肠道菌群-阿尔茨海默病防治的新靶标

阿尔茨海默病(Alzheimer's disease,AD)是一种渐进性中枢神经系统退行性疾病,其发病机制仍未完全阐明.近年来,随着菌群-肠-脑轴研究的兴起,肠道菌群在AD发生和发展中的作用日益得到重视.本文综述了AD患者的肠道菌群特征,肠道菌群影响AD的主要途径及益生菌、抗生素和饮食等对AD患者的干预作用,为制定靶向...     

运动调控肠道菌群在阿尔茨海默病防治中的应用

阿尔茨海默病（Alzheimer's disease,AD）是一种起病隐匿且呈进行性发展的中枢神经系统退行性疾病,以记忆障碍、语言功能和其他认知能力衰退为主要症状,可导致患者日常生活能力下降,出现精神行为异常,给家庭和社会带来极大的负担。肠道菌群已被发现不仅是免疫和代谢健康的重要组成部分,而且对胃肠道和中枢神经系统的发育具有重要作用。运动医学作为一种新兴的治疗手段,能显著改善肠道菌群紊乱,调节脾胃功能,改善代谢和睡眠,延缓AD的进程。本文通过总结运动及其相关因素对肠道菌群的影响,探讨AD的预防和控制。

     

肠道微生物群落与炎症性肠病关系研究进展

目的炎症性肠病（IBD）包括克罗恩病（CD）和溃疡性结肠炎（UC）,以持续性肠道非特异性炎症为特征,通常反复发作、迁延不愈,临床上仍无特效性的治疗手段。IBD确切的发病机制尚不清楚,涉及免疫、环境及遗传等因素,这些因素共同诱导肠道炎症、黏膜损伤和修复。肠道微生物群落及其代谢产物、宿主基因易感性及肠道黏膜免疫三方面共同参与了IBD的发病机制。本文从消化道微生态角度出发,对目前IBD相关的肠道微生物群落研究现状、宿主-微生物间免疫应答及益生菌治疗等内容进行探讨。     

Effect of dietary modulation of intestinal microbiota on reproduction and early growth

An optimal balance of intestinal microbiota is necessary for digestive and immune health. Poor performance, susceptibility to infections, and decreased growth rate can be signs of an imbalanced microbiome. Dietary strategies to establish and maintain an optimal balance of microbiota include prebiotics (food for indigenous microbiota in the gastrointestinal tract) and probiotics (beneficial microbiota consumed by the animal). Recent research regarding use of probiotics and prebiotics in reproducing and growing livestock and companion animals is summarized. Documented benefits include prevention of diarrhea, decreased mortality, establishment of a healthy microbiota balance, and improved immune function.     

The role of intestinal microbiota in cardiovascular disease

Accumulating evidence has indicated that intestinal microbiota is involved in the development of various human diseases, including cardiovascular diseases (CVDs). In the recent years, both human and animal experiments have revealed that alterations in the composition and function of intestinal flora, recognized as gut microflora dysbiosis, can accelerate the progression of CVDs. Moreover, intestinal flora metabolizes the diet ingested by the host into a series of metabolites, including trimethylamine N‐oxide, short chain fatty acids, secondary bile acid and indoxyl sulfate, which affects the host physiological processes by activation of numerous signalling pathways. The aim of this review was to summarize the role of gut microbiota in the pathogenesis of CVDs, including coronary artery disease, hypertension and heart failure, which may provide valuable insights into potential therapeutic strategies for CVD that involve interfering with the composition, function and metabolites of the intestinal flora.     

Nutritional modulation of the gut microbiota and immune system in preterm neonates susceptible to necrotizing enterocolitis

The gastrointestinal inflammatory disorder, necrotizing enterocolitis (NEC), is among the most serious diseases for preterm neonates. Nutritional, microbiological and immunological dysfunctions all play a role in disease progression but the relationship among these determinants is not understood. The preterm gut is very sensitive to enteral feeding which may either promote gut adaptation and health, or induce gut dysfunction, bacterial overgrowth and inflammation. Uncontrolled inflammatory reactions may be initiated by maldigestion and impaired mucosal protection, leading to bacterial overgrowth and excessive nutrient fermentation. Tumor necrosis factor alpha, toll-like receptors and heat-shock proteins are identified among the immunological components of the early mucosal dysfunction. It remains difficult, however, to distinguish the early initiators of NEC from the later consequences of the disease pathology. To elucidate the mechanisms and identify clinical interventions, animal models showing spontaneous NEC development after preterm birth coupled with different forms of feeding may help. In this review, we summarize the literature and some recent results from studies on preterm pigs on the nutritional, microbial and immunological interactions during the early feeding-induced mucosal dysfunction and later NEC development. We show that introduction of suboptimal enteral formula diets, coupled with parenteral nutrition, predispose to disease, while advancing amounts of mother's milk from birth (particularly colostrum) protects against disease. Hence, the transition from parenteral to enteral nutrition shortly after birth plays a pivotal role to secure gut growth, digestive maturation and an appropriate response to bacterial colonization in the sensitive gut of preterm neonates.     

