Vitamin A and vitamin D regulate the microbial complexity,barrier function,and the mucosal immune responses to ensure intestinal homeostasis

Diet is an important regulator of the gastrointestinal microbiota. Vitamin A and vitamin D deficiencies result in less diverse, dysbiotic microbial communities and increased susceptibility to infection or injury of the gastrointestinal tract. The vitamin A and vitamin D receptors are nuclear receptors expressed by the host, but not the microbiota. Vitamin A- and vitamin D-mediated regulation of the intestinal epithelium and mucosal immune cells underlies the effects of these nutrients on the microbiota. Vitamin A and vitamin D regulate the expression of tight junction proteins on intestinal epithelial cells that are critical for barrier function in the gut. Other shared functions of vitamin A and vitamin D include the support of innate lymphoid cells that produce IL-22, suppression of IFN-γ and IL-17 by T cells, and induction of regulatory T cells in the mucosal tissues. There are some unique functions of vitamin A and D; for example, vitamin A induces gut homing receptors on T cells, while vitamin D suppresses gut homing receptors on T cells. Together, vitamin A- and vitamin D-mediated regulation of the intestinal epithelium and mucosal immune system shape the microbial communities in the gut to maintain homeostasis.     

Importance of microbial colonization of the gut in early life to the development of immunity

The mammalian gastrointestinal tract harbors a complex microbiota consisting of between 500 and 1000 distinct microbial species. Comparative studies based on the germ-free gut have provided clear evidence that the gut microbiota is instrumental in promoting the development of both the gut and systemic immune systems. Early microbial exposure of the gut is thought to dramatically reduce the incidence of inflammatory, autoimmune and atopic diseases further fuelling the scientific viewpoint, that microbial colonization plays an important role in regulating and fine-tuning the immune system throughout life. Recent molecular diversity studies have provided additional evidence that the human gut microbiota is compositionally altered in individuals suffering from inflammatory bowel disorders, suggesting that specific bacterial species are important to maintaining immunological balance and health. New and exciting insights into how gut bacteria modulate the mammalian immune system are emerging. However, much remains to be elucidated about how commensal bacteria influence the function of cells of both the innate and adaptive immune systems in health and disease.     

Antagonistic activities of lactobacilli and bifidobacteria against microbial pathogens

The gastrointestinal tract is a complex ecosystem that associates a resident microbiota and cells of various phenotypes lining the epithelial wall expressing complex metabolic activities. The resident microbiota in the digestive tract is a heterogeneous microbial ecosystem containing up to 1 x 10(14) colony-forming units (CFUs) of bacteria. The intestinal microbiota plays an important role in normal gut function and maintaining host health. The host is protected from attack by potentially harmful microbial microorganisms by the physical and chemical barriers created by the gastrointestinal epithelium. The cells lining the gastrointestinal epithelium and the resident microbiota are two partners that properly and/or synergistically function to promote an efficient host system of defence. The gastrointestinal cells that make up the epithelium, provide a physical barrier that protects the host against the unwanted intrusion of microorganisms into the gastrointestinal microbiota, and against the penetration of harmful microorganisms which usurp the cellular molecules and signalling pathways of the host to become pathogenic. One of the basic physiological functions of the resident microbiota is that it functions as a microbial barrier against microbial pathogens. The mechanisms by which the species of the microbiota exert this barrier effect remain largely to be determined. There is increasing evidence that lactobacilli and bifidobacteria, which inhabit the gastrointestinal microbiota, develop antimicrobial activities that participate in the host's gastrointestinal system of defence. The objective of this review is to analyze the in vitro and in vivo experimental and clinical studies in which the antimicrobial activities of selected lactobacilli and bifidobacteria strains have been documented.     

Environmental filtering increases with elevation for the assembly of gut microbiota in wild pikas

Despite their important roles in host nutrition, metabolism and adaptability, the knowledge on how the mammalian gut microbial community assemble is relatively scanty, especially regarding the ecological mechanisms that govern microbiota along environmental gradients. To address this, we surveyed the diversity, function and ecological processes of gut microbiota in the wild plateau pika, Ochotona curzoniae, along the elevational gradient from 3106 to 4331 m on ‘the Roof of the World’—Qinghai-Tibet Plateau. The results indicated that the alpha, beta and functional diversity of gut microbiota significantly increased with elevation, and elevation significantly explained the variations in the gut microbial communities, even after controlling for geographical distance, host sex and body weight. Some gene functions (e.g. nitrogen metabolism and protein kinases) associated with metabolism were enriched in the high-altitude pikas. Null model and phylogenetic analysis suggest that the relative contributions of environmental filtering responsible for local gut communities increased with elevation. In addition, deterministic processes dominated gut microbial communities in the high-altitude (more than 3694 m) pikas, while the percentages of stochastic and deterministic processes were very close in the low-altitude (3106 and 3580 m) pikas. The observed mechanisms that influence pika gut microbiota assembly and function seemed to be mainly mediated by the internal gut environment and by the external environmental pressure (i.e. lower temperature) in the harsh high-altitude environment. These findings enhance our understanding of gut microbiota assembly patterns and function in wild mammals from extreme harsh environments.     

