Oral immunisation of pigs with fimbrial antigens of enterotoxigenic E. coli: an interesting model to study mucosal immune mechanisms

The intestinal mucosal immune system can discriminate actively between harmful pathogenic agents and harmless food antigens resulting in different immune responses namely IgA production and oral tolerance, respectively. Recently, a pig model has been developed for studying intestinal mucosal immune responses in which F4 fimbrial antigens of enterotoxigenic Escherichia coli (F4 ETEC) are used as oral antigens. A unique feature of this model is that soluble F4 antigens can be administered to pigs which have a receptor for this fimbriae (F4R(+)) on their small intestinal villous enterocytes and pigs which do not have this receptor (F4R(-)). Oral administration of F4 to the F4R(+) pigs results in an intestinal mucosal immune response that completely protects the pigs against a challenge infection. In F4R(-) pigs such an intestinal mucosal immune response does not occur. However, a priming of the systemic immune system can be seen similar to the priming in pigs fed with the same dose of a food antigen, suggesting that F4 in F4R(-) pigs behaves as a food antigen. The fact that different mucosal immune responses can be induced with soluble F4, makes it an interesting model to study mucosal immune mechanisms in the pig.     

Gut health:The results of microbial and mucosal immune interactions in pigs

There are a large number of microorganisms in the porcine intestinal tract. These microorganisms and their metabolites contribute to intestinal mucosal immunity, which is of great importance to the health of the host. The host immune system can regulate the distribution and composition of intestinal microorganisms and regulate the homeostasis of intestinal flora by secreting a variety of immune effector factors, such as mucin, secretory immunoglobulin A (sIgA), regenerating islet-derived III (RegIII)γ, and defensin. Conversely, intestinal microorganisms can also promote the differentiation of immune cells including regulatory T cells (T_reg) and Th17 cells through their specific components or metabolites. Studies have shown that imbalances in the intestinal flora can lead to bacterial translocation and compromised intestinal barrier function, affecting the health of the body. This review focuses on the composition of the pig intestinal flora and the characteristics of intestinal mucosal immunity, discusses the interaction mechanism between the flora and intestinal mucosal immunity, as well as the regulation through fecal microbiota transplantation (FMT), dietary nutritional composition, probiotics and prebiotics of pig intestinal microecology. Finally, this review provides insights into the relationship between intestinal microorganisms and the mucosal immune system.     

动物肠道菌群与病原微生物感染关系的研究进展

动物肠道内寄居着大量微生物,通常被称为共生菌群。它们对动物的生长、代谢和免疫状态至关重要,还与许多疾病的发生密切相关。病毒、细菌和寄生虫感染都会使机体的肠道菌群发生紊乱,表现在益生菌丰度减少而有害菌丰度增加。其机制包括引发宿主的炎症反应和抑制机体的免疫细胞两方面。同样肠道菌群也会调控病原菌的感染,如肠道菌群对不同的病毒会产生颉颃或促进作用,对细菌和寄生虫分别产生抑制和促进作用。肠道菌群抑制病原菌的机制包括与病原菌竞争代谢产物和诱导宿主的免疫反应。肠道菌群促进病毒感染的机制包括3点,分别为提高病毒的稳定性及其与靶细胞的黏附作用、抑制机体免疫系统和刺激靶细胞的增殖。肠道菌群促进寄生虫感染的可能机制包括降低Th2细胞因子(如IL-4和IL-13)并提高调节性T细胞的表达频率。肠道菌群、病原微生物和宿主不断相互作用,形成一个动态的平衡关系,并在感染过程中不断进化。作者主要综述了病毒、细菌和寄生虫感染对动物肠道菌群的组成和丰度的影响,动物肠道菌群如何影响病毒、细菌和寄生虫的感染进程并分析相关机制,以期了解疾病的发病机理,为疫苗佐剂的研发及制定更有效的预防和治疗策略提供新视角和理论依据。     

Intestinal microbiota and its interaction to intestinal health in nursery pigs

The intestinal microbiota has gained increased attention from researchers within the swine industry due to its role in promoting intestinal maturation,immune system modulation,and consequently the enhancement of the health and growth performance of the host.This review aimed to provide updated scientific information on the interaction among intestinal microbiota,dietary components,and intestinal health of pigs.The small intestine is a key site to evaluate the interaction of the microbiota,diet,and host because it is the main site for digestion and absorption of nutrients and plays an important role within the immune system.The diet and its associated components such as feed additives are the main factors affecting the microbial composition and is central in stimulating a beneficial population of microbiota.The microbiotaehost interaction modulates the immune system,and,concurrently,the immune system helps to modulate the microbiota composition.The direct interaction between the microbiota and the host is an indication that the mucosa-associated microbiota can be more effective in evaluating its effect on health parameters.It was demonstrated that the mucosa-associated microbiota should be evaluated when analyzing the interaction among diets,microbiota,and health.In addition,supplementation of feed additives aimed to promote the intestinal health of pigs should consider their roles in the modulation of mucosa-associated microbiota as biomarkers to predict the response of growth performance to dietary interventions.     

