源性配体主要由肠道菌群提供, 同时AHR可以通过肠道微生物来发挥作用。AHR信号传导可通过上述途径参与肠道疾病的发生、发展以及预后。本文主要对AHR在肠道中的作用展开综述, 为AHR在该领域的研究提供新的方向。     

肠道微生态重建在炎症性肠病治疗中的意义

尽管炎症性肠病(inflammatory bowel disease,IBD)的病因和发病机制尚未完全明确,但肠道中定植的大量微生物在肠道疾病发生中有着重要作用已是共识。既往的研究大多只关注细菌导致肠道炎症,而忽略了肠道中真菌、病毒、寄生虫等其他微生物对IBD的影响;并且饮食因素在改善肠道微生态环境和IBD症状上的重要作用也被很多研究者所忽略。近年来,"粪菌移植"作为一种整体的改善患者肠道微生态环境的方法也在IBD治疗过程中有良好的疗效。因此,本文就肠道微生态重建在IBD治疗中的意义作一概述。     

老年慢性阻塞性肺疾病患者肠道菌群的观察

目的通过观察老年慢性阻塞性肺疾病(COPD)患肠过细菌的变化，了解COPD与肠道菌群的关系。方法应用粪便培养方法，观察64例老年缓解期COPD患肠道需氧菌．厌氧菌及真菌的种类和数量，井设正常对照组．结果COPD组梭状杆菌较正常组多(P<0.05)，大肠杆菌及类杆菌数量均较正常人减少(P<0．001及P<0．01)．结论老年缓解期COPD患存在肠道菌群失调，可能与经常使用广诺抗生素以及长期缺氧导致胃肠道瘀血有关，是COPD患营养不良的一个重要因素．     

Adaptive changes in postprandial motility after intestinal resection and bypass

An electromyographic technique was used to study the changes in postprandial motility induced by jejunal and ileal resection and jejunal bypass (50% reduction of total length of small bowel). Electrodes were implanted in rats throughout the intestine. Compared to control animals, the duration of postprandial interruption of the myoelectric complex (DIMC) was rapidly increased after jejunal resection, more gradually augmented after jejunal bypass, and remained constant after ileal resection. The frequency of occurrence of spike bursts during the postprandial period was significantly decreased in the short remaining proximal segment after jejunal resection and was not changed in the ileum. The jejunal bypass induced no change in the frequency throughout the remaining bowel. Ileal resection was followed by a decrease on the jejunum. The percentage of slow waves superimposed by a spike burst remained constant after jejunal resection and bypass but was significantly decreased after ileal resection on the whole remaining intestine. These results show important modifications in postprandial motor activity of the small bowel, which appear rapidly after jejunal resection, more gradually after jejunal bypass, and which are less pronounced after ileal resection. This electromyographic study emphasizes the role of intestinal motility in the development of adaptation after small bowel resection or bypass.     

Influence of intestinal microecology in the development of gout or hyperuricemia and the potential therapeutic targets

Gout and hyperuricemia are common metabolic diseases. Patients with purine metabolism disorder and/or decreased uric acid excretion showed increased uric acid levels in the blood. The increase of uric acid in the blood leads to the deposition of urate crystals in tissues, joints, and kidneys, and causes gout. Recent studies have revealed that imbalance of the intestinal microecology is closely related to the occurrence and development of hyperuricemia and gout. Disorder of the intestinal flora often occurs in patients with gout, and high purine and high fructose may induce the disorder of intestinal flora. Short-chain fatty acids and endotoxins produced by intestinal bacteria are closely related to the inflammatory response of gout. This article summarizes the characteristics of intestinal microecology in patients or animal models with hyperuricemia or gout, and explores the relationship between intestinal microecology and gout or hyperuricemia from the aspect of the intestinal barrier, intestinal microorganisms, intestinal metabolites, and intestinal immune system. We also review the current status of hyperuricemia treatment by targeting intestinal microecology.     

The Effect of Polyacrylic Acid Polymers on Small-Intestinal Function and Permeability Changes Caused by Indomethacin

Non-steroidal anti-inflammatory drug (NSAID)-induced increased small-intestinal permeability appears to be a prerequisite for the development of NSAID enteropathy, which is a cause of much morbidity in patients with rheumatoid arthritis. We assessed, with a combined absorption-permeability test, the effects of Carbopol® (a polyacrylic acid polymer capable of increasing mucus strength and viscosity) on intestinal function and whether it protected against indomethacin-induced increased intestinal permeability. Using a test solution of 3-0-methyl-D-glucose, D-xylose, L-rhamnose, and ⁵¹Cr-labelled ethylenediaminetetraacetic acid with 5-h urine collections for marker analyses, we tested 16 subjects, as base line, after 20 ml Carbopol 4 times daily for 4 days, after indomethacin alone (75 + 75 mg), and after coadministration of Carbopol and indomethacin. Carbopol had no significant effect on the permeation or absorption of the test substances. Indomethacin increased intestinal permeability significantly, and this was unaffected when Carbopol was coadministered with indomethacin, showing that Carbopol does not limit the immediate damage of NSAIDs on the small intestine.     

