Recent gut health-related research
- This preprint analysis of metabolic pathways within the human gut microbiome suggests that some genera (e.g. Akkermansia, Faecalibacterium) use limited, highly conserved pathways, while others (e.g. Clostridium) seem more versatile, such that closely related strains may have distinct metabolic and functional differences. Certain Firmicutes and Fusobacteria are responsible for butyrate production, while propionate production is predominantly restricted to Bacteroidetes, and pathways that generate acetate appear less taxonomically restricted. It was interesting, but perhaps not surprising, that metabolic pathways did not correlate with plasma metabolite levels. Such functional and metabolic studies help unravel the complexity of the gut microbiome and indicate opportunities to shape the gut environment. Andreu et al., 2021, biorxiv www.biorxiv.org/content/10.1101/2021.02.25.432841v1
- Chicken growing feathers (GF) provide minimally invasive insights into local immune responses. Local immune responses involve complex dynamics involving changes in vasculature, cellular activity and signalling pathways, which differ from those observed systemically (blood). Moreover, growing feathers can be temporally sampled from the same individual and are relatively non-invasive to collect. In addition, coupled with systemic sampling, it is possible to evaluate changes in the systemic immune compartment (or elsewhere) with those occurring in GF. It is proposed that GF sampling enables the immunomodulatory potential of exogenous interventions to be assessed. French et al., 2020, Poultry Science doi.org/10.1016/j.psj.2020.09.078
Re-thinking the inflammatory potential of the gut microbiome? Did you know that not all lipopolysaccharides (LPS) induce inflammatory responses? Some LPS isoforms inhibit Toll-like receptor 4 (TLR4) signaling. The outcomes from this study suggest that, collectively, the 'healthy' human gut microbiome actively represses TLR4 signalling. Members of the order Bacteroidales were identified as key producers of antagonistic forms of LPS. Interestingly, in related work, it was reported that inhibition of TLR4 signalling may impair immune education (Vatanen et al., 2016). These results (particularly if transferable to other species) are valuable findings and may require reassessment of the gut microbiome's contribution to immune education and tolerance. d'Hennezel et al., 2017, mSystems msystems.asm.org/content/2/6/e00046-17 - Host defense peptides (HDP) are interesting molecules, considered key components of innate immune responses. Although reported to have broad antimicrobial activity, physiological conditions in-vivo are suggested to blunt these effects and thus other attributes (e.g. immunomodulation) are increasingly recognised as important. Cathelicidin (CATH) B1 is the least studied of the 4 chicken CATHs but this study indicates that CATH-B1 is an important chicken macrophage HDP that (at least partly) modulates immune cell responses via toll like receptor ligand binding. Peng et al., 2020, Veterinary Science veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-020-00849-y
- Feed delay and intestinal development. Broiler chickens often experience a delay between hatch and access to feed and water. This may affect intestinal development, integrity and growth performance. In this recent study, delayed access decreased ileal villus width, modified expression of tight junction proteins, and reduced body weight (to 14 days of age), although intestinal permeability (IP) was not measurably altered. The discussion also outlines some thoughtful comments on the use of fluorescein isothiocyanate-dextran methodologies to assess IP in chickens. Hollemans et al., 2020, Poultry Science doi.org/10.1016/j.psj.2020.08.079
Cost of coccidiosis? Updated calculation for the cost of coccidiosis in chickens, estimating a global cost of around £10.4 billion (at 2016 prices) or 16p per chicken produced. The wider use of live anticoccidial vaccines was the most significant addition to the earlier Dr R B Williams model. There are obviously various data and assumptions included in the model, which might be useful. Blake et al., 2020, Veterinary Research doi.org/10.1186/s13567-020-00837-2 - Where to start with gut health? There is often a push or desire to add 'something' to the diet to promote gut health and recent discussions were a reminder of the potentially overwhelming choice of additives and information available. However, as diet is a primary influencer of host-microbiome interactions, if the basal diet is not appropriate, the value of the additive(s) used is likely to be sub-optimal. Therefore, the basal diet should be suitably formulated and manufactured with quality ingredients to seek to meet nutritional requirements under relevant conditions (e.g. no AGPs, heat stress, etc.). Moreover, while appreciating the impact of anti-nutrients, the diet can be considered a rich source of potentially 'pro'-nutrients. For example, oligosaccharides derived from the enzymatic hydrolysis of cereal polysaccharides can be important contributors to gut health and function, even at relatively low levels. A recent article provided a helpful review of the role of poly and oligosaccharides in monogastric gut health. Tiwari et al., 2020, Journal of Nutritonal Science doi.org/10.1017/jns.2020.14
- Detailed investigation of intestinal barrier function, specifically epithelial tight junctions (TJs), using high-throughput screening. Various host- and microbiota-derived molecules disrupted the integrity of TJs. Numerous TJ stabilisers were effective against diverse disruptors, suggesting central regulatory mechanisms/pathway(s). Co-treatment with faecal extracts from healthy mice were able to protect against TJ disruption. Taurine was identified as particularly interesting for TJ stabilisation. Grosheva et al., 2020, Gastroenterology www.sciencedirect.com/science/article/pii/S0016508520349210
