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Review

Vaccine Immunogenicity versus Gastrointestinal Microbiome Status: Implications for Poultry Production

by
Chrysta N. Beck
1,
Jiangchao Zhao
2 and
Gisela F. Erf
1,*
1
Division of Agriculture, Department of Poultry Science, University of Arkansas, Fayetteville, AR 72701, USA
2
Division of Agriculture, Department of Animal Science, University of Arkansas, Fayetteville, AR 72701, USA
*
Author to whom correspondence should be addressed.
Appl. Sci. 2024, 14(3), 1240; https://doi.org/10.3390/app14031240
Submission received: 15 December 2023 / Revised: 24 January 2024 / Accepted: 31 January 2024 / Published: 2 February 2024
(This article belongs to the Special Issue Applied Microbial Biotechnology for Poultry Science)
Review Reports Versions Notes

Abstract

:
At the turn of the 21st century, the importance of maintaining a balanced microbiome was brought to the forefront of the microbiology, immunology, and physiology research fields. Exploring the complex interactions between vaccine administration, mucosal microbiome, oral tolerance, and enteric inflammation in health and disease is challenging since environmental factors (such as diet and sanitation) have major influences on gut microbiota composition. High enteric pathogen load has been shown to contribute to dampened cell-mediated and humoral immune responses to vaccines in human case studies, either through elevated enteric inflammation or increased tolerance to environmental microbes. Although antibiotic and probiotic interventions have been evaluated in human health as well as research animal models, effective measures to mediate vaccine hyporesponsiveness are still ill-defined. Research in this field is becoming increasingly important for managing flock health in commercial poultry production, especially as antibiotic-free production is more prevalent and vaccination programs remain extensive during the first weeks of a bird’s life. By understanding the cellular interactions between commensal microbiota, vaccine antigens, and the host immune system (particularly in avian models), advancements in bacterial and viral vaccine immunogenicity could lead to improved flock health in meat-type and egg-type chickens in the future.

1. Introduction

In recent years, there has been increasing evidence that homeostasis of the mucosal microbiota can decrease systemic inflammation [1]. Disruptions to the resting microbiome (dysbiosis) causes a disturbance in the symbiotic relationships between microbial communities and the host, which is correlated with many chronic inflammatory disorders [1,2]. This is, in part, because the mucosal immune system is constantly managing an intricate interplay of signals between epithelial cells and leukocytes through the expression of toll-like receptors (TLR), nucleotide-binding and oligomerization domain (NOD)-like receptors (NLR), and the secretion of pro- and anti-inflammatory cytokines [3,4]. However, the delicate relationship between the microbiota of the gut mucosa and immunological responses of the local lymphatic tissues is a complex system that is yet to be completely understood.
Over the past decade, it has been made evident that the gut microbiome is an important constituent for developing appropriate vaccine responses in a host. Ideally, effective vaccine responses consist of acute inflammation at the site of administration followed by antigen-specific cell-mediated and humoral immune responses that ultimately result in long-term immunological memory. However, environmental conditions that promote high fecal–oral microbe transmission or extensive antibiotic use can affect the gut microbial load and enteric inflammation, resulting in dampened immune responses to vaccine administration [5,6,7,8]. This point is especially pertinent when discussing effective vaccination programs administered during food animal production. In poultry production, the high environmental microbial load in commercial poultry houses could induce enteric inflammation among young chicks [9,10,11], which could theoretically lead to reduced vaccine immunogenicity in the flock [12,13]. Additionally, there is limited evidence which suggests that vaccine administration influences the established mucosal microbiota of various tissues in the days following vaccination [14].
In this review, a summary of the avian enteric immune system will be presented followed by a brief explanation of immunological tolerance to commensal microbiota. Next, we will attempt to discern the influence of the mucosal microbiome and supplementation with probiotic bacteria on vaccine immunogenicity, the impact of vaccine responses on mucosal microbiomes, and its implications in human medicine and livestock management. To conclude this review, we will discuss how this information can be applied to the poultry husbandry and management when considering antibiotic-free production practices and extensive vaccination programs administered to young commercial poultry flocks.

