The Editorial on the Research Topic
Gut Health: The New Paradigm in Animal Production
Optimal gut health is of vital importance to the performance of production animals.
Gut health is synonymous in animal production industries with animal health. Although
there does appear to be a direct relationship between animal performance and a “healthy”
gastrointestinal tract (GIT), there is no clear definition for “gut health” that encompasses
a number of physiological and functional features, including nutrient digestion and
absorption, host metabolism and energy generation, a stable microbiome, mucus layer
development, barrier function, and mucosal immune responses (1–8). The GIT is responsible
for regulating physiological homeostasis that provides the host the ability to withstand
infectious and non-infectious stressors (9–19). Understanding the interactions between
these diverse physiological features emphasizes the extent of areas encompassed by
gut health and the ability to regulate animal production. For our part, we will define
gut health as the absence/prevention/avoidance of disease so that the animal is able
to perform its physiological functions in order to withstand exogenous and endogenous
stressors. Furthermore, worldwide public concerns about the production animal industries’
dependency on the use of growth-promoting antibiotics (AGPs) have resulted in the
ban of AGPs by the European Union and a reassessment of their use in the United States.
Thus, current research is focused on alternatives to antibiotics for sustainable food
animal production (20).
A recent Research Topic in Frontiers in Veterinary Infectious Diseases was on gut
health and wondering whether we should consider gut health as the new standard when
considering animal production. The objective of this Editorial is not to review the
literature on gut health in production animals, but, rather, it is our attempt to
summarize findings of the 15 papers that were published within this Research Topic.
Obviously, the Topic was not comprehensive in the production animal commodity reported,
but it was a very good overview of the current status of the ongoing work in gut health
and physiology within the veterinary community.
Gut Microbiome
The complex gut microbiome is not a silent organ or a collection of passenger microorganisms;
but rather, the intestinal microbial community represents active participants in vertebrate
immunity and physiology. The gut microbiota confers health benefits to the host, including
aiding in the digestion and absorption of nutrients, contributing to the construction
of the intestinal epithelial barrier, the development and function of the host immune
system, and competing with pathogenic microbes to prevent their harmful propagation
(18, 21). Unlike the host genome, which is rarely manipulated by xenobiotic intervention,
the microbiome is readily changeable by diet, ingestion of antibiotics, infection
by pathogens, and other life events [Danzeisen et al.; Ballou et al.; Mon et al.;
Malmuthauge et al.; (8)].
Antibiotics have a great effect on the host normal microbiota upsetting the balance
and inducing a dysbiotic state (8). The use of sub-therapeutic doses of antibiotics
in animal diets have been a common practice for promoting growth due to their ability
to increase feed efficiency or preventing diseases. Danzeisen et al. used a sub-therapeutic
concentration of penicillin to define beneficial members of the microbiome in turkeys
that resulted in increased feed efficiency and enhanced growth. By identifying the
specific bacterial populations responsible for improved performance, the authors hypothesize
that these bacteria can then be used as probiotics.
The microbiome has a direct effect on the development and function of the mucosal
immune system. Malmuthauge et al. found significant associations between the microbiome
and the expression of genes regulating the mucosal barrier and innate immunity in
neonatal cattle. Regional differences in the microbiome were associated with regional
differences in innate immune gene transcription. Similar findings were described between
the microbiome of broiler chickens and the expression of avian cytokine RNA transcripts
(Oakley and Kogut). A negative correlation between pro-inflammatory cytokine genes
and the phylum Firmicutes was found; whereas a positive correlation was identified
with the pro-inflammatory cytokines and the phylum Proteobacteria.
Wigley and Ballou et al. asked the questions: what constitutes a normal or healthy
microbiome and what effects do treatments that are being used to improve gut health
(vaccines and probiotics) have on the development of the gut microbiome? Wigley pointed
out that certain bacteria, such as Escherichia coli, Clostridium perfringens, and
Campylobacter, are often considered commensals and part of the cecal microbiome. The
removal of AGPs, manipulation of the cecal microbiome, changing husbandry practices,
and other internal and external factors lead to changes in the host responses that
result in “new” infections (22–25). Using a live attenuated Salmonella vaccine or
a lactic acid bacteria probiotic, Ballou et al. characterized the effects of gut health
treatments have on the microbiome. Alterations in microbial diversity in the microbiome
of young chicks given the vaccine and, to a less extent with the probiotic, were found,
which were independent of bacterial colonization by the treatments. The microbiome
alterations were maintained through 28 days of age, suggesting that early exposure
to certain bacteria may permanently influence the microbial diversity in the microbiomes.
Similar results were described by Mon et al. where a Salmonella infection in day-old
chicks induced a profound decrease in microbial diversity in the cecum. Specifically,
there was an increase in Enterobacteriaceae and a decrease in butyrate-producing bacteria
in the Lachnospiraceae family implying that exposure to a Salmonella infection early
after hatch can impact the composition of the developing microbiome that affects colonization
resistance to microbial pathogens.
Yeast-derived dietary supplements are increasingly being used as pre- and probiotics
to improve gut health (26). Roto et al. detailed the effects of yeast-derived compounds
in livestock diets and their effect of the microbiome. The use of yeast-derived compounds
as supplements in livestock diets improved performance, increased beneficial bacteria
in the microbiome, and increased immune responsiveness. Additionally, the yeast-derived
products are cost-effective, do not induce antimicrobial resistance in pathogens,
and, because of their multiple mechanisms of action, can be used in the variety of
environments found in livestock industries.