- Infectious bursal disease virus (IBDV) and antiviral responses. This is an interesting study. Some previous work has indicated that very virulent (vv) strains of IBDV may cause increased, perhaps less well controlled, inflammatory responses leading to increased pathology (see doi.org/10.3382/ps/pey535), but this study reported that a vvIBDV strain down-regulated type I IFN and pro-inflammatory cytokine responses more than a classical strain, both in-vitro (chicken cell lines) and in-vivo (bursa), thus potentially giving it an advantage. Of course, only 2 strains were compared but insightful nonetheless. Dulwich et al., 2020, Frontiers in Cellular and Infection Microbiology www.frontiersin.org/articles/10.3389/fcimhttps://www.frontiersin.org/articles/10.3389/fcimb.2020.00315/fullb.2020.00315/full
- How important is IgA? IgA's abundance indicates its importance in host (mucosal) defence but deficiency has relatively mild consequences. T cell help produces affinity matured IgA but secretory IgA with microbiota-binding capacity can be generated without T cells. T cells are considered critical for full SIgA capability but T cell-independent responses are probably important early in a response and/or at an early age. T cell-dependent IgA seems to be targeted towards microbiota members with greater invasive and/or inflammatory potential. Pabst and Slack, 2020, Mucosal Immunology www.nature.com/articles/s41385-019-0227-4#citeas
- Host-microbiome interactions - the effects of an intervention cease (soon) after it's stopped? This can be a common belief but increasing evidence suggests otherwise. The impact likely depends on the nature of the intervention, duration of application, timing during host development, etc. Antibiotics are one of the best studied and it has been shown that even after ceasing administration, antibiotics have longer-term effects on the microbiome. Even where lasting microbiome modification is not detected, perhaps influenced by depth of interrogation, host responses could be, which likely shapes altered host-microbiome interactions. It might be that in some circumstances, these effects become lost in the noise of, or overpowered by, various environmental factors post the intervention. For example, https://mbio.asm.org/content/10/6/e02820-19 (mice); https://doi.org/10.1371/journal.pone.0116523 (pigs); doi.org/10.3382/ps/pew088 (chickens)
- How do parasites recognise their targets? The latest review (doi.org/10.3389/fvets.2020.00384) on Eimeria-host interactions in poultry was a reminder of our limited understanding of the underlying mechanisms of host and tissue tropisms. A recent paper discovered a critical role for intestinal delta-6-desaturase in host specificity (cats) for Toxoplasma gondii sexual reproduction, a related parasite. Thus, lipid metabolism and local composition could be significant factors influencing these tropisms. Di Genova et al., 2019. PLOS Biology doi.org/10.1371/journal.pbio.3000364
- Bile acid (BA) metabolism by gut microbes is associated with resistance to some enteric diseases through direct effects on pathogens and through immunomodulation (https://www.cell.com/cell/fulltext/S0092-8674(20)30628-0). Recently, in chickens, supplementation with a secondary BA reduced Clostridium perfringens luminal colonisation, ileal inflammation, bodyweight gain loss and helped maintain total ileal bile acid levels (https://jasbsci.biomedcentral.com/articles/10.1186/s40104-020-00441-6). In another recent pilot study, bile salt hydrolase (BSH) (deconjugate conjugated BAs & first step in subsequent microbial biotransformations) inhibition in chickens increased ileal conjugated BAs, reduced secondary BAs, with (numerical!) improvements in growth performance. Antibiotic growth promoter use has been linked with reduced BSH activity and improved fat digestion, absorption and metabolism (https://www.nature.com/articles/s41598-020-61723-7). Taken together, these studies point towards optimum intestinal BA profiles, probably dependent on specific conditions, to support disease resistance and/or growth performance. Theriot and Petri, 2020. Cell www.cell.com/cell/fulltext/S0092-8674(20)30628-0
- IL-17A: a gut health marker in chickens? Galacto-oligosaccharides associated with increased caecal Lactobacillus johnsonii, upregulated 'pro-inflammatory' IL-17A and downregulated 'anti-inflammatory' IL-10 in early-life, and improved growth performance of chickens. These results suggest that a 'proinflammatory' bias can benefit bird performance, perhaps through accelerated/enhanced intestinal immune system development and priming. IL-17A has previously been identified as important for barrier function, intestinal homeostasis and pathogen defence. Richards et al., 2020, MSystems https://doi.org/10.1128/mSystems.00827-19
- Intestinal epithelial cell (IEC) lineages are typically considered to have distinct functions. Some of these subsets (e.g. Paneth cells) have not been clearly defined in some species (e.g. pigs & poultry) though. This very interesting work indicates that IEC distribution and immune-related functions are less discrete in chickens than the traditional view. For example, in addition to mucin secretion, chicken goblet cells may store IgA and be the major location for avidin, lysozyme and secretory component. Bar Shira & Friedman, 2018, PLOS One https://doi.org/10.1371/journal.pone.0200393
- Where are we in understanding host-microbe interactions? This recent review helps to outline the current state of host(immune)-microbe research. Main points are:
- CURRENT: 1) Variable community composition across individuals, but seemingly similar functional potential; 2) Much data to date not resolved to strain level; 3) Microbes from one species may poorly colonise another; 4) Germ-free animals have immune defects, which can be (at least partly) reconstituted by administration of single or multiple microbe preparations; 5) Phenotype likely dependent on complex interactions between microbes present, including less well studied viruses, protozoa, etc.; 6) Microbial exposure necessary during key time-windows of host development; 7) Microbial metabolites shown to mediate many effects; 8) Specific microbes may be beneficial or detrimental depending on host factors and context.
