膳食纤维、 植物营养素与微营养素对肠道菌群及健康的影响

肠道菌群多数定殖在消化道较远端,与宿主共享许多酶反应,是人体必不可少的组成部分,对健康有重要影 响。 饮食中膳食纤维、植物营养素和微营养素等为肠道菌群提供营养、调节肠道菌群多样性与丰富度,同时也在预 防和治疗某些疾病中起着重要作用。 研究表明膳食纤维经肠道菌群高度发酵与膨胀,主要在结肠产生短链脂肪 酸,影响宿主新陈代谢和免疫系统,间接塑造肠道菌群,还参与细胞生长、肠道屏障与离子转运,并增加抗菌和宿主 防御基因表达等。 膳食植物营养素 90% ~ 95%经肠道菌群转化成高度生物可利用代谢物,显著改变菌群多样性, 对预防高脂饮食代谢综合征有积极作用。 维生素与微营养素为肠道菌群提供必需的营养,促进与致病菌竞争,调节免疫反应,改变肠道菌群与胃肠功能。 肠道菌群调节各种营养素全身的状态,有益于机体健康。     

A microbial symbiosis factor prevents intestinal inflammatory disease

Humans are colonized by multitudes of commensal organisms representing members of five of the six kingdoms of life; however, our gastrointestinal tract provides residence to both beneficial and potentially pathogenic microorganisms. Imbalances in the composition of the bacterial microbiota, known as dysbiosis, are postulated to be a major factor in human disorders such as inflammatory bowel disease. We report here that the prominent human symbiont Bacteroides fragilis protects animals from experimental colitis induced by Helicobacter hepaticus, a commensal bacterium with pathogenic potential. This beneficial activity requires a single microbial molecule (polysaccharide A, PSA). In animals harbouring B. fragilis not expressing PSA, H. hepaticus colonization leads to disease and pro-inflammatory cytokine production in colonic tissues. Purified PSA administered to animals is required to suppress pro-inflammatory interleukin-17 production by intestinal immune cells and also inhibits in vitro reactions in cell cultures. Furthermore, PSA protects from inflammatory disease through a functional requirement for interleukin-10-producing CD4+ T cells. These results show that molecules of the bacterial microbiota can mediate the critical balance between health and disease. Harnessing the immunomodulatory capacity of symbiosis factors such as PSA might potentially provide therapeutics for human inflammatory disorders on the basis of entirely novel biological principles.     

Transient cross-reactive immune responses can orchestrate antigenic variation in malaria

The malaria parasite Plasmodium falciparum has evolved to prolong its duration of infection by antigenic variation of a major immune target on the surface of the infected red blood cell. This immune evasion strategy depends on the sequential, rather than simultaneous, appearance of immunologically distinct variants. Although the molecular mechanisms by which a single organism switches between variants are known in part, it remains unclear how an entire population of parasites within the host can synchronize expression to avoid rapidly exhausting the variant repertoire. Here we show that short-lived, partially cross-reactive immune responses to parasite-infected erythrocyte surface antigens can produce a cascade of sequentially dominant antigenic variants, each of which is the most immunologically distinct from its preceding types. This model reconciles several previously unexplained and apparently conflicting epidemiological observations by demonstrating that individuals with stronger cross-reactive immune responses can, paradoxically, be more likely to sustain chronic infections. Antigenic variation has always been seen as an adaptation of the parasite to evade host defence: we show that the coordination necessary for the success of this strategy might be provided by the host.     

Reciprocal interactions of the intestinal microbiota and immune system

The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.     

Antigenic variation in trypanosomes

In its mammalian host, Trypanosoma brucei is able to change the antigenic character of its glycoprotein surface coat and so evade the host's immune response. This phenotypic change seems to occur spontaneously in 1 in 10,000 individuals but is not due to genetic mutation: host antibody is not necessary for its induction but plays a selective part in bringing about the gross changes in parasite numbers and antigenic character observed in the bloodstream by destroying the main component of what is actually a heterogeneous population. The infecting trypanosome population injected into the mammalian host by the tsetse fly vector may also be heterogeneous. Such heterogeneity complicates plans to vaccinate cattle and people against the African trypanosomes based on the premise that the metacyclic trypanosomes of a clone bear the same surface antigen.     