2. Mucosal Immune System of the Avian Gastrointestinal Tract

Regardless of host species, the functionality of the gastrointestinal tract is maintained through physical and chemical barriers preserved by various cells in the intestinal epithelium, leukocytes, and the local commensal microbiota [4].
A major barrier with physical and chemical properties in the gastrointestinal tract is mucus: a viscous, aqueous layer of glycosylated proteins that prevent microbes in the lumen from contacting intestinal epithelial cells [15]. Mucus is synthesized by goblet cells in the microvilli of the intestinal epithelium where it has direct contact with the intestinal lumen and creates a physical—(a thick layer with adhesins and secretory IgA) and chemical—(antimicrobial peptides, RegIII proteins, defensins, and cathelicidins) barrier that prevents the movement of pathogens past the epithelium [4,16]. Microbes in the lumen reside on this mucus layer where they metabolize short-chain fatty acids, synthesize lactic acid, and secrete ATP to communicate with the host immune system [17]. Further protection from microbial invasion is maintained by the glycocalyx, which consists of a complex system of glycolipids, carbohydrates, and mucin proteins that are associated with the intestinal epithelial surface [15].
A diverse array of cells coexists within the mucosal epithelium and is essential for signaling to the local immune system. Between intestinal epithelial cells are tight junctions which further prevent microbes from traveling through the epithelial layer. Additionally, Paneth cells reside at the bottom of crypts and secrete defensins (antimicrobial peptides) into the mucus layer [4]. Within the epithelial layer, there are intraepithelial leukocytes primarily consisting of γδ T cells with cytotoxic potential (CD3+CD8+TCRγδ+) and natural killer T cell-like leukocytes (CD3−CD8+) along with a marginal population of CD8− γδ T cells (CD3+CD8−TCRγδ+) that traverse within the epithelium [4,18,19]. Intestinal epithelial cells, dendritic cells, macrophages, natural killer cells, and innate lymphoid cells all exist within the epithelium to initiate inflammatory responses through pattern recognition receptors (TLRs, NLRs, RIG-like receptors, and C-type lectin receptors) and respond to anti-inflammatory molecules (short-chain fatty acids, bile acids, commensal microbe ATP, cytokines) to maintain gut homeostasis [16,17,18].
Below the intestinal epithelium is the lamina propria, where additional leukocytes reside in lymphatic tissues. Avian species (which lack lymph nodes) have diffuse lymphatic aggregates throughout the gastrointestinal tract as well as organized, non-encapsulated lymphatic tissues such as Peyer’s patches, Meckel’s diverticulum, and cecal tonsils [20]. Mammalian species also have encapsulated lymph nodes that receive lymph from the lymphatic ducts draining from the epithelium [21]. Even so, both organisms exhibit well-organized lymphatic structures along the gastrointestinal tract, where the lymphatic tissue’s germinal centers contain B lymphocyte populations and parafollicular zones contain T lymphocyte, macrophage, and dendritic cell populations. These leukocytes in the lamina propria migrate through the tissue to phagocytize microbes and/or secrete cytokines to activate or de-escalate the inflammatory responses at the surface of the epithelium [4].
The epithelial lining above these gastrointestinal lymphatic tissues is referred to as the follicle-associated epithelium and physiologically differs from other regions of the epithelium in the gastrointestinal tract: goblet cells are absent from the epithelium (reducing mucus presence), microvilli are shorter, and microfold (M) cells actively bind to microbes and antigens present in the lumen [22]. Glycoproteins and lectins are expressed on the luminal surface of M cells to capture intact microbes and molecules that are then endocytosed and transported across the M cell and released into gut-associated lymphoid tissues [23]. By doing this, M cells are “sampling” microbes by microbial adhesion-triggered endocytosis [24,25,26], where dendritic cells residing below the epithelium can respond to these endocytosed microbes. These dendritic cells can also extend dendrites between intestinal epithelial cells to reach into the glycocalyx and mucus to sense and retrieve pathogens [27].
In addition to intraepithelial γδ T cells, other leukocytes of the adaptive immune system participate in immune responses in the lamina propria. IgM+ B cells in the gastrointestinal lymphoid tissue undergo an IgA isotype-switch through T cell-dependent (CD40 and MHCII interaction) or T cell-independent (dendritic cells produce TGF-β, APRIL, and BAFF) systems [28]. After isotype switching, IgA+ plasma cells in the lamina propria produce IgA which binds to the polymeric immunoglobulin receptor at the base of epithelial cells. The IgA-bound complex is transported across the epithelial cells, proteolytically cleaved, and the secretory IgA is released into the lumen of the gastrointestinal tract to neutralize pathogens [29]. Within the lamina propria, most T cells are CD4+ effector T cells or resident memory T and B cells. Additionally, cytokine signals from dendritic cells activate specific CD4+ T helper cell subpopulations present in the lamina propria (Th1, Th2, or Th17). In a healthy gut, Th17 cells are essential for maintaining mucosal epithelial barriers and secreting cytokines such as IL-17 and IL-22. Additionally, CD4+FoxP3+ T regulatory (Treg) cells are much more abundant in gastrointestinal lymphatic tissues when compared to other tissues in the body [30,31]. Tregs play an essential role in peripheral tolerance, inhibiting activation of other T cells and regulating dendritic cells, macrophages, and epithelial cells through the secretion of TGF-β and IL-10 cytokines [30,32,33,34].