- FUTURE: 1) Need to focus more on causality rather than correlations; 2) More culturing alongside omics technologies to clarify microbe phenotypes; 3) More focus on non-bacterial microbiota members; 4) Need to identify key microbes, interactions & metabolites shaping desired phenotypes. Ahern & Maloy, 2019, Immunology https://doi.org/10.1111/imm.13150
- Should probiotics colonise? There are limited studies that have definitively looked at the intestinal colonisation ability of probiotic strains and their influence on the gut mucosa and indigenous microbiome, in part due to challenges resolving beyond the genus level in previous work. Professor Elinav’s lab looked at these aspects in humans and mice. They found that:
- Individuals can be categorised as probiotic ‘resisters’ or ‘permissive’ based on gut mucosa colonisation, probably inversely mediated by phylogenetically-related indigenous bacteria or functional need.
- The extent to which probiotics affected the microbiome (and host) was associated with their colonisation capacity.
- Interestingly, enhanced colonisation by probiotics after antibiotic administration may actually inhibit restoration of the indigenous microbiome, which could have health implications. Suez et al., 2019, Gut Microbes doi.org/10.1080/19490976.2019.1586039
- Good example for microbiome work? Daily (caecal) sampling, good replication and thorough explanation of the microbiome analyses performed. The authors confirmed some previous observations in broiler chickens, in that microbiome diversity rapidly increases to day 12 and stabilises from day 20, with competitive drivers suggested to be superseded by host factors. This shift in influence corresponds with significant changes in metabolic pathways and the appearance of Campylobacter. Such studies will only help improve our understanding. Ijaz et al., 2018, Frontiers in Microbiology doi.org/10.3389/fmicb.2018.02452
- Gut microbiome modulation to support respiratory health. The 'gut-lung axis' is emerging as another exciting gut-related 'axis'. The intestinal microbiome, notably absorbed short-chain fatty acids (SCFAs), are reported to influence the bone marrow environment, types of immune cells generated and thus help shape immune responses in the lung (and other sites). Dang and Marsland, 2019; Mucosal Immunology doi.org/10.1038/s41385-019-0160-6
- Trace minerals and gut health. Animals require minerals, normally in low amounts, but higher levels of supplementation (e.g. "pharmacological") have been established to enhance intestinal health and growth performance (e.g. copper and zinc). Such practices are under review, particularly in the EU, thus making this review of trace minerals and monogastric gut health very timely. Shannon and Hill, 2019; Frontiers in Veterinary Science doi.org/10.3389/fvets.2019.00073
- "Nutrient-niche" and "founder" hypotheses. The "nutrient-niche" and "founder" hypotheses propose that random effects determine the initial exposure of neonates to microbes, which then occupy specific nutrient niches within a particular site (e.g. intestine) and lead to taxonomic variation between individuals. These founding microbial occupant(s) have priority access to growth-limiting resources, and thus a competitive advantage, and so can exert colonisation resistance against other suitable microbial candidates for the same nutrient-niche. Mucosal pathogens seek to use their virulence factors to alter the local environment and create a nutrient-niche for themselves. Litvak and Bäumler, 2019; PLoS Pathogens 15(2): e1007563, doi.org/10.1371/journal.ppat.1007563
- Nutritional modulation of immune function. Good review of the effects of vitamins D and E, zinc and n-3 polyunsaturated fatty acids (as well as probiotics and epigallocatechin-3-gallate) on immune function, particularly Figure 1. It is increasingly recognised that optimal levels of these key nutrients, potentially above current recommendations, contribute to disease resistance and immune homeostasis. Many have, or will be, reviewing their provision of these nutrients, particularly when striving to reduce inappropriate use of antibiotics. Wu et al., 2019; Frontiers in Immunology doi.org/10.3389/fimmu.2018.03160
- Could pentraxin 3 be an important biomarker for inflammatory states in chickens? Burkhardt et al. (2019) report that pentraxin 3 is constitutively expressed in various tissues (not spleen) and is significantly up-regulated within hours following inflammatory stimuli, including bacterial and viral pathogens, in the spleen and bursa. Moreover, the up-regulation of pentraxin 3 in the spleen was dependent on the dose of avian pathogenic E. coli administered in sub-clinically infected chickens. Burkhardt et al., 2019; Frontiers in Immunology doi.org/10.3389/fimmu.2019.00124
- Interested in probiotics and immune responses? This article uses up-to-date data from different species, but with a focus on ruminants, to explore the establishment of the gut microbiota, effects on mucosal immune function, impact of feeding strategies and the influence of probiotics. There is still work to do to consistently exploit the benefits of probiotics but our understanding is continually improving. Raabis et al., 2018; Veterinary Immunology & Immunopathology doi.org/10.1016/j.vetimm.2018.12.006
- Understanding dysbiosis. Dysbiosis is often loosely defined as an imbalance in a microbial community that arises from direct (e.g. antibiotic) and/or indirect (e.g. host failure to control microbial community) disruption, which causes some degree of ill health. In this recent review, Byndloss et al. discuss our current understanding of host control over the (human) gastrointestinal microbiome. Various mechanisms, including secretion of antimicrobial peptides by Paneth cells, help the host to manage microbial populations in the small intestine and minimise competition for nutrients, while limiting oxygen availability in the hindgut supports an obligate anaerobic bacterial community and fermentation of complex carbohydrates to beneficial short-chain fatty acids. Colonocyte utilisation of butyrate through β-oxidation consumes oxygen and helps maintain the hypoxic state of the epithelial surface. Changes in intestinal conditions (such as epithelial repair) shifts colonocyte energy metabolism towards anaerobic glycolysis, thus increasing oxygen availability in the epithelium and intestinal lumen and resulting in dysbiosis and the characteristic shift from obligate to facultative anaerobes. These insights highlight the importance of epithelial cell types in controlling the gut microbiome and offer opportunities for interventions, some of which may have already been unknowingly utilised. Byndloss et al., 2018; Mucosal Immunology doi.org/10.1038/s41385-018-0010-y