环境温度对动物肠道微生物菌群影响的研究进展

温度是一个重要的非生物环境变量,能够驱动动物谱系的适应轨迹和动物群落的组成。环境温度作为影响动物肠道微生物菌群变化的众多因素之一,能够影响肠道微生物菌群的组成及丰度,进而调控宿主生长、发育、繁殖、免疫等生物学过程及功能。动物肠道核心菌群的组成及其代谢产物在不同温度下存在显著差异,在单胃动物、反刍动物等中都有相应的报道。极端温度主要通过诱导肠道微生物菌群产生结构和功能上的差异,进而对宿主表型产生影响。目前,对于温度如何影响动物肠道菌群的了解仍非常有限。本文针对不同环境温度条件下,肠道微生物菌群结构和功能的差异及相关研究进行了总结及综述。探讨由环境温度引起的肠道微生物菌群与宿主适应机制之间的关系,包括对宿主产热机制、消化系统和免疫系统等其他方面的影响并开展研究,将为肠道微生物对宿主健康的调节提供参考和思路。     

宏基因组学在哺乳动物肠道微生物中的应用

哺乳动物的肠道内栖息着庞大复杂的微生物群体，其微生物群体与宿主的消化吸收、物质的营养代谢和免疫功能密切相关，是影响机体健康的重要因素之一。随着分子生物学技术在肠道微生物领域的应用，特别是新一代测序技术的快速发展，使得人们对复杂的肠道微生物的研究更加深入。基于宏基因组学技术不仅能够研究肠道微生物组的多样性、揭示消化道微生物对宿主生理代谢的影响，还能进一步深入挖掘新的功能基因，并揭示宿主基因与微生物组间的互作关系和共同进化。作者综述了宏基因组学技术在哺乳动物肠道微生物中的主要应用和存在的不足，并展望了其在肠道微生物研究中的广阔应用前景，从而加深人们对肠道微生物影响宿主肠道健康作用的认识。     

Systemic adjuvant effect of cholera toxin in the chicken.

Cholera toxin (CT) is a well-known mucosal adjuvant in mammals, but it does not give conclusive results in chickens. Cells from the chicken immune system may be insensitive to CT activity. Our results showed that intravenously administered CT had strong immunomodulatory effects on chicken antigen-specific T- and B-cell immune responses. Seven and eight days post-inoculation (p.i.), chickens immunized with KLH and CT exhibited a faster and higher specific proliferative response in the spleen after in vitro restimulation than chickens immunized with KLH alone. At the same time, the specific antibody response in serum was significantly higher, with a strong IgG enhancement and a peak of IgA in chickens immunized with KLH and CT. The anti-KLH splenic antibody response in vitro involved a significant increase in specific IgG and IgA isotypes when CT was used as adjuvant. In conclusion, as in mammals, systemic CT demonstrated strong adjuvant properties in chickens enhancing T-cell priming in vivo and, thus, leading to increased specific antibody production, including IgA.     

Relationship between Mucosal Barrier Function of the Oviduct and Intestine in the Productivity of Laying Hens

The mucosa of the intestine and oviduct of hens are susceptible to pathogens. Pathogenic infections in the mucosal tissues of laying hens lead to worsened health of the host animal, decreased egg production, and bacterial contamination of eggs. Therefore, better understanding of the mechanisms underlying mucosal barrier function is needed to prevent infection by pathogens. In addition, pathogen infection in the mucosal tissue generally causes mucosal inflammation. Recently, it has been shown that inflammation in the oviduct and intestinal tissue caused by disruption of the mucosal barrier function, can affect egg production. Therefore, it is vitla to understand the relationship between mucosal barrier function and egg production to improve poultry egg production. This paper reviews the studies on (1) oviductal mucosal immune function and egg production, (2) intestinal inflammation and egg production, and (3) improvement of mucosal immune function by probiotics. The findings introduced in this review will contribute to the understanding of the mucosal barrier function of the intestine and oviduct and improve poultry egg production in laying hens.     

