Recent Advances in Understanding the Influence of Zinc, Copper, and Manganese on the Gastrointestinal Environment of Pigs and Poultry.

Zinc, copper, and manganese are prominent essential trace (or micro) minerals, being required in small, but adequate, amounts by pigs and poultry for normal biological functioning. Feed is a source of trace minerals for pigs and poultry but variable bioavailability in typical feed ingredients means that supplementation with low-cost oxides and sulphates has become common practice. Such trace mineral supplementation often provides significant 'safety margins', while copper and zinc have been supplemented at supra-nutritional (or pharmacological) levels to improve health and/or growth performance. Regulatory mechanisms ensure that much of this oversupply is excreted by the host into the environment, which can be toxic to plants and microorganisms or promote antimicrobial resistance in microbes, and thus supplying trace minerals more precisely to pigs and poultry is necessary. The gastrointestinal tract is thus central to the maintenance of trace mineral homeostasis and the provision of supra-nutritional or pharmacological levels is associated with modification of the gut environment, such as the microbiome. This review, therefore, considers recent advances in understanding the influence of zinc, copper, and manganese on the gastrointestinal environment of pigs and poultry, including more novel, alternative sources seeking to maintain supra-nutritional benefits with minimal environmental impact.

Host⁻Microbe Interactions and Gut Health in Poultry-Focus on Innate Responses.

Commercial poultry are continually exposed to, frequently pathogenic, microorganisms, usually via mucosal surfaces such as the intestinal mucosa. Thus, understanding host-microbe interactions is vital. Many of these microorganisms may have no or limited contact with the host, while most of those interacting more meaningfully with the host will be dealt with by the innate immune response. Fundamentally, poultry have evolved to have immune responses that are generally appropriate and adequate for their acquired microbiomes, although this is challenged by commercial production practices. Innate immune cells and their functions, encompassing inflammatory responses, create the context for neutralising the stimulus and initiating resolution. Dysregulated inflammatory responses can be detrimental but, being a highly conserved biological process, inflammation is critical for host defence. Heterogeneity and functional plasticity of innate immune cells is underappreciated and offers the potential for (gut) health interventions, perhaps including exogenous opportunities to influence immune cell metabolism and thus function. New approaches could focus on identifying and enhancing decisive but less harmful immune processes, improving the efficiency of innate immune cells (e.g., targeted, efficient microbial killing) and promoting phenotypes that drive resolution of inflammation. Breeding strategies and suitable exogenous interventions offer potential solutions to enhance poultry gut health, performance and welfare.

Deciphering desirable immune responses from disease models with resistant and susceptible chickens.

Coccidiosis and necrotic enteritis (NE) are among the most significant diseases affecting the poultry industry. These diseases have become more prominent in the wake of policies to reduce the use of antibiotics in animal production. This has led to more research focused on better understanding the immune system and its responses to pathogen challenge, and thus developing informed strategies to exploit immune responses that can support enhanced disease resistance and growth performance. Some chicken breeds and lines show greater resistance or susceptibility to various diseases, and thus these birds maybe able to shed light on immune processes or pathways that contribute to the more resistant/susceptible state. This review attempts to identify potentially important genes that show some consistency in (relative) up or downregulation in key tissues between the resistant and susceptible chickens. For coccidiosis and NE, relative downregulation of IL-10 and (slightly less consistently) upregulation of IFN-γ appear to be features of more resistant birds. Data for IFN-α, IL-12, and IL-17D are currently less consistent. Gene expression data from NE studies have identified some potentially interesting, perhaps less well understood, immune-related genes (e.g., TCF12, BCL2, IRF2, TRAF3, TAB3, etc.,) that maybe associated with the resistant and/or susceptible phenotype. Salmonella and Campylobacter are important foodborne pathogens harbored by the chicken intestinal tract, while infectious bursal disease and infectious bronchitis are also important viral diseases of poultry. We, therefore, consider whether there are consistent features from resistant/susceptible disease models with these pathogens that relate to findings from the coccidiosis and NE studies. It is not anticipated that ideal immune responses to these pathogens will be identical but rather that consistent elements maybe identified that could help inform breeding or alternative strategies to support general disease resistance and enhanced (and efficient) flock productivity.

Gut immunity: its development and reasons and opportunities for modulation in monogastric production animals.

The intestine performs the critical roles of nutrient acquisition, tolerance of innocuous and beneficial microorganisms, while retaining the ability to respond appropriately to undesirable microbes or microbial products and preventing their translocation to more sterile body compartments. Various components contribute to antimicrobial defenses in the intestine. The mucus layer(s), antimicrobial peptides and IgA provide the first line of defense, and seek to trap and facilitate the removal of invading microbes. If breached, invading microbes next encounter a single layer of epithelial cells and, below this, the lamina propria with its associated immune cells. The gut immune system has developmental stages, and studies from different species demonstrate that innate capability develops earlier than acquired. In addition, various factors may influence the developmental process; for example, the composition and activity of the gut microbiota, antimicrobials, maternally derived antibodies, host genetics, and various stressors (e.g. feed deprivation). Therefore, it is clear that particularly younger (meat-producing) animals are reliant on innate immune responses (as well as passive immunity) for a considerable period of their productive life, and thus focusing on modulating appropriate innate responses should be an intervention priority. The gut microbiota is probably the most influential factor for immune development and capability. Interventions (e.g. probiotics, prebiotics, antibodies, etc.) that appropriately modulate the composition or activity of the intestinal microbiota can play an important role in shaping the desired functionality of the innate (and acquired) response. In addition, innate immune mediators, such as toll-like receptor agonists, cytokines, etc., may provide more specific ways to suitably modulate the response. A better understanding of mucosal immunology, signaling pathways, and processes, etc., will provide even more precise methods in the future to boost innate immune capability and minimize any associated (e.g. nutrient) costs. This will provide the livestock industry with more effective options to promote robust and efficient productivity.