3. Antigen Sampling, Tolerance, and Immune Function of Commensal Bacteria

The culmination of leukocytes and epithelial cells in the gastrointestinal tract synthesizes specific, well-regulated inflammatory responses that eliminate pathogens from the gut, maintain the integrity of the epithelial barrier, and produce an immunological memory [17]. To properly function, these responses must also be capable of recognizing, maintaining, and protecting commensal gut microbiota [4,13,17], but there is limited information about the mechanistic relationships between commensal gut microbiota and the immune system [13]. However, there is clear evidence of antigen sampling and commensal microbiota tolerance in the intestinal epithelium and lamina propria.
Antigen sampling refers to the mechanistic practice of collecting peptides, glycolipids, and metabolites of gut microbes from the lumen to initiate immune responses or develop tolerance [3]. When studying the physiological source of environmental microbe sampling in the gut of a rat model, Bland and Britton [35] determined that consumption of ferritin-India dye exhibits passage through the follicle-associated epithelium but not in other regions of the epithelium. Additionally, avian species are capable of anti-directional peristaltic muscle contractions of the cloaca to push antigens from the external environment to the bursa of Fabricius located proximal to the vent (also known as bursal drinking) and upwards towards the cecal tonsils [36]. There is evidence that microbe sampling along with the establishment of commensal microbiota in the gastrointestinal tract are beneficial for development of the mucosa-associated immune system [16,37]. Like the transfer of maternal antibodies to offspring, maternal microbiota can be passed to offspring during and after birth. For avian species, environmental microbes from the eggshell, nesting material, and parental feathers contribute to hatched-offspring gut microbiota [37]. Moreover, by exposing the gastrointestinal tract to environmental microbes during infancy, organisms develop functional lymphatic tissues in the gastrointestinal tract and benefit from the symbiotic relationship of commensal microbiota [38].
A major contributor to early gut microbiota development is segmented filamentous bacteria (SFB): a vertically transmitted, host species-specific, unculturable bacterium whose life cycle is dependent on penetrating the mucus layers of the gut and latching onto gastrointestinal epithelial cells without initiating an inflammatory response in the host [39]. These bacteria have been defined in mammals as well as chicks [40,41] and can be enriched through probiotic supplementation in feed [42]. In recent years, it was determined that these bacteria play critical roles in protecting young organisms from pathogenic bacteria colonization while their immune systems develop [25,39]. SFB may also actively contribute to the maturation of mucosal immunity and development of Th17-type subpopulations in the lamina propria [25]. As previously stated, properly regulated Th17 subpopulations are essential for the maintenance of the gut mucosa. In turn, a balanced gastrointestinal microbiome also regulates Th17 populations to prevent autoimmune-type inflammation in the host [30].
Since leukocytes in the gastrointestinal lymphatic tissues are constantly sampling microbes from the intestinal lumen, oral tolerance to commensal microbiota is necessary to maintain homeostasis in the gut. Oral tolerance refers to the body’s ability to consume foods and non-pathogenic microbes without experiencing inflammation at the gut epithelial barrier [43]. There are many factors that may contribute to oral tolerance, including the expression of TLR and NOD-like receptors for microbial sensing [44,45,46]. For example, TLR4 expression is lower in the lamina propria when compared to other non-mucosal tissues [46]. There is also evidence that the innate immune system exhibits trained immunity, which allows for mucosal tolerance to commensal microbiota residing in the gut [47].

4. Interactions between Vaccine Administration and Gut Microbiome Status

Researchers have postulated that gut microbial communities and the host immune system have co-evolved over many centuries as mothers passed commensal microbes to offspring from generation to generation [6]. Even so, environmental variables such as maternal immunity, host diet, and sanitary conditions can have diverse impacts on the host’s mucosal microbiome and mucosal immune system [5]. For over a decade, investigations into the resting gut microbiome of humans and its interactions with vaccine immunogenicity have been conducted [8,48,49,50], with some of the most recent case studies concentrating on factors that influence the immunogenicity of the SARS-CoV-2 mRNA vaccine [51]. Although many have worked to disentangle the interactions between microbiome and host immune responses, these intricate interactions have proven to be complex networks of cell signaling that can vary according to host organism and region of the world.

4.1. Gut Dysbiosis and Its Influence on Vaccine Efficacy in Human Medicine

As vaccines targeting viral and bacterial diseases in humans continue to be developed, researchers have noticed differences in vaccine immunogenicity among various human populations. This has led to an extensive catalog of human case studies that have investigated vaccine efficacy among various human populations. Although the mechanisms are yet to be understood, many studies have discovered that children raised in regions with high incidences of enteric disease and environmental enteropathy display much lower antigen-specific immunological memory to viral or bacterial oral vaccines when compared to children raised in developed countries [8,48,49,50,52]. For example, Hallander et al. [52] observed that children raised in Sweden had higher antibody responses and lower enteric disease incidence after oral administration of a killed cholera vaccine than those raised in Nicaragua. Similar results were observed in infants who received an oral rotavirus vaccine, where infants from the United Kingdom had greater antigen-specific antibody production than those raised in Malawi or India [8].
Because of vaccine hyporesponsiveness (reduced vaccine response) among children with a greater incidence of enteric inflammation, it is hypothesized that dysbiosis of the gut microbiota may contribute to the dampened vaccine responses [6,7]. Although it is assumed that a host with a rich and diverse microbial community would inherently develop stronger vaccine responses, because commensal microbes drive maturation of the gastrointestinal lymphoid tissue [53,54], the current evidence suggests that low vaccine immunogenicity in human populations may be correlated with a high enteric pathogen load [48].
For example, Bangladeshi infants with high microbial diversity in stool samples exhibited greater gastrointestinal inflammation and lower antigen-specific responses to the tetanus toxin vaccine [55]. Similarly, Indian, and Malawian infants had higher microbial diversity in their stools when compared to infants born in the United Kingdom, but Indian and Malawian infants had lower antigen-specific antibody production after oral rotavirus vaccination than the United Kingdom infants [8]. However, the infants’ stool samples from each of these three nations contained different enriched genera with potentially pathogenic attributes (Prevotella in Malawian infants, Enterococcus in Indian infants, and Citrobacter in U.K. infants), indicating that region and diet influence gut microbiota which makes it difficult to link improved or dampened vaccine responses to specific genera [8]. Moreover, the fecal–oral transmission of enteric pathogens and subsequent high endotoxin (lipopolysaccharide) load in the gut can lead to chronic inflammation which could limit the host’s ability to respond to orally administered bacterial or viral vaccines.
The overabundance of enteric pathogens may drive vaccine hyporesponsiveness either through chronic enteric inflammation or through elevated oral tolerance to the environmental pathogens, but a lack of microbes can also reduce vaccine efficacy. More specifically, studies investigating the influence of antibiotic exposure on vaccine responses have provide insights into the importance of a balanced gut microbiota in the host. One clear example of this is in chicken pox vaccination regimens in China. Lin et al. [56] discovered that antibiotic exposure for at least seven days during the first two years of a child’s life was positively correlated (p < 0.01) with chicken pox disease incidence, regardless of chicken pox vaccination status. Similar results were emulated in the murine model, where various types of antibiotic treatment and durations of exposure lead to decreased vaccine immunogenicity along with decreased gut microbiota diversity [57,58,59,60].
Researchers have postulated that probiotics have vaccine adjuvant potential in human medicine because supplementation can beneficially modulate the gut microbiota [61], but the effectiveness of probiotic supplementation with vaccine administration remains undefined due to the highly variable results in the published research [62,63].