- 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. This review attempts to identify potentially important genes that show some consistency in (relative) up or downregulation in key tissues between resistant and susceptible chickens. 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. Broom and Kogut, 2018; Poultry Science doi.org/10.3382/ps/pey535
- Necrotic enteritis and the intestinal microbiota. Necrotic enteritis is estimated to be one of the costliest diseases for the global poultry industry, although the precise aetiology remains unclear. Certain strains of Clostridium perfringens are, however, recognised as the causative agent. In a recent study, Lacey et al. (2018) reported that, under their experimental conditions, the pre-challenge faecal microbiota composition did not influence disease outcomes, but pathogenic C. perfringens challenge did affect the caecal and faecal microbiotas, notably displacing commensal clostridia. Further work will thus need to clarify the relationship between the faecal microbiota and lesion-causing dynamics in the small intestine, whether even subtle differences in the pre-challenge (faecal) microbiota are important for disease progression and help identify the factors responsible for differences in disease outcomes (diseased vs. remaining healthy) and microbiota changes. Lacey et al., 2018; Veterinary Microbiology doi.org/10.1016/j.vetmic.2018.10.022
- Investigating the physiological effects of short-chain fatty acids (SCFA). High viscosity of gut contents, existence of bacterial biofilm and a mucus layer at the mucosal surface, and rapid absorption of SCFAs make it difficult to know their concentrations at the very surface of the mucosa. As lumen or faecal concentration of SCFAs does not reflect their rate of production, these parameters should not be used as measures of SCFA production or absorption. Effects of SCFA can vary and even become opposite at different doses, time of/after exposure or time of the day. Thus, results without dose–response, time‐course, and diurnal variance experiments can be misleading. It is also suggested that too much emphasis on n‐butyrate should be avoided. Sakata, 2018; Animal Science Journal onlinelibrary.wiley.com/doi/10.1111/asj.13118
- Immunosuppression, rather than uncontrolled inflammatory processes, leads to chronic inflammation/diseases? Challenging existing dogmas. Two recent papers challenge existing beliefs regarding inflammation-related disorders. Ulcerative colitis is characterised by inflammation of the colonic mucosa and management attempts generally focus on immunosuppressive therapies, but most patients still show disease progression. In recent work, Sham et al. (2018) revealed that activating, rather than suppressing, mucosal immune function through inactivated pathogenic E. coli administration reduced mucosal pathology and improved clinical symptoms. Similarly, fibrosis, cancer and autoimmunity, arising from particle exposure, have been linked with uncontrolled inflammation but a growing number of studies report that exaggerated and persistent immunosuppression reduces immune surveillance of tumour cells and microorganisms (Huaux, 2018). These findings encourage review of existing paradigms and objective consideration of less orthodox strategies. Sham et al., 2018; Frontiers in Immunology doi.org/10.3389/fimmu.2018.02211; Huaux, 2018; Frontiers in Immunology www.frontiersin.org/articles/10.3389/fimmu.2018.02364/abstract
- Variable probiotic responses? While probiotic definitions normally refer to viable microbes, non-viable microorganisms have been reported to adhere to the intestinal mucus and have effects, although the method used to make non-viable might be relevant. Non-viable microorganisms may thus be able to interact with host cells and modulate functions, but some ‘probiotic mechanisms’, such as in-situ SCFA and antimicrobial compound production, as well as prolonged colonisation, would be features of viable microbes. In a recent study, it was reported that the existing or native gut mucosal microbiome can exert colonisation resistance to an orally administered, viable, multi-strain probiotic, which in humans was person-, region- and strain-specific. The implications are that an individual’s microbiome determines the degree of permissibility or resistance to mucosal probiotic colonisation, which would influence efficacy and thus contribute to variable probiotic responses. Moreover, as expected, gut mucosal microbe composition and function only partially correlated with the faecal microbiome and thus the presence/abundance of probiotic strain(s) in the faeces does not discriminate between permissive and resistant individuals and/or indicate efficacy. Human developments are/will move towards personalised probiotics according to an individual’s microbiota composition and function, but this will clearly be more challenging to apply in most animal production scenarios. Zmora et al., 2018; Cell: www.cell.com/cell/fulltext/S0092-8674(18)31102-4
- IL-10: friend or foe depending on the nature of pathogenic bacteria. IL-10 is a key immunoregulatory cytokine with anti-inflammatory functions. Generally, IL-10 is considered to facilitate the persistence and dissemination of intracellular or inflammation modulating bacterial infections, whereas it helps reduce tissue damage and promote host survival during extracellular or highly inflammatory bacterial infections. It is reported that the model holds true for multi-drug resistant bacterial strains (even though their virulence is often different from drug susceptible strains) and evidence suggests it extends to other types of pathogen (e.g. Eimeria), and should help inform our immunomodulation or therapeutic strategies. Peñaloza et al., 2018; Frontiers in Microbiology: doi.org/10.3389/fmicb.2018.02047