Interplay between gut microbiota and antimicrobial peptides

The gut microbiota is comprised of a diverse array of microorganisms that interact with immune system and exert crucial roles for the health. Changes in the gut microbiota composition and functionality are associated with multiple diseases. As such, mobilizing a rapid and appropriate antimicrobial response depending on the nature of each stimulus is crucial for maintaining the balance between homeostasis and inflammation in the gut. Major players in this scenario are antimicrobial peptides (AMP), which belong to an ancient defense system found in all organisms and participate in a preservative co-evolution with a complex microbiome. Particularly increasing interactions between AMP and microbiota have been found in the gut. Here, we focus on the mechanisms by which AMP help to maintain a balanced microbiota and advancing our understanding of the circumstances of such balanced interactions between gut microbiota and host AMP. This review aims to provide a comprehensive overview on the interplay of diverse antimicrobial responses with enteric pathogens and the gut microbiota, which should have therapeutic implications for different intestinal disorders.     

Triennial Growth Symposium: a review of science leading to host-targeted antibody strategies for preventing growth depression due to microbial colonization

In this review, the science used to develop host-targeted therapies for improving animal growth and feed efficiency is presented. In contrast to targeting the microbiota of the host, endogenous host proteins are targeted to regulate an overactive inflammatory response in the host. Activation of the immune/inflammatory systems of an animal is costly in terms of growth and feed efficiency. For example, reduced rates of BW gain and poorer feed efficiency in vaccinated animals compared with nonvaccinated animals have been well documented. Also, the growth rate and feed efficiency of animals colonized by microorganisms is only 80 to 90% of their germ-free counterparts. Further evidence of a cost associated with immune activation is that strategies that enhance the immune capability of an animal can reduce animal growth and feed efficiency. Research now indicates that the growth-promoting effects of antibiotics are indirect, and more likely the result of reduced immune activation due to decreased microbial exposure. Studies of mechanisms by which immune/inflammatory activation reduces animal growth and feed efficiency have shown that cytokines of the acute inflammatory response (i.e., IL-1 and tumor necrosis factor α) are key triggers for host muscle wasting. Cytokine-induced muscle wasting is linked to PG signaling pathways, and it has been proposed that regulation of the PG signaling pathways provide host targets for preventing an overreactive or unwarranted inflammatory event. Intestinal secretory phospholipase A(2) (sPLA(2)) has been found to be a useful and accessible (i.e., found in the intestinal lumen) host target for the regulation of an overreactive inflammatory response to conventional environments. This review presents the science and strategy for the regulation of intestinal sPLA(2) using orally administered egg yolk antibody against the enzyme. Clinically healthy animals fed egg antibodies to sPLA(2) had improved growth and feed efficiency. Literature presented indicates that use of host-targeted strategies for regulating the overexpression of inflammatory processes in an animal may provide new mechanisms to improve animal growth and feed efficiency.     

Mutual interaction between gut microbiota and protein/amino acid metabolism for host mucosal immunity and health

In recent years, many studies have shown that the intestinal microflora has various effects that are linked to the critical physiological functions and pathological systems of the host. The intestinal microbial community is widely involved in the metabolism of food components such as protein, which is one of the essential nutrients in diets. Additionally, dietary protein/amino acids have been shown to have had a profound impact on profile and operation of gut microbiota. This review summarizes the current literature on the mutual interaction between intestinal microbiota and protein/amino acid metabolism for host mucosal immunity and health.     

以16S rRNA为基础的检测技术在肠道菌群研究中的应用

肠道微生态菌群是一个非常复杂的微生态系统。胃肠菌群对于宿主的健康和生产成绩非常重要。依赖于以细菌分离培养为主的传统分析方法已经远远不能适应深入研究的需要。近些年围绕16S rRNA发展起来的分子方法在肠道微生态菌群研究中的应用越来越广,本文将就这些方法的应用情况作一简述。     