4.2. Gut Dysbiosis and Its Influence on Vaccine Efficacy in Poultry

As detailed in the previous section, human case studies have evaluated causative agents of reduced vaccine immunogenicity over the past two decades and discovered that chronic enteric inflammation or extensive antibiotic use may lead to vaccine hyporesponsiveness in children. Human health is diversely influenced by a multitude of factors (socio-economic background, diet, region, age), and comparisons between discoveries in human health and those in research animal models (including poultry) must be made with ample trepidation. Conversely, understanding factors that influence vaccine inefficacy in human case studies could help evaluate causes of vaccine hyporesponsiveness in animal health management.
When discussing vaccine hyporesponsiveness in poultry, investigations regarding the relationship between gut microbiome status and vaccine efficacy have been very limited (Table 1). As previously noted, commercial poultry houses have high microbial loads [10,11] that could disrupt the microbiome of young chicks with undeveloped immune systems [16,33,64]. Only in recent years have exploratory studies evaluated the effects of antibiotic administration in broiler flocks on the efficacy of a variety of vaccines [65,66] or inflammation when challenged with live pathogens [67]. Several studies have also investigated the influence of probiotic supplementation on the immunological and gut microbiome states of poultry flocks [68,69,70].
Antibiotic growth promoters were a common management practice in commercial poultry production [71]. Although the poultry industry in the U.S. and E.U. are moving away from antibiotic applications used solely for growth promotion [72], recent studies have evaluated the effects of prolonged antibiotic applications on vaccine responses in poultry flocks. Yitbarek et al. [66] observed that specific pathogen-free (SPF) layer chickens treated with an antibiotic cocktail in drinking water for 35 days and vaccinated with an avian influenza vaccine had greater IFN-γ expression by splenocytes along with lower levels of Firmicutes and Bacteroidetes phyla in the ceca when compared to birds receiving the same antibiotic cocktail but treated with fecal microbial transplantation or a probiotic formulation during vaccine administration. Firmicutes and Bacteroidetes are both major contributors to the gastrointestinal tract microbiota and are generally associated with commensal microbes that secrete lactic acid (like Lactobacillus spp.) and microbes essential for complex polysaccharide degradation and bile acid deconjugation, respectively [73]. Similar immunological responses were observed in White Leghorn chickens that were intramuscularly vaccinated with an inactivated H9N2 influenza virus and supplemented with a Lactobacillus probiotic cocktail, i.e., greater IFN-γ mRNA expression in splenocytes as well as increased hemagglutination inhibition titers in serum [74].
In mouse models, opposing results have been observed with antibiotic-induced dysbiosis in the gut. Following an aerosol Mycobacterium tuberculosis challenge, mice subcutaneously vaccinated against M. tuberculosis and administered an antibiotic cocktail exhibited lower CD4+ and CD8+ T cell proliferation in the lung mucosa following a secondary immunization [58]. Additionally, C57BL/6 mice reared in specific pathogen-free conditions that were administered oral antibiotic treatments found that the type of antibiotic cocktail can influence the antibody isotype response to a variety of vaccine antigens without affecting the expression of lymphocyte chemotaxis receptors in splenic and mesenteric tissues [75]. More specifically, broad-spectrum antibiotic administration increased serum and secretory IgA levels among the vaccine antigen treatments but did not induce IgG1 responses in the serum, indicating regulatory effects of antibody responses by the microbiome that are not yet understood [75].
Table 1. Influences of gut microbiota dysbiosis on vaccine efficacy in avian and mouse models.
Table 1. Influences of gut microbiota dysbiosis on vaccine efficacy in avian and mouse models.
ModelSource of DysbiosisVaccine/Challenge TreatmentVaccine Immune ResponseRef. 1
Specific
Pathogen-Free layer chicks,
0–43 doa 2		Antibiotic cocktail, in water
(for 0–12 or 0–35 doa):
Vancomycin, Neomycin, Metronidazole, and Amphotericin-B 		Inactivated H9N2Antibiotic supplementation for 0–12 doa:
 ↓3 splenocyte IFN-γ expression
 ↓ HI 4 antibody titer at 7 and 14 doa, n.d. 5 at 21 and 28 doa
 n.d. virus neutralization antibody titer at 21 doa
 ↓ H9N2 Serum IgG at 7 and 14 doa
Antibiotic supplementation for 0–35 doa:
 n.d. splenocyte IFN-γ expression
 ↓ HI antibody titer at 7 and 14 doa, n.d. at 21 and 28 doa
 ↑ virus neutralization antibody titer at 21 doa
 ↓ H9N2 Serum IgG at 7 and 14 doa		[66]
Broiler chicks (male),
0–28 doa		Antibiotic treatment,