- 2nd International Symposium on Alternatives to Antibiotics. A collection of useful articles considering recent developments aimed at reducing the use of antibiotics in animal production. These articles principally focus on vaccines, phytochemicals, immunoglobulins, host defense peptides, microbial-derived products, enzymes, chemicals and some other innovative drugs. A common theme associated with alternative strategies to antibiotics is modulation and/or enhancement of the host's immune capability and there is growing interest in innate mechanisms, which provide the initial response to microbial challenge and have recently been demonstrated to exhibit adaptive and memory features (Netea et al., 2016). Gay et al., 2018; Veterinary Research www.biomedcentral.com/collections/alternatives-to-antibiotics
- Cellular effects of phytogenics and AGP. Study investigating the effect of select phytogenic additives and a macrolide antibiotic (tylosin) on indicators of oxidative and inflammatory status of porcine intestinal epithelial cells. A complex phytogenic mix, liquorice, oregano and grape seed all reduced cellular reactive oxygen species (ROS) following hydrogen peroxide stimulation. Phytogenic mix and oregano inhibited the expression of IL-6, CXCL8 and CCL2 after TNF-α stimulation. Interestingly, given the proposed direct anti-inflammatory effects of AGPs, tylosin did not affect inflammatory markers under the study conditions (for thoughts on AGP effects – The sub-inhibitory theory for antibiotic growth promoters, Poultry Science, 96: 3104-3108). Kaschubek et al., 2018, Journal of Animal Science academic.oup.com/jas/advance-article/doi/10.1093/jas/sky263/5049610
- Could faecal ovotransferrin be used as a marker for intestinal damage? Ovotransferrin is an acute phase protein produced by the liver (and oviduct) in chickens in response to proinflammatory cytokines. Ovotransferrin is principally an iron-binding protein, which explains at least part of its antimicrobial activity through deprivation of iron for microbial growth. In addition, ovotransferrin has also been reported to have more direct effects on bacteria, immune cell responses and tissue repair. In a recent study, positive correlations between faecal ovotransferrin concentrations and coccidiosis or necrotic enteritis severity (based on intestinal lesion scoring) were reported. One concern, however, is that ovotransferrin appears to be rapidly degraded by faecal proteases, which must considered/counteracted for any future application. Goossens et al., 2018, Veterinary Research veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-018-0548-4#Sec8
- Biomarkers for monitoring intestinal health in poultry: present status and future perspectives. There remains a fundamental need to better understand/define 'intestinal heath'. In conjunction, establishing biological indicators (biomarkers) that accurately relate to intestinal health status would be of great value to the industry. Such biomarkers would ideally be as non-invasive as possible, simple to analyse (on farm) and be sufficiently sensitive to detect early changes to gut health status. This review considers some of the most interesting current and future biomarkers for assessing intestinal health of poultry. As the authors suggest, current and future studies will generate novel biomarkers (that will need validation) and will contribute to the development of algorithms, with technologies eventually enabling real-time monitoring on farm. Ducatelle et al., 2018, Veterinary Research veterinaryresearch.biomedcentral.com/articles/10.1186/s13567-018-0538-6
- 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/beneficial microorganisms, whilst retaining the ability to respond appropriately to undesirable microbes or microbial products. Various components contribute to antimicrobial defences in the intestine. 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’s 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. Broom and Kogut, 2018, Animal Health Research Reviews, doi.org/10.1017/S1466252318000026
- Inflammatory phenotypes in the intestine of poultry: not all inflammation is created equal. To facilitate host homeostasis, the gut immune system ensures that the intestinal microbial load is tolerated, but anatomically contained, while remaining reactive to microbial invasion. Inflammation is the most prevalent manifestation of host defense in reaction to alterations in tissue homeostasis and is elicited by innate immune receptors that recognize and detect infection, host damage, and danger signalling molecules that activate a highly regulated network of immunological and physiological events for the purpose of maintaining homeostasis and restoring functionality. However, the efficacy, duration and consequences of an inflammatory response is dependent upon the type of trigger that is recognised by the innate immune receptors. Further, because of different triggers, there are multiple phenotypes of inflammation - physiologic, pathologic, metabolic and sterile. The common denominator with all intestinal inflammatory phenotypes is the central role of the gut microbiota. Kogut et al., 2018; Poultry Science, doi.org/10.3382/ps/pey087
- Gut microbiome and inflammatory cytokine responses. The Human Functional Genomics Project (http://www.humanfunctionalgenomics.org/site/) is helping to clarify our understanding of the interplay between microbial communities and host physiological processes, specifically immune responses. Recent studies have investigated the relationships between individual gut microbial community composition and (systemic) inflammatory cytokine responses to microbial stimulus. Five different microbial stimuli were employed (three bacterial- and two fungal-derived), of which four were pathogen-associated and one was a common gut commensal. Results confirmed that specific gut microbial organisms and functions influence an individual’s cytokine response, which was proposed to be primarily mediated by microbial metabolites and specific metabolites (e.g. tryptophan and palmitoleic acid metabolism). It is estimated that host genetics explain 25-50% of the variability of some cytokine responses. with the microbiome accounting for up to 10%, with some cytokines (e.g. TNFα and IFNγ) appearing more strongly influenced by the microbiome than others. Schirmer et al., 2016, Cell 167:1125–1136. dx.doi.org/10.1016/j.cell.2016.10.020