Gut barrier function: Effects of (antibiotic) growth promoters on key barrier components and associations with growth performance.

The gut barrier, comprising the microbiota and their products, mucus layers, host-derived antimicrobial compounds [e.g., host defense peptides (HDP), IgA], epithelium, and underlying immune tissues, performs the essential function of preventing the passage of harmful microorganisms and substances into the body, while enabling the acquisition of dietary nutrients. Antibiotic growth promoters (AGP) are widely accepted as the "gold standard" of performance-enhancing feed additives, which had become integral and valuable components of modern, efficient animal production, but are now being phased out in many parts of the world. This review, therefore, examines the reported effects of AGP on the key components of gut barrier function, particularly where corresponding (positive) growth performance data were provided to indicate that any changes were beneficial, and some important trends do emerge. Certain bacterial families (e.g., Lachnospiraceae), genera (e.g., Faecalibacterium, Propionibacterium, and Ruminococcus), or species (e.g., F. prausnitzii, B. fragilis, and some Lactobacillus spp.) have been reported to increase with AGP use, are associated with improved growth performance, and show benefit across species, which may be related to their production of short-chain fatty acids (SCFA). Various studies have investigated the effects of AGP on mucus-related parameters (e.g., goblet cell size, density, and mucin mRNA expression) but these do not always seem to correlate well with the actual physical characteristics of the mucus layer(s). Surprisingly, there are little data relating to HDP or IgA, even though they have recognized benefits. There are clear AGP benefits on epithelial structure and function (e.g., nutrient digestibility), and these may (currently) provide the most reliable indicators of the efficacy of growth promoters. Data investigating effects on gut immune parameters (e.g., cell populations, cytokines, and chemokines), with corresponding growth performance, are limited and require further detailed interrogation. This review highlights both important observations related to the effects of AGP on key gut barrier components, with associated growth performance, and areas that require further investigation, thus providing an informative basis for assessing the potential of AGP alternatives.

The role of the gut microbiome in shaping the immune system of chickens.

Most animals are colonised by at least as many microbial cells as somatic cells, potentially comprising at least 100 times more genes within just the gut microbiota than the host itself. It is, therefore, evident that such a conglomeration can have a profound effect on various bodily systems, particularly the (gut) immune system. Chickens are major providers of efficiently produced protein for humans but also harbour common foodborne pathogens and are susceptible to significant and costly diseases, making a thorough understanding of the influence of the gut microbiome on the immune system very pertinent. Major colonisation of the chicken intestine occurs after hatch and this, along with subsequent microbiota composition and activity, are influenced by numerous host and environmental factors, such that each individual has a unique microbiome signature. However, both extreme (e.g. germ free) and more subtle (e.g. diet changes) microbiome modifications can profoundly impact the development of the gut immune system, particularly adaptive immune apparatus and function. This review will consider the influence of the chicken gut microbiome on immune system development, the implications of this relationship in terms of disease susceptibility, vaccine response, optimal health and productivity, and thus exogenous approaches to positively shape microbiome-immune system interactions.

Inflammation: friend or foe for animal production?

Inflammation is an essential immune response that seeks to contain microbial infection and repair damaged tissue. Increased pro-inflammatory mediators have been associated with enhanced resistance to a range of important poultry and pig pathogens. However, inflammation may also have undesirable consequences, including potentially exacerbating tissue damage and diverting nutrients away from productive purposes. The negative effects of inflammation have led to the active pursuit of anti-inflammatory feed additives and/or strategies. These approaches may, however, impair the ability of an animal to respond appropriately and effectively to the array of pathogens that are likely to be encountered in commercial production, and specifically young animals who may be particularly reliant on innate immune responses. Thus, promoting an animal's capacity to mount a rapid, acute inflammatory response to control and contain the infection and the timely transition to anti-inflammatory, tissue repair processes, and a homeostatic state are suggested as the optimum scenario to maintain an animal's resistance to pathogens and minimize non-productive nutrient losses. Important future studies will help to unravel the trade-offs, and relevant metabolic pathways, between robust immune defense and optimum productive performance, and thus provide real insight into methods to appropriately influence this relationship.

The sub-inhibitory theory for antibiotic growth promoters.

Antibiotics have played a critical role in the prevention, control, and treatment of bacterial diseases in humans and animals, and as growth promoters (AGPs) when used at sub-therapeutic concentrations in animal production. Numerous hypotheses have been proposed for the effectiveness of AGPs, which have largely centered on the beneficial modulation of the intestinal microbiota. However, these hypotheses have been doubted by some researchers, as AGPs are fed at concentrations that would typically be below minimum inhibitory concentrations (sub-MIC) for the antibiotic used. More recently, pro-inflammatory immune responses have been associated with poor growth performance, and this, along with reported direct, anti-inflammatory effects of some antibiotics, have led to suggestions that reducing the nutrient cost of (intestinal) inflammation may explain the growth promoting or permitting effect of AGPs. However, doubts about antibacterial effects of AGPs, and the search for alternative explanations, overlook the sub-MIC effects of antibiotics. This paper summarizes some of the reported sub-MIC effects of antibiotics and considers these in the context of helping to explain the mode of action of AGPs and effects seen in studies in vivo. This leads to suggestions for the features that alternatives to AGPs could exhibit to achieve similar performance efficacy as AGPs.