in feed:
Bacitracin methylene
disalicylate		Avian pathogenic
E. coli challenge		 ↑ relative spleen weight (% body weight) at 14 doa
 n.d. relative or gross spleen weight at 28 doa		[67]
C57BL/6 miceAntibiotic treatments,
oral gavage:
(1)
Targeted treatment (neomycin)
(2)
Cocktail treatment (Ampicillin, vancomycin, neomycin, gentamicin, metronidazole)
Ovalbumin (OVA), recombinant cholera toxin B subunit (CTB), or
Bacillus anthracis protective antigen (PA)		(1) Targeted treatment:
 n.d. serum IgA-specific OVA, CTB, or PA
 n.d. secretory (fecal) IgA-specific OVA, CTB, or PA
 ↑ splenic and mesenteric α4β7CD19+ cells when compared to cocktail only
(2) Cocktail treatment:
 ↑ serum IgA-specific OVA and CTB
 ↑ secretory (fecal) IgA-specific OVA
 n.d. splenic and mesenteric α4β7CD19+ cells		[75]
1 Ref.: Reference; 2 doa: days of age; 3 ↓ and ↑ indicate decrease and increase, respectively (p ≤ 0.05); 4 HI: hemagglutination inhibition; 5 n.d.: no difference from respective publication’s control treatment (p > 0.05).
Since dysbiosis associated with antibiotic treatments may result in dampened immune responses to vaccinations, the positive modulation of the gut microbiota through probiotic supplementation has been investigated in poultry. Commensal bacteria and probiotics have been referred to as “endogenous vaccine adjuvants” that aid in developing antigen-specific adaptive immune responses to pathogens present in the gut mucosa [76]. For example, Gao et al. [65] observed that broiler chickens provided ad libitum access to diets formulated with lincomycin had diminished microbial metabolic activities essential for nutrient utilization, such as vitamin biosynthesis and nitrogen metabolism, when compared to chicks fed the same diet but supplemented with Lactobacillus plantarum P-8 probiotic in the water. Additionally, the Simpson index (evenness of microbial species populations) of fecal samples collected from broilers supplemented only with lincomycin in feed was higher (p = 0.02) than those receiving lincomycin in feed and L. plantarum P-8 in water, indicating lower microbial diversity [65]. Similarly, Cai et al. [69] vaccinated Mahuang broilers with a commercially available coccidiosis vaccine and investigated the influence of Clostridium butyricum probiotic inclusion on live performance and gut microbiota status after a coccidiosis challenge. In summary, C. butyricum inclusion increased the richness and evenness of cecal pouch microbiota, regardless of vaccination status prior to challenge. Prior to coccidiosis challenge (15 days of age), birds only vaccinated for coccidiosis had at least a four-fold lower abundance of the Bacteroides, Barnesiella, and Megamonas genera and a four-fold greater abundance of the Enterococcus genus when compared to those that were vaccinated for coccidiosis and supplemented with C. butyricum [69].
These alterations to gut microbiota may be associated with improved mucosal immune responses. For example, White Roman chickens orally vaccinated with Newcastle disease virus vaccine and supplemented with a yeast cell wall product had an elevated serum hemagglutination titer, greater presence of IgA+ cells in the mucosa of the duodenum, and greater fecal shedding of Newcastle disease virus-specific secretory IgA when compared to birds that were vaccinated but not supplemented with a yeast cell wall product [77]. Additionally, supplementing with a yeast cell wall product in the feed of vaccinated birds produced greater cecal pouch microbiota richness than that of non-supplemented, vaccinated birds [77]. These results indicate that the beneficial modulation of the gut microbiota could effectively increase protective immunity at the surface of the mucosa.
Apart from in-feed probiotic and prebiotic supplementation, another method of probiotic supplementation that has advanced in recent years is in ovo, or in-egg, administration of beneficial microbes into the amniotic sac of 18-day-old chicken embryos. It has been shown that these in ovo-supplemented microbes colonize in the gastrointestinal tract of the embryo [78] and that some species of probiotics could decrease TLR4- and iNOS-mRNA expression in the cecal tonsils [79] as well as increasing cytokine mRNA expression (IL-1β, IFN-γ) in the spleen [80] in the days and weeks post-hatch when compared to age-matched chicks that were not supplemented with in ovo probiotics. Additionally, in ovo probiotic supplementation could aid in the developing chick’s microbiota while effectively minimizing Salmonella colonization [81]. However, minimization of colonization by pathogenic bacteria, such as avian pathogenic E. coli, through in ovo probiotic supplementation is not consistently observed [82].
Moreover, there is currently no clear management strategy that defines how to effectively apply probiotics in a manner that universally benefits vaccine efficacy in poultry flocks.