益生菌、肠道菌群与人体健康

 肠道菌群与人体长期互作、共同进化,帮助宿主消化吸收食物中的营养物质、代谢宿主肠道中产生的有毒废物,同时产生人体必需的氨基酸、维生素、短链脂肪酸等功能物质为宿主所用。肠道菌群紊乱将导致诸如糖尿病、肠易激综合征等多种人体疾病的发生。因此,维护健康的肠道菌群平衡状态对维持机体健康十分关键。益生菌可以调节人体肠道菌群结构、抑制致病菌在肠道中的定殖,同时帮助宿主建立健康的肠黏膜保护层,增强肠道屏障作用,增强宿主的免疫系统。本文综述了乳酸菌、益生菌、人体肠道菌群的研究进展,论述了中国人群的肠道菌群特征,分析了基因型与饮食对肠道菌群的影响,指出了肠道菌群领域的研究热点及发展趋势。     

HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria

The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response. HVEM was recently reported as a colitis risk locus in patients, and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM, but its mechanism of action in the mucosal immune system was unknown. Here we report an important role for epithelial HVEM in innate mucosal defence against pathogenic bacteria. HVEM enhances immune responses by NF-κB-inducing kinase-dependent Stat3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli infection, Hvem?/? mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens and increased mortality. We identified the immunoglobulin superfamily molecule CD160 (refs 7 and 8), expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection, HVEM is also required for host defence. Our results pinpoint HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicates that targeting HVEM with agonists could improve host defence.     

Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis

Intestinal epithelial cells (IECs) provide a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestinal (GI) tract, but the influence of IECs on the development and regulation of immunity to infection is unknown. Here we show that IEC-intrinsic IkappaB kinase (IKK)-beta-dependent gene expression is a critical regulator of responses of dendritic cells and CD4+ T cells in the GI tract. Mice with an IEC-specific deletion of IKK-beta show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4+ T helper type 2 (T(H)2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-alpha, increased levels of CD4+ T-cell-derived interferon-gamma and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-beta in IECs to promote CD4+ T(H)2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the GI tract. These results indicate that the balance of IKK-beta-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.     

6 A-resolution X-ray structure of a variable surface glycoprotein from Trypanosoma brucei

The variable surface glycoprotein (VSG) is the predominant component of the surface coat of the African trypanosome. The expression of antigenically distinct VSGs on minor populations during infection allows the parasite to escape the host immune response. Purification of the protein is facilitated by the enzymatic release of a soluble form of VSG (sVSG) which occurs on cell lysis. The soluble form is a dimer with an approximate molecular weight of 120,000-130,000. Partial proteolysis of sVSG reveals a protease-sensitive link between an amino-terminal domain which comprises about two-thirds of the molecule, and a C-terminal domain which contains the membrane attachment site. We have obtained crystals suitable for high-resolution structural analysis from preparations of three sVSG: MITat 1.2, ILTat 1.25 and ILTat 1.22. The crystal structure of the dimer of the MITat 1.2 amino-terminal domain has been solved to 6 A resolution. We report here that the dimer is an unusual 90 A rod-like molecule composed of a helical bundle of at least four 80 A-long alpha-helices.     

Reduction of disulphide bonds unmasks potent antimicrobial activity of human β-defensin 1

Human epithelia are permanently challenged by bacteria and fungi, including commensal and pathogenic microbiota. In the gut, the fraction of strict anaerobes increases from proximal to distal, reaching 99% of bacterial species in the colon. At colonic mucosa, oxygen partial pressure is below 25% of airborne oxygen content, moreover microbial metabolism causes reduction to a low redox potential of -200?mV to -300?mV in the colon. Defensins, characterized by three intramolecular disulphide-bridges, are key effector molecules of innate immunity that protect the host from infectious microbes and shape the composition of microbiota at mucosal surfaces. Human β-defensin 1 (hBD-1) is one of the most prominent peptides of its class but despite ubiquitous expression by all human epithelia, comparison with other defensins suggested only minor antibiotic killing activity. Whereas much is known about the activity of antimicrobial peptides in aerobic environments, data about reducing environments are limited. Herein we show that after reduction of disulphide-bridges hBD-1 becomes a potent antimicrobial peptide against the opportunistic pathogenic fungus Candida albicans and against anaerobic, Gram-positive commensals of Bifidobacterium and Lactobacillus species. Reduced hBD-1 differs structurally from oxidized hBD-1 and free cysteines in the carboxy terminus seem important for the bactericidal effect. In vitro, the thioredoxin (TRX) system is able to reduce hBD-1 and TRX co-localizes with reduced hBD-1 in human epithelia. Hence our study indicates that reduced hBD-1 shields the healthy epithelium against colonisation by commensal bacteria and opportunistic fungi. Accordingly, an intimate interplay between redox-regulation and innate immune defence seems crucial for an effective barrier protecting human epithelia.     