Outside the liver box: The gut microbiota as pivotal modulator of liver diseases

The gut microbiota affects host physiology and has evolved as an important contributor to health and disease. Gut and liver are closely connected and communicate via the portal vein and the biliary system so the liver is constantly exposed to gut-derived bacterial products and metabolites. The intestinal barrier is important for maintaining physical and functional separation between microbes in the gut and the interior of the host and disruption of the barrier function can lead to bacterial translocation and increased leakage of bacterial metabolites. Liver diseases have been associated with dysbiotic changes in the gut microbiota and impaired gut barrier integrity, thus a future strategy to treat liver disease may be to target the gut microbiota and thereby restore the gut barrier function. This review will summarize and discuss studies that have shown a link between the gut microbiota and liver disease with the main focus on non-alcoholic fatty liver disease and alcoholic liver disease.     

Motility allows S. Typhimurium to benefit from the mucosal defence

The mammalian intestine is colonized by a dense bacterial community, called microbiota. The microbiota shields from intestinal infection (colonization resistance). Recently, we have shown that enteropathogenic Salmonella spp. can exploit inflammation to compete with the intestinal microbiota. The mechanisms explaining the enhanced pathogen growth in the inflamed intestine are elusive. Here, we analysed the function of bacterial flagella in the inflamed intestine using a mouse model for acute Salmonella Typhimurium enterocolitis. Mutations affecting flagellar assembly (Fla^-) and chemotaxis (Che^-) impaired the pathogen's fitness in the inflamed intestine, but not in the normal gut. This was attributable to a localized source of high-energy nutrients (e.g. galactose-containing glyco-conjugates, mucin) released as an element of the mucosal defence. Motility allows Salmonella Typhimurium to benefit from these nutrients and utilize them for enhanced growth. Thus, nutrient availability contributes to enhanced pathogen growth in the inflamed intestine. Strategies interfering with bacterial motility or nutrient availability might offer starting points for therapeutic approaches.     

The multi-tasking gut epithelium of insects

The insect gut epithelium plays a vital role in multiple processes, including nutrition, immunity and osmoregulation. Recent research is revealing the molecular and biochemical basis of these functions. For example, the pattern of nutrient acquisition by the gut epithelium is integrated into the overall regulation of nutrient allocation, as illustrated by evidence for systemic controls over expression of key genes coding digestive enzymes and transporters in carbohydrate acquisition; and the abundance and diversity of microorganisms in the gut lumen is regulated by multiple molecular properties of the gut epithelial cells, including the synthesis of enzymes that produce reactive oxygen species and anti-microbial peptides. These traits are underpinned by the function of the gut epithelium as a selective barrier which mediates the controlled movement of water, ions, metabolites and macromolecules between the gut lumen and insect tissues. Breakdown of the gut epithelial barrier has been implicated in muscle paralysis of insects at low temperatures (chill coma) and in aging. The key challenge for future research is to understand how the multiple functions of the insect gut epithelium are integrated by signaling interactions among epithelial cells, the gut microbiota and other insect organs.     

Shuttling of information between the mucosal and luminal environment drives intestinal homeostasis

The gastrointestinal tract is a passageway for dietary nutrients, microorganisms and xenobiotics. The gut is home to diverse bacterial communities forming the microbiota. While bacteria and their metabolites maintain gut homeostasis, the host uses innate and adaptive immune mechanisms to cope with the microbiota and luminal environment. In recent years, multiple bi-directional instructive mechanisms between microbiota, luminal content and mucosal immune systems have been uncovered. Indeed, epithelial and immune cell-derived mucosal signals shape microbiota composition, while microbiota and their by-products shape the mucosal immune system. Genetic and environmental perturbations alter gut mucosal responses which impact on microbial ecology structures. On the other hand, changes in microbiota alter intestinal mucosal responses. In this review, we discuss how intestinal epithelial Paneth and goblet cells interact with the microbiota, how environmental and genetic disorders are sensed by endoplasmic reticulum stress and autophagy responses, how specific bacteria, bacterial- and diet-derived products determine the function and activation of the mucosal immune system. We will also discuss the critical role of HDAC activity as a regulator of immune and epithelial cell homeostatic responses.     