4.3. Vaccine Administration and Its Influence on Gut Microbiome Status in Poultry and Other Non-Human Hosts

The state of the gut microbiota at the time of vaccination can influence the immunogenicity of a wide variety of vaccines [5,6]. Recent research has discovered that vaccines may influence the host microbiome as it mounts an inflammatory response and develops an antigen-specific memory following vaccine administration. Investigations regarding the effects of commercial vaccine administration regimens on gut microbiome status among poultry flocks are limited (Table 2), although there is a collection of investigations in other monogastric animal models.
For example, Borey et al. [14] discovered that pigs vaccinated for influenza A virus had no changes in microbial diversity or abundance in fecal samples after primary and secondary vaccinations. However, vaccinated pigs had a higher abundance of lactic acid-producing microbes (Lactobacillus genus) at the time of the secondary immunization, and microbial families associated with fiber fermentation (Lachnospiraceae) and short-chain fatty acid generation (Ruminococcaceae) were enriched one week after the secondary vaccination. Additionally, pigs that exhibited weak immune responses to the influenza A vaccine had greater levels of microbes associated with enteric inflammation (including Helicobacter and Escherichia-Shigella) after primary vaccination [14]. Alternatively, Cai et al. [69] observed that 15-day-old broilers vaccinated for coccidiosis, an enteric protozoon, had an increased abundance of the Enterococcus genus, which is associated with bacteriocin production but also foodborne disease outbreaks in humans [83].
Unlike the results from Borey et al. [14], several reports have indicated that vaccine administration does not negatively or positively alter gut microbiota. Zhao et al. [84] determined that vaccination with a trivalent avian influenza vaccine combined with an anthelmintic treatment in red-crowned cranes triggered temporary deviations in stool microbiota populations. After vaccine administration, lactic acid-secreting microbes (Lactobacillus genus) decreased while microbes associated with fortification of the mucosal barrier (genera within the Proteobacteria and Actinobacteria phyla) increased. Even with these responsive changes, microbiota homeostasis began to be re-established in the red-crowned cranes by 15 days post-vaccination and anthelmintic treatment [84]. In SPF chicks, Zhang et al. [85] evaluated immune responses and cecal microbiome status following oral administration of an H9N2 recombinant protein as a vaccine candidate attached to a yeast (Saccharomyces cerevisiae) vector. There was higher richness and more diverse microbial community composition in the cecal contents of chicks vaccinated with the recombinant protein attached to yeast when compared to the control (PBS) vaccination. Additionally, the Firmicutes phylum was enriched while the abundance of the Lactobacillus genus was not altered when comparing recombinant protein-vaccinated chicks to those of the PBS-vaccinated control [85].
Similar results were observed when candidate and commercial non-typhoidal Salmonella vaccines were applied to broiler [86,87] and egg-type chickens [68,88]. Park et al. [86] observed that various candidate Salmonella vaccines did not affect critical populations in broiler cecal microbiota, including genera such as Ruminococcus (short-chain fatty acid generation), Faecalibacterium (secretion of anti-inflammatory metabolites [89]), and Lactobacillus (lactic acid secretion). These results resembled those of Lyimu et al. [87]. Following vaccination of 16-day-old Ross 308 broilers with commercially available live Salmonella Enteritidis and Typhimurium vaccines, there were alterations to the cecal microbiota at 14 days post-oral-gavage vaccination. Whilst no differences in cecal microbiota diversity were observed between broilers of the vaccine treatments and the control group, microbiota composition was influenced by the vaccine treatment. Among broilers vaccinated with Salmonella Enteritidis or Typhimurium, the Firmicutes phylum (including Lactobacillus and Ruminococcus genera) was enriched while Bacteroidetes phylum and Alistipes genus abundance were diminished. Firmicutes are commonly associated with initial establishment in the cecal microbiota of young chicks while the abundance of Bacteroidetes increases as the birds age [90]. Additionally, the Alistipes genus (belonging to the Bacteroidetes phylum) has been identified in broiler chick cecal microbiota [91], but its implication in broiler performance and mucosal immunity is not understood at this time.
Table 2. Influences of poultry vaccination programs on gut microbiota status.
Table 2. Influences of poultry vaccination programs on gut microbiota status.
ModelVaccinationCeca Pouch Microbiota ResponseRef. 1
Mahuang broilers3 and 10 doa 2: Coccidiosis vaccine (unnamed source), in water 15 doa (coccidiosis vaccination vs. vaccination + C. butyricum):
 n.d. 3 for Chao1 index, Shannon index, or inverse Simpson index among treatments
 ↓ 4 abundance of Bacteroides, Barnesiella, and Megamonas genera
 ↑ abundance of Enterococcus genus		[69]
Mahuang broilers3 doa: Live coccidiosis vaccine (QiluTsingta Biopharmaceutical Co., Ltd., Jinan, China), in water15 doa (live coccidiosis vaccination vs. vaccination + probiotic):
 n.d. Chao1 index, Shannon index, or Simpson index
 ↑ abundance of Enterococcus genus 		[70]
White Roman chickens (male)14 doa: Live Newcastle disease virus (NDV) vaccine, Strain La Sota (Qingdao YEBIO Bio-engineering Co., Ltd., Qingdao, China), oral gavage42 doa (NDV vaccination vs. vaccination + yeast cell wall product inclusion):
 ↓ average observed species and Chao1 index
 ↓ abundance of Ruminococcaceae family
 ↑ abundance of Bacteroidaceae, Tannerellaceae, and Desulfovibrionaceae families		[77]
Cobb broilers (male)2 and 7 doa: 3 different Salmonella Typhimurium vaccine candidate strains, oral gavageTrt 5 1: Unvaccinated
Trt 2: PBAD-mviN S. Typhimurium UK-1
Trt 3: Wild type S. Typhimurium UK-1
Trt 4: ∆∆metRmetD S. Typhimurium UK-1		42 doa:
 Trt 1: ↑ proportion of Oscillospira genus when compared to 2
 Trt 2: ↓ proportion of Clostridiales order compared to 1 and 4,
  ↑ proportion of Ruminococcaceae and Lachnospiraceae families compared to 1 and 4
 Trt 3: ↓ proportion of Clostridiales order compared to 1 and 4
  ↑ proportion of Bacteroidales and Verucomicrobiales orders compared to 1, 2, and 4
  ↑ proportion of Ruminococcaceae and Lachnospiraceae families compared to 1 and 4
 Trt 4: ↑ proportion of Clostridiales order compared to 2 and 3		[85]
Ross
broilers		7, 14, and 21 doa: Clostridium perfringens recombinant proteins (7 vaccine candidates), intramuscular33 doa (C. perfringens recombinant proteins vs. vaccine adjuvant):
 ↓ observed OTUs for Ruminococcaceae family among all vaccine candidates
 ↑ observed OTUs for Bacteroidaceae family among most vaccine candidates
 ↑ observed OTUs for Erysipelatoclostridiaceae family among two vaccine candidates		[87]
Ross 308 broilers (male and female)2-(5 and 12 doa) or 4-dose (5, 12, 19, 28 doa) vaccine regimens: Campylobacter jejuni recombinant YP437 protein, intramuscular2-dose vaccine regimen vs. C. jejuni challenge:
 n.d. for inverse Simpson index
 ↓ Shannon index
 ↑ proportion of Faecalibacterium genus
 ↓ proportion of Blautia and Subdoligranulum genera
4-dose vaccine regimen vs. C. jejuni challenge:
 n.d. for inverse Simpson index
 n.d. for Shannon index
 n.d. for proportion of genera		[88]
1 Ref.: Reference; 2 doa: days of age; 3 n.d.: no difference (p > 0.05); 4 ↓ and ↑ indicate decrease and increase, respectively (p ≤ 0.05); 5 Trt: Vaccine treatment.