Probiotics alleviate autoimmune hepatitis in mice through modulation of gut microbiota and intestinal permeability

Autoimmune hepatitis (AIH) is an immune-mediated type of chronic liver inflammation accompanied by intestinal flora imbalance. Probiotics have been reported to ameliorate imbalances in the intestinal flora. This study aimed to investigate the effects of compound probiotic in the AIH mouse model. AIH mice were gavaged with compound probiotic and injected intraperitoneally with dexamethasone (dex) for 42 days. The results showed that these treatments suppressed hepatic inflammatory cell infiltration, serum transaminase, and Th1 and Th17 cells. However, Treg cells were increased only in the probiotics group, which indicates an immunomodulatory role of the compound probiotic. The compound probiotic maintained intestinal barrier integrity, blocked lipopolysaccharide (LPS) translocation, and inhibited the activation of the TLR4/NF-κB pathway and the production of inflammatory factors in the liver and ileum. Moreover, the compound probiotic treatment increased the abundance of beneficial bacteria and reduced the abundance of potentially harmful bacteria in gut. Compound probiotic may improve ileal barrier function while increasing the diversity of the intestinal flora, blocking the translocation of gut-derived LPS to the liver and therefore preventing activation of the TLR4/NF-κB pathway. The resulting inhibition of pro-inflammatory factor production facilitates AIH remission.     

Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis

Enteric glial cells (EGC) actively mediate acute and chronic inflammation in the gut; EGC proliferate and release neurotrophins, growth factors, and pro-inflammatory cytokines which, in turn, may amplify the immune response, representing a very important link between the nervous and immune systems in the intestine. Cannabidiol (CBD) is an interesting compound because of its ability to control reactive gliosis in the CNS, without any unwanted psychotropic effects. Therefore the rationale of our study was to investigate the effect of CBD on intestinal biopsies from patients with ulcerative colitis (UC) and from intestinal segments of mice with LPS-induced intestinal inflammation. CBD markedly counteracted reactive enteric gliosis in LPS-mice trough the massive reduction of astroglial signalling neurotrophin S100B. Histological, biochemical and immunohistochemical data demonstrated that S100B decrease was associated with a considerable decrease in mast cell and macrophages in the intestine of LPS-treated mice after CBD treatment. Moreover the treatment of LPS-mice with CBD reduced TNF-α expression and the presence of cleaved caspase-3. Similar results were obtained in ex vivo cultured human derived colonic biopsies. In biopsies of UC patients, both during active inflammation and in remission stimulated with LPS+INF-γ, an increased glial cell activation and intestinal damage were evidenced. CBD reduced the expression of S100B and iNOS proteins in the human biopsies confirming its well documented effect in septic mice. The activity of CBD is, at least partly, mediated via the selective PPAR-gamma receptor pathway. CBD targets enteric reactive gliosis, counteracts the inflammatory environment induced by LPS in mice and in human colonic cultures derived from UC patients. These actions lead to a reduction of intestinal damage mediated by PPARgamma receptor pathway. Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases.     

Chronic kidney disease after 5/6 nephrectomy disturbs the intestinal microbiota and alters intestinal motility