Bacterial interspecies quorum sensing in the mammalian gut microbiota

The mammalian gastrointestinal tract harbors a diverse and complex resident bacterial community, which interacts with the host in many beneficial processes required for optimal host health. We are studying the importance of bacterial cell-cell communication mediated by the interspecies quorum-sensing signal autoinducer-2 (AI-2) in the beneficial properties of the gut microbiota. Our recent work provided the first evidence that AI-2 produced by Escherichia coli can influence the species composition of this community in the mouse gut. We showed that, under conditions of microbiota imbalances induced by antibiotic treatments, E. coli, which increases intestinal AI-2 levels, not only had an effect on the overall structure of the microbiota community, but specifically favored the expansion of the Firmicutes phylum. Because the Firmicutes are very important for many gut functions and were the group of bacteria most severely affected by antibiotic treatment with streptomycin, we are addressing the possibility that AI-2 can influence the balance of the major bacterial groups in the gut and promote recovery of gut homeostasis. Overall, we want to understand how bacterial chemical signaling shapes the multi-species bacterial communities in the mammalian gut and how these communities affect host physiology.     

Alteration of the gastrointestinal microbiota of mice by edible blue-green algae

Aims:  To characterize the effect of edible blue-green algae (cyanobacteria) on the gastrointestinal microbiota of mice.
Methods and Results:  C57BL/6J mice were fed a diet supplemented with 0% or 5% dried Nostoc commune , Spirulina platensis or Afanizominon flos-aquae (w/w) for 4 weeks. Molecular fingerprinting of the colonic microbiota using denaturing gradient gel electrophoresis revealed that administration of N. commune induced major alterations in colonic microbiota composition, while administration of S. platensis or A. flos-aquae had a more subtle impact. Community profile analysis revealed that administration of N. commune did not reduce microbial diversity indices of the colonic microbiota. Despite its pronounced effects on the bacterial composition in the colon, total bacterial numbers in the gut of mice fed N. commune were not reduced as assessed by quantitative real-time PCR and bacteriological culture.
Conclusions:  The results presented here show that administration of blue-green algae, and especially N. commune , alters colonic microbiota composition in mice with limited effects on total bacterial numbers or microbial diversity.
Significance and Impact of the Study:  Blue-green algae are consumed in many countries as a source of nutrients and to promote health, and they are intensively studied for their pharmaceutical value. Given the importance of the gut microbiota for many host functions, the effects of blue-green algae on gut microbial ecology revealed during this study should be considered when using them as food supplements or when studying their pharmaceutical properties.     

肠黏膜屏障与肠道菌群的相互关系

人类肠道中微生物群与肠道环境相互作用以维持机体健康。肠黏膜屏障主要由黏液层、肠道菌群、肠道免疫系统和肠上皮细胞本身的完整性等构成。肠道作为直接与大量菌群接触的器官,其屏障功能在肠道健康中的作用尤为显著。肠道菌群与肠道屏障相互作用,保持肠道菌群与肠道屏障相对稳定,肠道菌群参与肠道免疫反应的建立,共同建立机体天然防御系统,在保持肠道免疫的动态平衡中具有重要作用。当两者之间的平衡被打破时,可诱发功能性胃肠病（如肠易激综合征）及免疫相关性疾病（如炎症性肠病）。本文主要阐述肠黏膜屏障与肠道菌群之间的相互关系以及与肠道屏障功能障碍相关的肠道疾病。     

Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits

The gastrointestinal tract harbors a complex and diverse microbiota that has an important role in host metabolism. Microbial diversity is influenced by a combination of environmental and host genetic factors and is associated with several polygenic diseases. In this study we combined next-generation sequencing, genetic mapping, and a set of physiological traits of the BXD mouse population to explore genetic factors that explain differences in gut microbiota and its impact on metabolic traits. Molecular profiling of the gut microbiota revealed important quantitative differences in microbial composition among BXD strains. These differences in gut microbial composition are influenced by host-genetics, which is complex and involves many loci. Linkage analysis defined Quantitative Trait Loci (QTLs) restricted to a particular taxon, branch or that influenced the variation of taxa across phyla. Gene expression within the gastrointestinal tract and sequence analysis of the parental genomes in the QTL regions uncovered candidate genes with potential to alter gut immunological profiles and impact the balance between gut microbial communities. A QTL region on Chr 4 that overlaps several interferon genes modulates the population of Bacteroides, and potentially Bacteroidetes and Firmicutes-the predominant BXD gut phyla. Irak4, a signaling molecule in the Toll-like receptor pathways is a candidate for the QTL on Chr15 that modulates Rikenellaceae, whereas Tgfb3, a cytokine modulating the barrier function of the intestine and tolerance to commensal bacteria, overlaps a QTL on Chr 12 that influence Prevotellaceae. Relationships between gut microflora, morphological and metabolic traits were uncovered, some potentially a result of common genetic sources of variation.     