- Various antibiotics promote inflammation through bacterial translocation? Studies associate antibiotic exposure with development of inflammatory diseases, which is probably linked with disruption of the gut microbiota (dysbiosis). In addition, oral antibiotic therapy is a frequently used mechanism to induce enteric infection (models). Recent work by Knoop et al. (2016) reported that a number of oral antibiotics/regimes given to mice, including sub-therapeutic treatment, induced the translocation of live (colonic) commensal bacteria to the mesenteric lymph node (MLN), which resulted in inflammatory responses. These effects seemed to be mediated by/dependent on impaired microbial sensing by goblet cells, the formation of associated antigen passages and increased trafficking of dendritic cells to MLN. A few of the tested antibiotics did not induce bacterial translocation and inflammation. These findings highlight differing effects between antibiotics (e.g. class, bacteriostatic vs. bacteriocidal, etc.), that some antibiotics may affect specific bacteria involved in sensing/translocation, and that both therapeutic, or subtherapeutic, use of various antibiotics may induce mechanisms that promote bacterial translocation and inflammatory responses, which has important implications for their use in both humans and animals. Knoop et al., 2016, Gut 65:1100–1109. dx.doi.org/10.1136/ gutjnl-2014-309059
- Ancient immune responses, the key to future success? Exploiting rapidly responding innate immune responses has become of great interest to scientists seeking to combat antimicrobial resistance and/or promote animal health and performance. However, whilst critical, innate responses can be costly in terms of collateral damage and nutrient usage, but recent and current research is helping to identify specific approaches/pathways to enhance pathogen destruction and minimise negative consequences for the host. Work in mice has shown that targeting/inhibiting certain (transcription) factors regulating interferon production (e.g. interferon regulatory factor 7 (IRF-7)) can protect against infection and tissue damage (Puthia et al., 2016). Similarly, a UK-based consortium was recently awarded £3.5m to develop understanding to achieve maximal bacterial killing by innate (phagocytic) cells with minimal tissue damage (http://www.rcuk.ac.uk/media/news/160519-1/). In addition, the importance of stimulating innate immunity for effective vaccine responses is well understood and continues to be explored (https://www.frontiersin.org/articles/10.3389/fimmu.2017.01563/full). Puthia et al., 2016, Science Translational Medicine 8:336ra59 stm.sciencemag.org/content/8/336/336ra59
- Pathogen-host immunity interactions: Porcine reproductive and respiratory syndrome virus (PRRSV) as an intriguing example. This well written review paper, focussed on an important viral pathogen of swine (PRRSV), discusses some interesting aspects of pathogen-host immune system interactions. There is often a delay in a sufficiently protective immune response to PRRSV and thus the virus can remain in the host for at least 150 days, but is eventually cleared. In contrast, some other viral infections (e.g. influenza) are typically cleared within 14 days. This raises important questions about the immune response, and pathogen interference, which results in prolonged infection but is ultimately resolved. As PRRSV infects permissive macrophages and dendritic cells, which are classified as key innate cells and inducers of an adaptive immune response, it has been proposed that such infection contributes to a sub-optimal innate and thus adaptive immune response, which may relate to type 1 interferon suppression during early infection. This paper underlines the importance of appropriate innate immune responses for infection control and elimination by adaptive immunity, as well as identifying key areas to better understand the immune response to PRRSV infection and thus effective vaccine development. Rahe and Murtaugh, 2017; Viruses dx.doi.org/10.3390/v9060148
- Inflammation: friend or foe for animal production? Inflammation is a hot research topic. In animal production, inflammatory processes are almost invariably presented and considered only in the context of their negative consequences. However, inflammation is a critical immune response that seeks to contain microbial infection and repair damaged tissue. This article attempts to bring some balance to the current conversation surrounding promotion of anti-inflammatory processes as a strategy in animal production. The paper highlights the numerous studies that report benefits (e.g. reduced disease susceptibility) associated with enhanced pro-inflammatory mediators. Often, studies assessing inflammatory mediators in animal production/challenge studies do not report animal performance to fully assess the implications. It is important to investigate these aspects further, particularly under commercially-representative conditions. Given the dynamics of inflammatory responses (e.g. speed of onset, timing of transition to anti-inflammatory, tissue repair processes, etc.), it is critical that suitable samples are taken at the most appropriate time points to be truly informative. It is necessary to better understand the importance of inflammatory mediators in different compartments (e.g. systemic vs. gut mucosa), in animals of different ages/production phases, and their relationship with efficient and optimal commercial productivity. Broom and Kogut, 2017; Poultry Science, pex314 doi.org/10.3382/ps/pex314