Characteristics of intestinal tuberculosis in ultrasonographic techniques

Objective. There is a paucity of data on the sonographic criteria for the diagnosis of intestinal tuberculosis. The purpose of this study was to further characterize the potential sonographic signs of intestinal tuberculosis and to increase the diagnostic sensitivity and specificity of ultrasound. Material and methods. Seven patients with a final diagnosis of gastrointestinal tuberculosis and a control group of 18 patients suffering from tuberculosis limited to the lungs were prospectively evaluated for sonographic criteria of intestinal tuberculosis and the findings were compared with those in 50 healthy controls. Results. The following signs of intestinal tuberculosis were detectable: asymmetric thickened bowel wall (100%), intramural abscesses (86%), fistula (43%), extramural abscesses (29%), mesenteric thickening (29%), “white bowel” sign (29%), hypoechoic edema of Kerckring's folds with mesenterial thrombosis (14%), enlarged mesenteric lymph nodes with inhomogeneous echotexture and circumscribed hypoechoic spots <3 mm (86%), ascites (29%) and enlarged spleen (14%). These signs were exclusively present in patients with intestinal tuberculosis as compared with patients with tuberculosis limited to the lungs or with healthy controls. We could confirm the endoscopically reported right-sided prevalence of these wall thickenings. In contrast to the reported literature, a much higher prevalence of these sonographic signs was found as they were present in all patients. Six of 7 patients (86%) showed enlarged mesenteric lymph nodes. This was particularly interesting as mesenteric lymph nodes have not been described as being enlarged in the majority of other differential diagnoses of the ileocecal region. Conclusions. The combination of bowel-wall thickening of the ileocecal region with intramural abscesses with or without fistula, abscesses and mesenteric thickening accompanied by enlarged mesenteric lymph nodes was highly predictive of intestinal tuberculosis.     

Effects of psychological stress on small intestinal motility and bacteria and mucosa in mice

AIM: To investigate the effects of psychological stress on small intestinal motility and bacteria and mucosa in mice, and to explore the relationship between small intestinal dysfunction and small intestinal motility and bacteria and mucosa under psychological stress. METHODS: Sixty mice were randomly divided into psychological stress group and control group. Each group were subdivided into small intestinal motility group (n= 10), bacteria group (n = 10), and D-xylose administered to stomach group (n= 10). An animal model with psychological stress was established housing the mice with a hungry cat in separate layers of a two-layer cage. A semi-solid colored marker (carbon-ink) was used for monitoring small intestinal transit. The proximal small intestine was harvested under sterile condition and processed for quantitation for aerobes (Escherichia coli) and anaerobes (Lactobacilli). The quantitation of bacteria was expressed as Iog10(colony forming units/g). D-xylose levels in plasma were measured for estimating trie damage of small intestinal mucosa. RESULTS: Small intestinal transit was inhibited (39.80±9.50% vs 58.79±11.47%,P<0.01) in mice after psychological stress, compared with the controls. Psychological stress resulted in quantitative alterations in the aerobes (E.coli). There was an increase in the number of E coli in the proximal small intestinal flora (1.78±0.30 log10(CFU/g) vs 1.37±0.21 log10(CFU/g), P<0.01), and there was decrease in relative proportion of Lactobacilli and E.coli of stressed mice (0.53±0.63 vs 1.14±1.07,P<0.05), while there was no significant difference in the anaerobes (Lactobacilli) between the two groups (2.31±0.70 log10 (CFU/g) vs 2.44±0.37 log10(CFU/g), P>0.05). D-xylose concentrations in plasma in psychological stress mice were significantly higher than those in the control group (2.90±0.89 mmol/L vs 0.97±0.33 mmol/L, P<0.01). CONCLUSION: Small intestinal dysfunction under psychological stress may be related to the small intestinal motility disorder and dysbacteriosis and the damage of mucosa probably caused by psychological stress.     