Recognition of microorganisms and activation of the immune response

The mammalian immune system has innate and adaptive components, which cooperate to protect the host against microbial infections. The innate immune system consists of functionally distinct 'modules' that evolved to provide different forms of protection against pathogens. It senses pathogens through pattern-recognition receptors, which trigger the activation of antimicrobial defences and stimulate the adaptive immune response. The adaptive immune system, in turn, activates innate effector mechanisms in an antigen-specific manner. The connections between the various immune components are not fully understood, but recent progress brings us closer to an integrated view of the immune system and its function in host defence.     

Parasitology: parasite survives predation on its host

As prisoners in their living habitat, parasites should be vulnerable to destruction by the predators of their hosts. But we show here that the parasitic gordian worm Paragordius tricuspidatus is able to escape not only from its insect host after ingestion by a fish or frog but also from the digestive tract of the predator. This remarkable tactic enables the worm to continue its life cycle.     

A colonization factor links Vibrio cholerae environmental survival and human infection

Many bacteria that cause diseases must be able to survive inside and outside the host. Attachment to and colonization of abiotic or biotic surfaces is a common mechanism by which various microorganisms enhance their ability to survive in diverse environments. Vibrio cholerae is a Gram-negative aquatic bacillus that is often found in the environment attached to the chitinous exoskeletons of zooplankton. It has been suggested that attachment to zooplankton enhances environmental survival of Vibrio spp., probably by providing both an abundant source of carbon and nitrogen and protection from numerous environmental challenges. On ingestion by humans, some serogroups of V. cholerae cause the diarrhoeal disease cholera. The pathophysiology of cholera is a result of the effects of cholera toxin on intestinal epithelial cells. For sufficient quantities of cholera toxin to reach the intestinal epithelium and to produce clinical symptoms, colonization of the small bowel must occur. Because most V. cholerae do not colonize humans, but all probably require strategies for survival in the environment, we considered that colonization factors selected for in the environment may be the same as those required for intestinal colonization of humans. In support of this hypothesis, here we have identified a single protein required for efficient intestinal colonization that mediates attachment to both zooplankton and human epithelial cells by binding to a sugar present on both surfaces.     

Therapeutic potential of monovalent monoclonal antibodies

One therapeutic use for monoclonal antibody technology is the elimination of categories of unwanted cells by virtue of their distinct cell surface antigens. The efficiency of cell destruction by complement lysis or opsonization depends on a number of factors such as antibody specificity and isotype as well as certain properties of the target antigen. In some instances cells can escape destruction by redistributing and eventually losing the antigen-antibody complexes from their surface. This process, known as antigenic modulation, generally depends on bivalent antibody binding. Starting from the observation that rabbit antisera can be made more effective at killing tumour cells if they are first rendered univalent by limited proteolysis, we have now prepared a number of monovalent rat monoclonal antibodies to human cell-surface antigens. We find that these antibodies are no longer able to bring about modulation of their target antigens and have an enhanced facility for lysis with human complement. These special properties should greatly increase the therapeutic potential of monoclonal antibodies.     