Mucosal Immune Response
The intestinal tract is an active immunological organ with more resident immune cells
than anywhere else in the body. They are organized in lymphoid structures called Peyer’s
patches and isolated lymphoid follicles, such as the cecal tonsils. Macrophages, dendritic
cells, various subsets of T cells, B cells, and secretory IgA all contribute to the
generation of a proper immune response to invading pathogens, while keeping the resident
microbial community in check without generating an overt inflammatory response.
In addition to the immune cells, the intestinal epithelial cells contribute to mucosal
immunity (21). A single layer of epithelial cells separates the densely colonized
and environmentally exposed intestinal lumen from the sterile subepithelial tissue,
maintains homeostasis in the presence of the enteric microbiota, and contributes to
rapid and efficient antimicrobial host defense in the event of infection with pathogens.
Both epithelial antimicrobial host defense and homeostasis rely on signaling pathways
induced by innate immune receptors demonstrating the active role of epithelial cells
in the host–microbial interplay. Lastly, a layer of mucus overlying the intestinal
epithelium forms a physical barrier between the mucosa and the resident microbiota,
minimizing both microbial translocation and excessive immune activation by the resident
microbes.
Intestinal integrity is fundamentally important for the growth and performance of
food animals. One of the main advantages of AGPs in animal feed was the reduction
in the low-grade, food-induced chronic inflammation that would otherwise be detrimental
to animal growth (27). Removal of AGPs from animal feeds results in an increase in
enteric disorders, infections, and diseases (24, 25, 28, 29). One of the issues with
determining dysfunction of the gut barrier is the lack of specific biomarkers. Two
papers in the Research Topic described new methods that: (a) identify serum and tissue
biomarkers of gut barrier function (Chen et al.) and (b) identify a non-invasive means
to measure gut inflammation as a marker of gut leakage (Kuttappan et al.). Additionally,
Ayoola et al. found that the addition of supplemental enzymes (β-mannanase, a blend
of xylanase, amylase, protease) to the diet of turkeys reduced food-induced inflammation.
One of the main immune functions of the epithelial cell surface is the production
of antimicrobial peptides or host defense peptides [HDPs; Ref. (30)]. HDPs are a diverse
group of small molecules that possess antimicrobial, immunomodulatory, and barrier
function enhancing activities. Robinson et al. described several classes of small-molecule
compounds that induce specific induction of endogenous HDP. Furthermore, supplementation
of these HDP-inducing compounds enhanced bacterial clearance, improved enteric barrier
integrity, and improved animal production efficiency with minimal intestinal inflammation.
The host/pathogen interactome leads to a number of immune and biochemical changes
at the infection site as the pathogen tries to derive nutrients from the host, while
the host uses immunometabolic countermeasures against the pathogen. Arsenault and
Kogut developed a novel tool that characterizes the immunometabolic phenotype of infected
cells/tissues. The kinome peptide array identifies alterations in phosphorylation
events in both immunity and metabolism simultaneously. The kinome array was used to
identify the immune changes occurring in the cecum of chickens during the establishment
of a persistent, asymptomatic Salmonella infection (Kogut and Arsenault). A number
of immune signaling pathways were activated at the site of infection that indicates
the development of a tolerogenic response allowing the bacteria to establish a persistent
infection.
Direct Fed Microbials
The increased use of grains as alternative energy sources in poultry diets has led
to an issue with higher levels of less digestible carbohydrates that result in an
increase in digesta viscosity and food-induced inflammation. One alternative to optimize
digestibility of these complex carbohydrates is the inclusion of dietary enzyme supplements.
Latorre et al. took this concept a step further and described the selection of a Bacillus
spp. direct fed microbial (DFM) candidate based on their capacity to produce enzymes
that breakdown these complex carbohydrates. Bacillus spp. that produced cellulose
and xylanase were used as DFM and were found to reduce digesta viscosity and reduce
C. perfringens growth in a number of different diets containing different complex
carbohydrates.
A group of natural products known as phytobiotics have been the focus of several studies
in recent years as antibiotic alternatives (31). Phytobiotics are plant-derived products
used in feed that possess antimicrobial activity, provide antioxidative effects, enhance
palatability, improve gut functions, and promote growth. Murugesan et al. compared
the effects of a commercial phytogenic feed additive on growth, intestinal morphology,
and microbial composition in chickens to the effects of an AGP. Improved growth, increased
intestinal villus height, and decreased total cecal numbers of Clostridium and anaerobic
bacteria were comparable between the two treatments. However, birds fed the phytobiotic
additives had a significant reduction in coliforms and an increase in Lactobacillus
spp. implying an environment that was more suitable for the establishment of growth-promoting
bacteria in the microbiome.
Although the GIT is frequently described simply as “the gut,” it is actually made
up of (1) an epithelium; (2) a diverse and robust immune arm, which contains most
of the immune cells in the body; and (3) the commensal bacteria, which contain more
cells than are present in the entire host organism. Understanding of the crosstalk
between ALL of these interrelated components of the gut is what cumulatively makes
the gut the basis for the health of animals and the motor that drives their performance.
Author Contributions
All authors listed have made substantial, direct, and intellectual contribution to
the work and approved it for publication.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.