Organ–organ crosstalk is involved in homeostasis. Gastrointestinal symptoms are common in patients with renal failure. The aim of this study was to elucidate the relationship between gastrointestinal motility and gastrointestinal symptoms in chronic kidney disease. We performed studies in C57BL/6 mice with chronic kidney disease after 5/6 nephrectomy. Gastrointestinal motility was evaluated by assessing the ex vivo responses of ileum and distal colon strips to electrical field stimulation. Feces were collected from mice, and the composition of the gut microbiota was analyzed using 16S ribosomal RNA sequencing. Mice with chronic kidney disease after 5/6 nephrectomy showed a decreased amount of stool, and this constipation was correlated with a suppressed contraction response in ileum motility and decreased relaxation response in distal colon motility. Spermine, one of the uremic toxins, inhibited the contraction response in ileum motility, but four types of uremic toxins showed no effect on the relaxation response in distal colon motility. The 5/6 nephrectomy procedure disturbed the balance of the gut microbiota in the mice. The motility dysregulation and constipation were resolved by antibiotic treatments. The expression levels of interleukin 6, tumor necrosis factor-α, and iNOS in 5/6 nephrectomy mice were increased in the distal colon but not in the ileum. In addition, macrophage infiltration in 5/6 nephrectomy mice was increased in the distal colon but not in the ileum. We found that 5/6 nephrectomy altered gastrointestinal motility and caused constipation by changing the gut microbiota and causing colonic inflammation. These findings indicate that renal failure was remarkably associated with gastrointestinal dysregulation.     

Beneficial modulation of the gut microbiota

The human gut microbiota comprises approximately 100 trillion microbial cells and has a significant effect on many aspects of human physiology including metabolism, nutrient absorption and immune function. Disruption of this population has been implicated in many conditions and diseases, including examples such as obesity, inflammatory bowel disease and colorectal cancer that are highlighted in this review. A logical extension of these observations suggests that the manipulation of the gut microbiota can be employed to prevent or treat these conditions. Thus, here we highlight a variety of options, including the use of changes in diet (including the use of prebiotics), antimicrobial-based intervention, probiotics and faecal microbiota transplantation, and discuss their relative merits with respect to modulating the intestinal community in a beneficial way.     

The intestinal microbiota: from health to disease,and back

Our understanding of the composition and the function of the intestinal microbiota has significantly increased over the past few years. In a series of reviews focusing on the role of the intestinal microbiota in health and disease, we explore recent conceptual and technological advances in this rapidly evolving research arena.     

The role of the gut microbiota in the pathology and prevention of liver disease

Several microorganisms belonging to the intestinal microbiota act in an ecosystem responsible for maintaining the homeostasis and vital functions of human beings. From birth to old age the diversity of the intestinal microbiota may change due to environmental factors such as nutrition, immunity, diseases or the use of antibiotics leading to dysbiosis. Improvement in microbiota diversity can be achieved by modifying related risk factors through changes in lifestyle and a healthy diet. Besides, the addition of probiotics, prebiotics or the combination of both (symbiotics), can result in the improvement of the intestinal permeability, inflammatory pathways and the immune system. Also, the use of probiotics prevents harmful bacteria and their derived products (e.g., bacteriocins, endotoxins, hydrogen sulfide, etc.) to leak through the intestinal wall to the circulation that results in the activation of signaling pathways that may be implicated in liver disease. The liver receives a constant flow of noxious entities that promote inflammation and oxidative stress. The use of probiotics with clinical evidence in liver disease, represent a novel therapeutic alternative, inducing positive changes in the balance of the intestinal microbiota which lead to improvement in liver function tests (AST and ALT), decreasing tumor necrosis factor-α (TNF-α), andblood cholesterol, among other risk factors. In this review, we discuss the main elements that play a leading role in the development of steatosis as well as the benefits of using probiotics and the impact in the quality of life of patients that develop cirrhosis.     

Correlations between intestinal innate immune genes and cecal microbiota highlight potential for probiotic development for immune modulation in poultry

Immune function is influenced by the diversity and stability of the intestinal microbiota. A likely trade-off of immune function for growth has been demonstrated in heavier breeds of poultry that have been genetically selected for growth and feed efficiency traits. We investigated the expression of selected innate immune genes and genes encoding products involved in intestinal barrier function to determine whether function changes could be consistently linked to the phenotypic expression of feed conversion ratio (FCR), a common measure of performance within poultry broiler flocks. In addition, we compared individual cecal microbial composition with innate immune gene expression. Samples were utilised from two replicate trials termed P1E1 and P1E2. High (n = 12) and low (n = 12) performing birds were selected based on their individual FCR data from each replicate and combined for microbiota phylogenetic composition and immune gene expression analysis. Toll-like receptor 1 (TLR1La) and zonula occludens 1 (ZO1) were differentially expressed between high- and low-performing broilers. Several taxa were correlated with FCR; of these, unclassified YS2 and ZO1 were also positively correlated with each other. Interactions between taxa and differentially expressed innate immune genes between P1E1 and P1E2 were much greater compared to relationships between high- and low-performing birds. At the level of phylum, reciprocal correlations between tight junction proteins and Toll-like receptors with Bacteroidetes and Firmicutes were evident, as were correlations at the genus level.