单胃动物肠道菌群与宿主肠道免疫系统的互作关系及可能机制

单胃动物的肠道中存在着庞大而复杂的菌群,它们与宿主肠道免疫系统协同进化。肠道细菌及其代谢产物在维持肠道稳态方面发挥着重要的作用。正常的肠道菌群能促进免疫系统发育,参与维持宿主免疫功能,协同拮抗病原菌的增殖和入侵。反过来,宿主肠道免疫系统对肠道菌群又有制约和调控作用,如对正常共生菌表现为免疫耐受,对病原菌表现为免疫排斥。一旦这种动态平衡被破坏,就会导致疾病的发生。本文综述了单胃动物肠道菌群与宿主肠道免疫系统的相互关系,并基于现有的研究结果,对其可能的互作机制做了较为系统的总结。     

The postnatal development of the mucosal immune system and mucosal tolerance in domestic animals

The mucosal immune system is exposed to a range of antigens associated with pathogens, to which it must mount active immune responses. However, it is also exposed to a large number of harmless antigens associated with food and with commensal microbial flora, to which expression of active, inflammatory immune responses to these antigens is undesirable. The mucosal immune system must contain machinery capable of evaluating the antigens to which it is exposed and mounting appropriate effector or regulatory responses. Since the immune system is likely to have evolved initially in mucosal tissues, the requirement to prevent damaging allergic responses must be at least as old as the adaptive immune system, and studies of the mechanisms should include a range of non-mammalian species. Despite the importance for rational design of vaccines and for control of allergic reactions, the mechanisms involved are still largely unclear. It is not clear that the classical experimental protocol of "oral tolerance" is, in fact, measuring a biologically important phenomenon, nor is it clear whether tolerance is regulated in the evolutionarily recent organised lymphoid tissue (the lymph nodes) or the more ancient, diffuse architecture in the intestine. The capacity of the immune system to discriminate between "dangerous" and "harmless" antigens appears to develop with age and exposure to microbial flora. Thus, the ability of an individual or a group of animals to correctly regulate mucosal immune responses will depend on age, genetics and on their microbial environment and history. Attempts to manipulate the mucosal immune system towards active immune responses by oral vaccines, or towards oral tolerance, are likely to be confounded by environmentally-induced variability between individuals and between groups of animals.     

The development and role of microbialhost interactions in gut mucosal immune development

At birth the piglet's immune system is immature and it is dependent upon passive maternal protection until weaning.The piglet's mucosal immune system develops over the first few weeks but has not reached maturity at weaning ages which are common on commercial farms. At weaning piglets are presented with a vast and diverse range of microbial and dietary/environmental antigens. Their ability to distinguish between antigens and mount a protective response to potential pathogens and to develop tolerance to dietary antigens is critical to their survival and failure to do so is reflected in the high incidence of morbidity and mortality in the post-weaning period. A growing recognition that the widespread use of antibiotics to control infection during this critical period should be controlled has led to detailed studies of those factors which drive the development of the mucosal immune system, the role of gut microbiota in driving this process, the origin of the bacteria that colonise the young piglet's intestine and the impact of rearing environment. This review briefly describes how the mucosal immune system is equipped to respond "appropriately" to antigenic challenge and the programmed sequence by which it develops. The results of studies on the critical interplay between the host immune system and gut microbiota are discussed along with the effects of rearing environment. By comparing these with results from human studies on the development of allergies in children, an approach to promote an earlier maturation of the piglet immune system to resist the challenges of weaning are outlined.     

Enhancement of mucosal immune responses by intranasal co-delivery of Newcastle disease vaccine plus CpG oligonucleotide in SPF chickens in vivo

Immunostimulatory CpG oligodeoxynucleotides (ODN) have been tested as immunoadjuvants for various vaccines in mice and human. Findings from previous reports suggest that CpG ODN can be used to enhance magnitude and balance of an immune response while reducing undesirable side effects of commercial vaccine, when delivered by parenteral route. Recently, it has been showed that CpG ODN is a promising mucosal adjuvant in mice, but data on mucosal immune responses induced by CpG ODN in other animals, especially in chickens, are scarce. Herein, we evaluated intranasal (IN) delivery of CpG ODN with newcastle disease (ND) vaccine (NDV) to determine its potential as a mucosal adjuvant to a commercial vaccine. CpG ODN augmented systemic (IgG in serum, T cell proliferation) and mucosal (IgA in intestinal washings and feces) immune responses against antigen. CpG ODN stimulated effectively both systemic and mucosal immune responses when delivered intranasally. Results from this study indicate that stimulatory CpG ODN is a potential effective mucosal adjuvant for the NDV in SPF chickens and may be applicable to husbandry animals.     