- The healthy (human) microbiome. This paper reviews our current understanding of ‘healthy’ microbiomes. It is already understood that there is significant variation in taxonomic composition among heathy individuals, which makes characterisation of ‘healthy’ microbiomes on this basis very difficult. Therefore, attention has now turned to characterisation based on functional potential, which appears to be more consistent across individuals, even if taxonomic difference is significant. A ‘healthy, dynamic functional core’ provides for essential microbial life, specific functions for a particular habitat not provided by host cells and resilience and recovery from perturbations. The paper also highlights how early microbiome studies, based on culture and physiological properties, were biased for organisms that grow well in laboratory conditions, which has undoubtedly distorted accurate representation of microbiome composition. Anaerobic and culture-independent (DNA sequencing) techniques have subsequently helped reveal the true complexity of the gut microbiome through better characterisation. On-going investigations will reveal crucial molecular functions provided by the gut microbiome and how these core functions can be encouraged or restored prior to, or after, perturbations. Lloyd-Price et al., 2016; Genome Medicine, 8:51 doi.org/10.1186/s13073-016-0307-y
- Issues and consequences of using nutrition to modulate the avian immune response. With the focus on antibiotic reduction/removal from animal production, there is increased interest in immunomodulation as a strategy to improve animal health and performance. This paper first provides an overview of the immune system before considering modulation of host immunity as an alternative to antibiotics. The author highlights some of the reasons why modulating the innate response maybe particularly advantageous. The article then discusses some of the challenges and inconsistencies reported by studies attempting to successfully employ nutritional immunomodulation to enhance protection against infectious diseases, and how, where direct nutritional effects on the immune system are purported, the influence of/on the gut microbiota/microbiome is often excluded. Furthermore, the article explores the causes and consequences of feed-induced and/or meta/chronic low-grade inflammation, particularly in the context of modern poultry production. Kogut, 2017; The Journal of Applied Poultry Research: doi.org/10.3382/japr/pfx028
- Is sunlight good for your gut health? Vitamin D deficiency may be a common issue among both human and farm animal populations exposed to insufficient sunlight. For example, the supplementary vitamin D requirement of modern poultry may be much higher than some (e.g. NRC, 1994) recommendations for maximising health and performance (Swiatkiewicz et al., 2017). Vitamin D has many recognised and important functions, including its role in intestinal calcium absorption, as well as its perhaps less recognised functions in immune responses and cell differentiation. This recent work (in mice) highlighted that sufficient vitamin D maintains or promotes expression of intestinal antimicrobial, tight junction and mucin proteins, and that impairment of these led to dysbiosis (gut microbiota imbalance). Whilst caution should be exercised when extrapolating data across species, these findings indicate an important role for sufficient vitamin D in maintaining intestinal barrier integrity and homeostasis. Su et al., 2016; Frontiers in Physiology: doi.org/10.3389/fphys.2016.00498
- MicroRNAs (miRNAs): Future opportunities in animal production? MicroRNAs (miRNAs), discovered in the last 20 years, are able to silence genes through RNA interference, which prevents the protein, encoded by the affected mRNA, from being produced and thus causes a resultant change in cellular function. It is possible to produce synthetically-produced RNA to silence proteins in a cell with great specificity and thus target, for example, genes involved in pathogen virulence, host response, or just normal physiology. Therefore, there are numerous potential applications for miRNAs and, in humans, this area is currently considered one of the most exciting for future therapeutics. There are currently a number of synthetic miRNAs undergoing clinical evaluation in humans. There will be various obstacles to overcome for their practical application in agriculture, including delivery, regulation and, probably, consumer acceptance, but this is a space to watch! Bradford et al., 2017; Animal Production Science, 57:1-15. dx.doi.org/10.1071/AN15437
- Knowing your probiotic/DFM (and the gut microbiota)! Differences even at the strain level; For example, only 2 of 4 Bifidobacterium longum strains were protective against enterohaemorrhagic Escherichia coli. In addition, different bacteria drive different immune (e.g. T) cell populations and one species/strain can influence another’s gene expression profile. Gene expression; Gene expression data may not correlate well with functional protein or metabolite production. Will become important to characterise the functional phenotype of the microbiota. Confounding factors; Some studies exploring the importance of specific host genes on the gut microbiota and/or disease have used knock-out and wild type mice that were raised in separate colonies, which likely caused/contributed to any observed differences. Cause of vs. result of; Currently, it is often not well established whether gut microbiota changes associated with intestinal disorders are a cause, or result, of the diseased state. Implications; Important to understand the benefits of individual microbial strains and their interaction with host immunity and the gut ecosystem as a whole. Data beyond gene expression changes are required to properly understand the functional influence of the microbiome. Studies need to avoid confounding factors and determine truly causative/beneficial microbial shifts in disease situations. Caballero and Pamer, 2015; Annual Review of Immunology: doi.org/10.1146/annurev-immunol-032713-120238
- Antibiotic growth promoter (AGP) mode(s) of action? A view. Numerous hypotheses have been proposed to try and explain how AGPs enhance growth and feed efficiency. AGPs are fed at sub-therapeutic concentrations and this has led to doubts about direct modulation of the gut microbiota, and some suggestions of direct anti-inflammatory effects on host cells as a primary mechanism. In a recently published paper, the sub-inhibitory (beyond visible growth) effects of antibiotics on bacteria, such as reducing their growth rates, virulence factor production and resistance to host defences are outlined. These benefits are generally not well understood or considered in animal studies investigating the effects of AGPs, or in the development of effective alternatives. Broom, 2017; Poultry Science: doi.org/10.3382/ps/pex114