     

Assembly of the human intestinal microbiota

Complex microbial ecosystems occupy the skin, mucosa and alimentary tract of all mammals, including humans. Recent advances have highlighted the tremendous diversity of these microbial communities and their importance to host physiology, but questions remain about the ecological processes that establish and maintain the microbiota throughout life. The prevailing view, that the gastrointestinal microbiota of adult humans is a climax community comprised of the superior competitors for a stable set of niches, does not account for all of the experimental data. We argue here that the unique history of each community and intrinsic temporal dynamics also influence the structure of human intestinal communities.     

Nutritional influences on the gut microbiota and the consequences for gastrointestinal health

The human colonic microbiota degrades dietary substrates that are indigestible in the upper GIT (gastrointestinal tract), releasing bacterial metabolites, some of which are important for gut health. Advances in molecular biology techniques have facilitated detailed analyses of the composition of the bacterial community resident in the lower GIT. Such analyses have indicated that more than 500 different bacterial species colonize an individual, and that, although there is much functional consistency in the resident bacterial groups, there is considerable inter-individual variation at the species/strain level. The bacterial community develops during early childhood until it reaches an adult-like composition. Whereas colonization and host factors influence the species composition, dietary factors also have an important impact, with specific bacterial groups changing in response to specific dietary interventions. Since bacterial species have different metabolic activities, specific diets have various consequences for health, dependent on the effect exerted on the bacterial population.     

Amoxicillin treatment modifies the composition of Bifidobacterium species in infant intestinal microbiota

ObjectivesAmoxicillin is a beta-lactam antibiotic largely used in childhood. However only few studies described its impact on composition of children gut microbiota, in particular on Bifidobacterium populations considered as beneficial microorganisms. In this study, the impact on faecal Bifidobacterium species of a seven-day amoxicillin treatment was quantitatively and qualitatively assessed in infants during an episode of acute respiratory infection.MethodsFaecal samples from 31 infants were obtained on day 0 (just before amoxicillin therapy) and on day 7 (the end of therapy). Total DNA was extracted and bifidobacteria were quantified using real-time PCR. Predominant Bifidobacterium species were then identified using specific PCR-TTGE.ResultsBifidobacteria concentrations were not significantly altered by amoxicillin compared to the healthy group. However, amoxicillin treatment induced a complete disappearance of Bifidobacterium adolescentis species (occurrence rate of 0% versus 36.4% in healthy group, P < 0.001), a significant decrease in the occurrence rate of Bifidobacterium bifidum (23% versus 54.5% in healthy group, P < 0.05), but did not affect Bifidobacterium longum (93.5% versus 100% in healthy group) and Bifidobacterium pseudocatenulatum/B. catenulatum (about 55% in both groups). The number of Bifidobacterium species per microbiota significantly decreased from 2.5 ± 1 for healthy group to 1.8 ± 0.9 for treated infants (P < 0.05).ConclusionsThis study showed that a 7 day amoxicillin treatment did not alter the counts of Bifidobacterium. However amoxicillin can have an impact by changing the microbiota at the species level and decreased the diversity of this population.     

Long‐term monitoring of the human intestinal microbiota composition

The microbiota that colonizes the human intestinal tract is complex and its structure is specific for each of us. In this study we expand the knowledge about the stability of the subject‐specific microbiota and show that this ecosystem is stable in short‐term intervals (< 1 year) but also during long periods of time (> 10 years). The faecal microbiota composition of five unrelated and healthy subjects was analysed using a comprehensive and highly reproducible phylogenetic microarray, the HITChip. The results show that the use of antibiotics, application of specific dietary regimes and distant travelling have limited impact on the microbiota composition. Several anaerobic genera, including Bifidobacterium and a number of genera within the Bacteroidetes and the Firmicutes phylum, exhibit significantly higher similarity than the total microbiota. Although the gut microbiota contains subject‐specific species, the presence of which is preserved throughout the years, their relative abundance changes considerably. Consequently, the recently proposed enterotype status appears to be a varying characteristic of the microbiota. Our data show that the intestinal microbiota contains a core community of permanent colonizers, and that environmentally introduced changes of the microbiota throughout adulthood are primarily affecting the abundance but not the presence of specific microbial species.