Enhancement of mucosal immune responses by intranasal co-delivery of Newcastle disease vaccine plus CpG oligonucleotide in SPF chickens in vivo

Immunostimulatory CpG oligodeoxynucleotides (ODN) have been tested as immunoadjuvants for various vaccines in mice and human. Findings from previous reports suggest that CpG ODN can be used to enhance magnitude and balance of an immune response while reducing undesirable side effects of commercial vaccine, when delivered by parenteral route. Recently, it has been showed that CpG ODN is a promising mucosal adjuvant in mice, but data on mucosal immune responses induced by CpG ODN in other animals, especially in chickens, are scarce. Herein, we evaluated intranasal (IN) delivery of CpG ODN with newcastle disease (ND) vaccine (NDV) to determine its potential as a mucosal adjuvant to a commercial vaccine. CpG ODN augmented systemic (IgG in serum, T cell proliferation) and mucosal (IgA in intestinal washings and feces) immune responses against antigen. CpG ODN stimulated effectively both systemic and mucosal immune responses when delivered intranasally. Results from this study indicate that stimulatory CpG ODN is a potential effective mucosal adjuvant for the NDV in SPF chickens and may be applicable to husbandry animals.     

益生菌对硬骨鱼肠道黏膜免疫影响的研究进展

益生菌在健康硬骨鱼肠道中不仅起到抑制致病微生物的作用,而且更重要的是,益生菌能够刺激和增强肠道黏膜免疫系统,在肠道免疫中起重要作用。近年来,硬骨鱼黏膜免疫因其多样性及其不明确的定义,已成为热门的研究课题。硬骨鱼与水生环境直接接触,使肠道黏膜表面易受各种病原体的侵袭。免疫调节是硬骨鱼中有效的预防性措施,而益生菌能够提高肠道黏膜表面固有的免疫活性细胞和因子,对病原体起颉颃作用。益生菌主要通过口服方式进入鱼体,而肠道作为其主要靶器官,对鱼体产生特异性免疫应答。因此,关于益生菌影响肠道黏膜免疫系统的研究值得关注。相比于哺乳动物,硬骨鱼具有更加弥散的肠淋巴系统。局部免疫应答所必需的免疫细胞大量存在于肠道黏膜中,并且可以在免疫后的鱼体肠道中监测到局部免疫应答。文章综述了近年来硬骨鱼肠道黏膜免疫系统以及益生菌对硬骨鱼肠道黏膜免疫的影响,并对鱼类益生菌的进一步研究进行了展望,以期为后续研究益生菌与硬骨鱼之间相互作用提供参考。     

The immunologists' debt to the chicken

The immune system of the chicken is an invaluable model for studying basic immunology and has made seminal contributions to fundamental immunological principles. Graft versus host responses and the key role of lymphocytes in adaptive immunity were first described in work with chicken embryos and chickens. 2. Most notably, the bursa of Fabricius provided the first substantive evidence that there are two major lineages of lymphocytes. Bursa-derived lymphocytes, or B cells, make antibodies while thymus-derived, or T cells, are involved in cell-mediated immune responses. 3. Gene conversion, the mechanism used by the chicken to produce its antibody repertoire, was first described in the chicken and requires the unique environment of the bursa. Subsequently it has been shown that some mammals also use gene conversion. 4. The chicken's Major Histocompatibility Complex (MHC), the first non-mammalian MHC to be sequenced, is minimal, compact and some 20-fold smaller than that of mammals. Uniquely, the chicken MHC is strongly associated with resistance to infectious diseases. 5. The first attenuated vaccine was developed by Louis Pasteur against a chicken pathogen, fowl cholera, and the first vaccine against a natural occurring cancer agent, Marek's disease virus, was developed for the chicken. 6. Vaccination of chick embryos on the 18th d of incubation, another breakthrough using chickens, provides protection early after hatching. In ovo vaccination now is widely practised by the poultry industry. 7. Evidence that widespread and intensive vaccination can lead to increased virulence with some pathogens, such as Marek's disease virus and infectious bursal disease virus, was first described with chicken populations. It warns of the need to develop mo resustainable vaccination strategies in future and provides useful lessons for other species, including in the human population. 8. Recombinant DNA technologies now provide the opportunity for the rational design of new vaccines. Such vaccines could contain the protective immunogenic elements from several pathogens and immunomodulatory molecules to direct and enhance immune responses so providing improved protection. The important thing will be to design vaccines that are sustainable and do not drive pathogens to ever-increasing virulence.