Similarly, Beirão et al. [68] demonstrated that egg-type chickens vaccinated at 1 and 28 days of age with a commercial live Salmonella vaccine did not exhibit negative changes to the gut microbiome; specifically, the only changes in gut microbiome status were associated with vaccine treatments that also supplemented probiotic bacteria in feed during the vaccination period. Moreover, the type of vaccine and its associated “adjuvant” may contribute to unique alterations to gut microbiota. For example, Park et al. [86] determined that three different Salmonella vaccine candidates stimulated unique alterations to cecal microbiota in broiler chicks, where the microbiota composition of cecal pouch content among individuals within a Salmonella vaccine treatment group were more closely related to each other than to samples from different Salmonella vaccine treatment groups.
Jan et al. [88] also evaluated the ceca microbiota status in SPF chicks and commercial egg-type pullets following vaccination with a commercial Salmonella vaccine and a live Salmonella challenge. When compared to non-vaccinated control groups, the cecal microbiota composition of 30-day-old vaccinated, non-challenged SPF chicks was dominated by Faecalibacterium prausnitzii, Blautia hominis, and Subdoligranulum variabile species while the cecal microbiota composition of 27-week-old vaccinated, non-challenged commercial pullets were dominated by Subdoligranulum variabile, Negativibacillus massiliensis, and Mediterraneibacter glycyrrhizinilyticus [88]. Previously, genera like Faecalibacterium and Subdoligranulum were detected in the cecal pouch contents of broiler chickens [92], and their contribution to the human microbiota is considered beneficial [93,94]. Alternatively, Subdoligranulum and Faecalibacterium abundance in cecal pouch contents of 42-day-old Ross 708 broiler chicks negatively correlated (p = 0.03 and p = 0.0004, respectively) with body weight (i.e., the smaller the bird, the greater the abundance of these genera). Furthermore, the implications for the enrichment of these genera in a bird’s cecal pouch are not yet understood [95].
In response to antibiotic-free production practices, avian pathogenic E. coli vaccination programs are being integrated into commercial poultry management to reduce the prevalence of colibacillosis in flocks [96,97,98,99]. For example, Beirão et al. [98] vaccinated Cobb broiler chicks with a commercially available aroA-deleted E. coli vaccine and assessed the cecal microbiota. Following vaccination with E. coli at 1 day of age, richness of cecal pouch microbiota was lower than that of the control group at 3, 14, and 25 days of age. This one-time vaccination with the aroA-deleted E. coli vaccine also enriched genera like Lactobacillus and Escherichia at 3 days of age, Streptococcus and Peptoclostridium at 14 days of age, and Subdoligranulum, Ruminococcus, and Alistipes at 25 days of age [98].
To reduce the prevalence of common poultry pathogens, vaccination programs are constantly being developed for commercial poultry flocks [100,101,102,103,104,105]. Some of these pathogens may be associated with elevated flock morbidity (Clostridium perfringens) while others are more closely associated with human foodborne illnesses (Campylobacter jejuni). Along with assessing pathogen reduction and immunological memory, several of these studies have also evaluated flock microbiome status during the vaccination period [104,105]. For example, Heidarpanah et al. [104] evaluated recombinant protein antigens from Clostridium perfringens as vaccine candidates to prevent necrotic enteritis in Ross broiler chicks. Broiler chicks were vaccinated with one of five different candidate protein antigens at 7, 14, and 21 days of life and cecal microbiota were assessed. The abundance of Bacteroidaceae, Lactobacillaceae, and Clostridia (unclassified) families were higher in several of the candidate protein antigen immunization groups while Enterobacteriaceae family abundance decreased in other candidate protein antigen groups when compared to the adjuvant control group [104]. Even though the effects of vaccination programs on ceca microbiota status are not completely understood, it is pertinent to note that the increased abundance in the Lactobacillaceae family observed by Heidarpanah et al. [104] differs from the jejunal microbiota status of broilers exhibiting subclinical and clinical C. perfringens infections (depressed abundance of the Lactobacillaceae family) [103]. Additionally, evenness, but not richness, of broilers’ cecal microbiota was influenced by the vaccination of several candidate C. perfringens protein antigens [104].
Alternatively, Campylobacter jejuni is a pathogen that is of little concern for poultry health but is a major pathogen associated with human foodborne illnesses. Gloanec et al. [105] evaluated the cecal pouch microbiota of Ross 308 broiler chicks administered with two regimens (two- versus four-intramuscular administrations) of a Campylobacter jejuni recombinant protein vaccine candidate and challenged with live C. jejuni. At 42 days of age, compositional differences in the genera of cecal pouch microbiota were evident between the two vaccine administration regimens: Faecalibacterium and Oscillibacter genera increased among broilers vaccinated with the two-administration regimen of a candidate protein antigen, while Blautia and Subdogralinum genera increased among broilers vaccinated with the four-administration regimen of a candidate protein antigen [105]. However, these genera did not differ from each regimen’s respective control group, indicating that the vaccination procedure rather than the protein administered altered the cecal pouch microbiota. Furthermore, broilers vaccinated and challenged with C. jejuni exhibited lower cecal microbiota diversity when compared to those that were non-vaccinated and challenged, but there was no difference in richness among vaccinated and unvaccinated broiler groups [105].
Although not tested in a poultry model, Elizaldi et al. [106] correlated antigen-specific adaptive immune responses to changes in mucosal microbiota during the vaccination period. Intradermal vaccination with an HIV-1 DNA vaccine in female rhesus macaques increased the T cell responses in the blood at 7- and 14-days post-tertiary immunization along with elevated serum IL-6, CXCL10, IL-21, and IL-17 protein concentrations at 7 days post-immunization. At the same time, the presence of lactic acid-producing microbes (Lactobacillus and Streptococcus genera) decreased in the rhesus macaque vaginal mucosa from one to four weeks post-tertiary immunization, while the abundance of microbes associated with bacterial vaginosis (Atopobium genus) were negatively correlated with HIV-1-specific antibodies in the serum at 8 weeks post-tertiary immunization [106].
Ultimately, the influence of vaccine administration on gut microbiota appears to be as variable as the beneficial effects of probiotic supplementation during vaccine administration (Table 2). The type of vaccine (bacterial versus viral; attenuated versus killed) and the test subject (human versus animal; regional variations) seem to play critical roles in how the gut microbiota is altered during vaccine administration. For example, results such as those from Park et al. [86] exhibit diverse microbiome states that are usually individual- or flock-specific. Even so, regardless of the experimental animals, it appears that microbes essential for fiber digestion and lactic acid secretion play critical roles in regulating inflammatory responses to vaccine administration [55,86,106].