Structural basis for co-stimulation by the human CTLA-4/B7-2 complex

Regulation of T-cell activity is dependent on antigen-independent co-stimulatory signals provided by the disulphide-linked homodimeric T-cell surface receptors, CD28 and CTLA-4 (ref. 1). Engagement of CD28 with B7-1 and B7-2 ligands on antigen-presenting cells (APCs) provides a stimulatory signal for T-cell activation, whereas subsequent engagement of CTLA-4 with these same ligands results in attenuation of the response. Given their central function in immune modulation, CTLA-4- and CD28-associated signalling pathways are primary therapeutic targets for preventing autoimmune disease, graft versus host disease, graft rejection and promoting tumour immunity. However, little is known about the cell-surface organization of these receptor/ligand complexes and the structural basis for signal transduction. Here we report the 3.2-A resolution structure of the complex between the disulphide-linked homodimer of human CTLA-4 and the receptor-binding domain of human B7-2. The unusual dimerization properties of both CTLA-4 and B7-2 place their respective ligand-binding sites distal to the dimer interface in each molecule and promote the formation of an alternating arrangement of bivalent CTLA-4 and B7-2 dimers that extends throughout the crystal. Direct observation of this CTLA-4/B7-2 network provides a model for the periodic organization of these molecules within the immunological synapse and suggests a distinct mechanism for signalling by dimeric cell-surface receptors.     

Protection against enteric salmonellosis in transgenic mice expressing a human intestinal defensin

Genetically encoded antibiotic peptides are evolutionarily ancient and widespread effector molecules of immune defence. Mammalian defensins, one subset of such peptides, have been implicated in the antimicrobial defence capacity of phagocytic leukocytes and various epithelial cells, but direct evidence of the magnitude of their in vivo effects have not been clearly demonstrated. Paneth cells, specialized epithelia of the small intestinal crypt, secrete abundant alpha-defensins and other antimicrobial polypeptides including human defensin 5 (HD-5; also known as DEFA5). Although antibiotic activity of HD-5 has been demonstrated in vitro, functional studies of HD-5 biology have been limited by the lack of in vivo models. To study the in vivo role of HD-5, we developed a transgenic mouse model using a 2.9-kilobase HD-5 minigene containing two HD-5 exons and 1.4 kilobases of 5'-flanking sequence. Here we show that HD-5 expression in these mice is specific to Paneth cells and reflects endogenous enteric defensin gene expression. The storage and processing of transgenic HD-5 also matches that observed in humans. HD-5 transgenic mice were markedly resistant to oral challenge with virulent Salmonella typhimurium. These findings provide support for a critical in vivo role of epithelial-derived defensins in mammalian host defence.     

Aberrant innate immune response in lethal infection of macaques with the 1918 influenza virus

The 1918 influenza pandemic was unusually severe, resulting in about 50 million deaths worldwide. The 1918 virus is also highly pathogenic in mice, and studies have identified a multigenic origin of this virulent phenotype in mice. However, these initial characterizations of the 1918 virus did not address the question of its pathogenic potential in primates. Here we demonstrate that the 1918 virus caused a highly pathogenic respiratory infection in a cynomolgus macaque model that culminated in acute respiratory distress and a fatal outcome. Furthermore, infected animals mounted an immune response, characterized by dysregulation of the antiviral response, that was insufficient for protection, indicating that atypical host innate immune responses may contribute to lethality. The ability of influenza viruses to modulate host immune responses, such as that demonstrated for the avian H5N1 influenza viruses, may be a feature shared by the virulent influenza viruses.     

Shigella flexneri induces apoptosis in infected macrophages.

The Gram-negative bacterial pathogen Shigella flexneri causes dysentery by invading the human colonic mucosa. Bacteria are phagocytosed by enterocytes, escape from the phagosome into the cytoplasm and spread to adjacent cells. After crossing the epithelium, Shigella reaches the lamina propria of intestinal villi, the first line of defence. This tissue is densely populated with phagocytes that are killed in great numbers, resulting in abscesses. The genes required for cell invasion and macrophage killing are located on a 220-kilobase plasmid. We report here on the mechanism of cytotoxicity used by S. flexneri to kill macrophages. Each of four different strains was tested for its capacity to induce cell death. An invasive strain induced programmed cell death (apoptosis), whereas its non-invasive, plasmidcured isogenic strain was not toxic; neither was a mutant in ipa B (ref. 10) (invasion protein antigen), a gene necessary for entry. A non-invasive strain expressing the haemolysin operon of Escherichia coli induced accidental cell death (necrosis), demonstrating that other bacterial cytotoxic mechanisms do not lead to apoptosis. This is the first evidence that an invasive bacterial pathogen can induce suicide in its host cells.