Vascular and lymphatic regulation of gastrointestinal function and disease risk

The vascular and lymphatic systems in the gut regulate lipid transport while restricting transfer of commensal gut microbiota and directing immune cell trafficking. Increased permeability of the endothelial systems in the intestine associates with passage of antigens and microbiota from the gut into the bloodstream leading to tissue inflammation, the release of pro-inflammatory mediators and ultimately to abnormalities of systemic metabolism. Recent studies show that lipid metabolism maintains homeostasis and function of intestinal blood and lymphatic endothelial cells, BECs and LECs, respectively. This review highlights recent progress in this area, and information related to the contribution of the lipid transporter CD36, abundant in BECs and LECs, to gastrointestinal barrier integrity, inflammation, and to gut regulation of whole body metabolism. The potential role of endothelial lipid delivery in epithelial tissue renewal after injury and consequently in the risk of gastric and intestinal diseases is also discussed.     

Nest specificity of the bacterial community in termite guts (Hodotermes mossambicus)

While recent results have provided strong evidence for the presence of a stable gut microbiota among several termite species, little is known about variations at the colony or individual level. Using a cultivation-independent approach, we investigated the structure of the bacterial community in the gut of termites from four different colonies of Hodotermes mossambicus. 16S rRNA-based terminal restriction fragment length polymorphism (T-RFLP) analysis of the bacterial gut microbiota revealed (1) a high consistency of the gut microbiota among nestmates and (2) subtle but distinct differences in community structure between individuals from different colonies. Since products of bacterial metabolism may contribute to a colony odor that can be used as discriminatory signal, the presence of a colony-specific bacterial community adds support to the hypothesis that the gut microbiota of termites is involved in nestmate recognition. Received 12 July 2005; revised 10 February and 15 March 2006; accepted 7 April 2006.     

A role for IL-22 in the relationship between intestinal helminths,gut microbiota and mucosal immunity

The intestinal tract is home to nematodes as well as commensal bacteria (microbiota), which have coevolved with the mammalian host. The mucosal immune system must balance between an appropriate response to dangerous pathogens and an inappropriate response to commensal microbiota that may breach the epithelial barrier, in order to maintain intestinal homeostasis. IL-22 has been shown to play a critical role in maintaining barrier homeostasis against intestinal pathogens and commensal bacteria. Here we review the advances in our understanding of the role of IL-22 in helminth infections, as well as in response to commensal and pathogenic bacteria of the intestinal tract. We then consider the relationship between intestinal helminths and gut microbiota and hypothesize that this relationship may explain how helminths may improve symptoms of inflammatory bowel diseases. We propose that by inducing an immune response that includes IL-22, intestinal helminths may enhance the mucosal barrier function of the intestinal epithelium. This may restore the mucosal microbiota populations from dysbiosis associated with colitis and improve intestinal homeostasis.     

Recovery of human gut microbiota genomes with third-generation sequencing

Human gut microbiota modulates normal physiological functions, such as maintenance of barrier homeostasis and modulation of metabolism, as well as various chronic diseases including type 2 diabetes and gastrointestinal cancer. Despite decades of research, the composition of the gut microbiota remains poorly understood. Here, we established an effective extraction method to obtain high quality gut microbiota genomes, and analyzed them with third-generation sequencing technology. We acquired a large quantity of data from each sample and assembled large numbers of reliable contigs. With this approach, we constructed tens of completed bacterial genomes in which there were several new bacteria species. We also identified a new conditional pathogen, Enterococcus tongjius, which is a member of Enterococci. This work provided a novel and reliable approach to recover gut microbiota genomes, facilitating the discovery of new bacteria species and furthering our understanding of the microbiome that underlies human health and diseases.Subject terms: DNA sequencing, Mechanisms of disease     