Effect of pacing on small intestinal motor activity and hormonal response in dogs

In seven beagle dogs with a Thiry-Vella loop, the effect of pacing on small intestinal motor activity was examined by means of extraluminal strain gauge force transducers. Recordings were obtained from the loop and from the remaining small intestine. Our study showed that pacing of the loop results in a significant reduction of the motility of the loop in the overnight fasted state (up to 39%), during loop feeding (up to 55%), and oral feeding (up to 39%); a similar reduction of the motility of the remaining small intestine (up to 43%); and a significant postprandial increase of insulin (9.0 U/ml) and decrease of glucagon (94 pg/ml). The motility reduction of the loop and of the remaining small intestine as well as the anabolically improved pancreatic endocrine function (shown by an increase of the insulin — glucagon ratio) suggests that this form of pacing could be of benefit for motility disorders with decreased transit time.The present study was supported by Deutsche Forschungsgemeinschaft.     

Comparison of Four Markers of Intestinal Permeability in Control Subjects and Patients with Coeliac Disease

Bjarnason I, Maxton D, Reynolds AP, Catt S, Peters TJ, Menzies IS. Comparison of four markers of intestinal permeability in control subjects and patients with coeliac disease. Scand J Gastroenterol 1994;29:630-639

Background: Controversy surrounds the issue of intestinal permeability in patients with coeliac disease, polyethylene glycol 400 indicating reduced and di-/mono-saccharide urine excretion ratios and ^5lCr-labeled ethylenediaminetetraacetic acid (EDTA) indicating increased permeability.

Methods: We assessed the suitability of polyethylene glycol 400, L-rhamnose, lactulose, and ⁵¹Cr-EDTA as markers of intestinal permeability by assessing urine excretions after simultaneous intravenous instillation of these markers and after oral administration in normals and patients with coeliac disease.

Results: After intravenous administration the 24-h urine excretion of polyethylene glycol 400, L-rhamnose, lactulose, and ⁵¹Cr-EDTA was 40%, 72%, 93%, and 97%, respectively. There was no significant difference between controls and patients with coeliac disease. Oral administration of the markers in an iso- and hyperosmolar test solution demonstrates reduced permeation due to an osmotic retention effect of lactulose. In contrast, hyperosmolar glycerol increases permeation of all markers except L-rhamnose. Timing of urines and altering osmolality is important for the behaviour of individual markers but does not enhance the discrimination between controls and patients when the differential urine excretion of lactuIose/L-rhamnose is used. The sensitivity of the urine excretion ratio of Iactulose/L-rhamnose was comparable to that of ⁵¹Cr-EDTA used by itself. Whereas lactulose/L-rhamnose and ⁵¹Cr-EDTA showed increased intestinal permeability in coeliac disease, the permeation of polyethylene glycol was reduced. Permeation of the markers did not correlate significantly with jejunal histology. Conclusions: Correlations of marker permeation rates with test dose osmolality in controls and patients with coeliac disease shows a variable lack of conformity, suggesting that the markers may permeate the intestine by different routes, which are affected to a different extent in coeliac disease.     

Postischemic intestinal motility in rat is inversely correlated to length of ischemia

An inverse correlation between postischemic gastrointestinal motility and the length of intestinal ischemia was found in an animal model. Intestinal ischemia was caused without concurrent laparotomy and for a predetermined time period (ischemia time) by pulling on an external nylon thread that was threaded through a double-lumen catheter. This catheter was passed into the abdominal cavity to encircle the superior mesenteric artery. Gastrointestinal motility was determined by the introduction of a color-marked meal into the animal's stomach and the measurement of the proportionate length of the small bowel filled with it (transit index). This simple and reliable animal model can also be used for the evaluation of techniques and pharmacological manipulations aimed at modulation of the effects of intestinal ischemia on intestinal motility and its consequences.     

Short-term intestinal ischemia-reperfusion alters intestinal motility that can be preserved by xanthine oxidase inhibition

While the effects of transient intestinal ischemia on mucosa have been well investigated, less is known about its effect on motor function. An experimental study was designed to investigate the effects of ischemia–reperfusion (I/R) on intestinal motility and intestinal muscular microcirculation. Wistar albino rats were divided into four groups: (1) baseline, (2) sham operation, (3) I/R, and (4) I/R with allopurinol pretreatment. Ischemia was induced by clamping the superior mesenteric artery (SMA) for 10 min. Gastroanal transit time (GATT) was measured with serial x-rays after instillation of barium sulfate to the stomach. Intestinal muscular microcirculation was evaluated by determining the number of carbon-perfused intestinal muscular microvessels (CPIMM). I/R prolonged GATT and decreased CPIMM significantly (P < 0.01). Pretreatment with allopurinol prevented prolongation of GATT and returned the number of CPIMM to the level of sham treatment (P < 0.01). In conclusion, reperfusion after 10 min of SMA ischemia alters intestinal motility. The no-reflow phenomenon plays an important role in this alteration of motility. Administration of allopurinol before reperfusion preserves intestinal motility by preventing the occurrence of no-reflow phenomenon.