- Can animal production learn anything from Crohn’s disease? Traditionally, Crohn’s disease has been considered a chronic, autoimmune, intestinal disorder, characterised by inflammation without a known causative agent(s). However, results from various disciplines now suggest that Crohn’s disease occurs due to an inherent deficiency in innate immunity. Studies have shown that an impaired acute inflammatory response may delay clearance of invading microbes and lead to chronic inflammation. Intestinal disorders, often of unknown aetiology, are frequently associated with the withdrawal of antibiotic growth promoters (AGPs) from the diets of farmed animals, which has led to the development of alternative strategies/products. This new paradigm for Crohn’s disease may challenge the wisdom of anti-inflammatory approaches as an alternative strategy to AGPs in commercial animal production. Smith et al., 2014; Immunology: dx.doi.org/10.1111/imm.12338
- Should we be resistant to tolerance? Infection tolerance is a relatively new immunological concept as a host defence strategy. This host tolerance, distinct from immune tolerance (unresponsiveness) and resistance (pathogen killing/elimination), limits tissue damage caused by both the pathogen and immune response, and may also help lessen the evolution of more virulent strains. This review focuses on Salmonella infection biology in chickens, where, after inducing an initial host inflammatory response, which is sufficient to help control invasion, the immune response switches to a more tolerant state that allows Salmonella to remain in the intestine for many weeks without causing disease. This active process, which appears to be a survival strategy coordinated by both the host and pathogen, has minimal impact on the host and enables the pathogen to persist. Better understanding and exploiting this concept could be advantageous for animal production, although, in the case of foodborne pathogens, it is not without potential issues. Kogut & Arsenault, 2017; Frontiers in Immunology: doi.org/10.3389/fimmu.2017.00372
- What am I? I am approximately 2% of body mass, have more cells and genes than the host and am more metabolically active than the liver. Yes, it's the gut microbiome! These facts confirm the importance of the microbiome and the growing acceptance for it to be considered an organ. There is increasing evidence that the foetus does not develop in a sterile environment and that interactions between microbes and the intestine occur before birth. Colonisation, and the types of microbes or their metabolites, have long-term effects on immune development and the ability to regulate responses and maintain homeostasis. Initial colonisation patterns and microbial source(s) profoundly influence subsequent colonisation phases, immune function and the likelihood of dysregulation. This review, whilst focusing on humans, has clear implications for farmed animals. Walker, 2017; Paediatric Research: doi:10.1038/pr.2017.111
- Recent work demonstrates that sub-clinical enterotoxigenic E. coli challenge of broiler chickens compromises their intestinal morphology, caecal microbiology, immune responses and growth performance. These effects were largely counteracted by the addition of organic acid-based feed additives to the diet. This study demonstrates the potential of these organic acid blends to promote broiler (enteric) health and growth performance, which is particularly pertinent at a time when antibiotic use in broiler production is a key industry issue. Khodambashi Emami et al., 2017; Poultry Science: doi.org/10.3382/ps/pex106
- This excellent review describes intestinal growth and development in young poultry. Following hatch, the relative growth of the intestine exceeds that of bodyweight, peaking at 6 to 10 days of age, thus identifying the first weeks posthatch as a critical period. The paper reports how different species, but with similar egg weights, incubation periods and hatchling weights, showed significantly different intestinal development at hatch, and the days thereafter, and vastly different growth rates (Pekin ducklings vs. turkey poults). Further, the influence of the gut microbiome and the prioritisation of nutrients (e.g. fatty acids) for intestinal development are explored. Lilburn and Loeffler, 2015; Poultry Science 94:1569-1576. dx.doi.org/10.3382/ps/pev104
- Don't know your metagenome from your metabolome? This paper provides a good overview of the definitions and techniques used in determining the structure and function of the intestinal microbiome. It also outlines some of the complexities and difficulties of interpreting microbiome studies, as well as describing recognised strategies to influence the gut microbiome. Young, 2017; BMJ 356:j831. doi.org/10.1136/bmj.j831
- Necrotic enteritis (NE) remains a key, and costly, gut health issue for poultry production, particularly when AGP use is reduced. This paper outlines the fundamental dietary-related factors that should be addressed to reduce the likelihood of NE. Broom, 2017; World's Poultry Science Journal 73: doi.org/10.1017/S0043933917000058
- Generally, it has been considered that the metabolic cost of a robust inflammatory immune response is detrimental to animal growth performance and thus the desire for (feed) additives with anti-inflammatory effects has increased. This paper, however, shows that selecting birds for increased pro-inflammatory mediators results in greater resistance to pathogen challenge, thus highlighting the potential dichotomy between efficient growth and disease resistance. Swaggerty et al., 2016; Poultry Science 95:370–374. doi.org/10.3382/ps/pev348
- Probiotics are typically considered to be (most) effective when viable. However, components of non-viable microorganisms can still exert immunomodulatory effects and thus influence gut health. This paper demonstrates that a heat-inactivated probiotic is at least as effective as the viable form, although the modes of action may be somewhat different. Palamidi et al., 2016; Poultry Science 95:1598–1608. doi.org/10.3382/ps/pew052