5. Conclusions

The influence of vaccine responses on the gut microbiota and the impact of established microbiota on vaccine immunogenicity are still developing fields of research. Although many unanswered questions remain, the current research makes it clear that the intricate interactions between host and microbe play important roles in systemic inflammation as well as the development of immunological memory. By understanding these complex interactions in the host and the effects of environmental factors on gut microbiome, more effective and safe vaccination regiments for poultry can continue to be developed. Continued investigations of the complex vaccine–gut microbiome interactions in poultry flocks may also allow for the development of effective vaccination programs that utilize prebiotic and probiotic supplementations to ameliorate inflammation and improve immunological memory, although these programs may need to be tailored to farm or region. Altogether, gut microbiome status continues to be a persistent and influential factor for health and disease and continued investigative research is needed.

Author Contributions

Conceptualization, C.N.B., J.Z. and G.F.E.; writing—original draft preparation, C.N.B.; writing—review and editing, J.Z. and G.F.E.; supervision, G.F.E. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

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Beck, C.N.; Zhao, J.; Erf, G.F. Vaccine Immunogenicity versus Gastrointestinal Microbiome Status: Implications for Poultry Production. Appl. Sci. 2024, 14, 1240. https://doi.org/10.3390/app14031240

AMA Style

Beck CN, Zhao J, Erf GF. Vaccine Immunogenicity versus Gastrointestinal Microbiome Status: Implications for Poultry Production. Applied Sciences. 2024; 14(3):1240. https://doi.org/10.3390/app14031240

Chicago/Turabian Style

Beck, Chrysta N., Jiangchao Zhao, and Gisela F. Erf. 2024. "Vaccine Immunogenicity versus Gastrointestinal Microbiome Status: Implications for Poultry Production" Applied Sciences 14, no. 3: 1240. https://doi.org/10.3390/app14031240

APA Style

Beck, C. N., Zhao, J., & Erf, G. F. (2024). Vaccine Immunogenicity versus Gastrointestinal Microbiome Status: Implications for Poultry Production. Applied Sciences, 14(3), 1240. https://doi.org/10.3390/app14031240

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