动物宿主——肠道微生物代谢轴研究进展

肠道中栖息着数量庞大且复杂多样的微生物菌群,在维持宿主肠道微环境稳态中发挥重要作用。微生物菌群可以利用宿主肠道的营养素,发酵产生代谢产物,与宿主机体形成宿主—微生物代谢轴(host-microbe metabolic axis)。该代谢轴既能影响营养素吸收和能量代谢,又可调控宿主各项生理过程。本文主要阐述宿主-肠道微生物代谢轴的概念、肠-肝轴、肠-脑轴、肠道微生物与宿主肠道代谢轴的互作以及对机体健康的影响。     

Decipher enzymes from human microbiota for drug discovery and development

The human microbiota plays an important role in human health and contributes to the metabolism of therapeutic drugs affecting their potency. However, the current knowledge on human gut bacterial metabolism is limited and lacks an understanding of the underlying mechanisms of observed drug biotransformations. Despite the complexity of the gut microbial community, genomic and metagenomic sequencing provides insights into the diversity of chemical reactions that can be carried out by the microbiota and poses new challenges to functionally annotate thousands of bacterial enzymes. Here, we outline methods to systematically address the structural and functional space of the human microbiome, highlighting a combination of in silico and in vitro approaches. Systematic knowledge about microbial enzymes could eventually be applied for personalized therapy, the development of prodrugs and modulators of unwanted bacterial activity, and the further discovery of new antibiotics.     

Targeting the gut microbiota with resveratrol: a demonstration of novel evidence for the management of hepatic steatosis

Resveratrol is a natural polyphenol that has been reported to reduce the risk of obesity and nonalcoholic fatty liver disease (NAFLD). Recent evidence has demonstrated that the gut microbiota plays an important role in the protection against NAFLD and other metabolic diseases. The present study aimed to investigate the relationship between the gut microbiota and the beneficial effects of resveratrol on the amelioration of NAFLD in mice. We observed marked decreases in body weight and liver steatosis and improved insulin resistance in high-fat diet (HFD)-fed mice treated with resveratrol. Furthermore, we found that resveratrol treatment alleviated NAFLD in HFD-fed mice by improving the intestinal microenvironment, including gut barrier function and gut microbiota composition. On the one hand, resveratrol improved gut intestinal barrier integrity through the repair of intestinal mucosal morphology and increased the expression of physical barrier- and physiochemical barrier-related factors in HFD-fed mice. On the other hand, in HFD-fed mice, resveratrol supplementation modulated the gut bacterial composition. The resveratrol-induced gut microbiota was characterized by a decreased abundance of harmful bacteria, including Desulfovibrio, Lachnospiraceae_NK4A316_group and Alistipes, as well as an increased abundance of short-chain fatty acid (SCFA)-producing bacteria, such as Allobaculum, Bacteroides and Blautia. Moreover, transplantation of the HFDR-microbiota into HFD-fed mice sufficiently decreased body weight, liver steatosis and low-grade inflammation and improved hepatic lipid metabolism. Collectively, resveratrol would provide a potentially dietary intervention strategy against NAFLD through modulating the intestinal microenvironment.     

Predominant role of host genetics in controlling the composition of gut microbiota

Background

The human gastrointestinal tract is inhabited by a very diverse symbiotic microbiota, the composition of which depends on host genetics and the environment. Several studies suggested that the host genetics may influence the composition of gut microbiota but no genes involved in host control were proposed. We investigated the effects of the wild type and mutated alleles of the gene, which encodes the protein called pyrin, one of the regulators of innate immunity, on the composition of gut commensal bacteria. Mutations in MEFV lead to the autoinflammatory disorder, familial Mediterranean fever (FMF, MIM249100), which is characterized by recurrent self-resolving attacks of fever and polyserositis, with no clinical signs of disease in remission.

Methodology/Principal Findings

A total of 19 FMF patients and eight healthy individuals were genotyped for mutations in the MEFV gene and gut bacterial diversity was assessed by sequencing 16S rRNA gene libraries and FISH analysis. These analyses demonstrated significant changes in bacterial community structure in FMF characterized by depletion of total numbers of bacteria, loss of diversity, and major shifts in bacterial populations within the Bacteroidetes, Firmicutes and Proteobacteria phyla in attack. In remission with no clinical signs of disease, bacterial diversity values were comparable with control but still, the bacterial composition was substantially deviant from the norm. Discriminant function analyses of gut bacterial diversity revealed highly specific, well-separated and distinct grouping, which depended on the allele carrier status of the host.

Conclusions/Significance

This is the first report that clearly establishes the link between the host genotype and the corresponding shifts in the gut microbiota (the latter confirmed by two independent techniques). It suggests that the host genetics is a key factor in host-microbe interaction determining a specific profile of commensal microbiota in the human gut.