ArticlePDF AvailableLiterature Review

Implications of butyrate and its derivatives for gut health and animal production

Authors:

Abstract

Butyrate is produced by microbial fermentation in the large intestine of humans and animals. It serves as not only a primary nutrient that provides energy to colonocytes, but also a cellular mediator regulating multiple functions of gut cells and beyond, including gene expression, cell differentiation, gut tissue development, immune modulation, oxidative stress reduction, and diarrhea control. Although there are a large number of studies in human medicine using butyrate to treat intestinal disease, the importance of butyrate in maintaining gut health has also attracted significant research attention to its application for animal production, particularly as an alternative to in-feed antibiotics. Due to the difficulties of using butyrate in practice (i.e., offensive odour and absorption in the upper gut), different forms of butyrate, such as sodium butyrate and butyrate glycerides, have been developed and examined for their effects on gut health and growth performance across different species. Butyrate and its derivatives generally demonstrate positive effects on animal production, including enhancement of gut development, control of enteric pathogens, reduction of inflammation, improvement of growth performance (including carcass composition), and modulation of gut microbiota. These benefits are more evident in young animals, and variations in the results have been reported. The present article has critically reviewed recent findings in animal research on butyrate and its derivatives in regard to their effects and mechanisms behind and discussed the implications of these findings for improving animal gut health and production. In addition, significant findings of medical research in humans that are relevant to animal production have been cited.
Review Article
Implications of butyrate and its derivatives for gut health and animal
production
Andrea Bedford, Joshua Gong
*
Guelph Research and Development Centre, Agriculture and Agri-food Canada, Guelph, Ontario N1G 5C9, Canada
article info
Article history:
Received 20 July 2017
Accepted 10 August 2017
Available online 13 September 2017
Keywords:
Butyrate
Butyrins
Antibiotic alternatives
Gut health
Nutrition
Animal production
abstract
Butyrate is produced by microbial fermentation in the large intestine of humans and animals. It serves as
not only a primary nutrient that provides energy to colonocytes, but also a cellular mediator regulating
multiple functions of gut cells and beyond, including gene expression, cell differentiation, gut tissue
development, immune modulation, oxidative stress reduction, and diarrhea control. Although there are
a large number of studies in human medicine using butyrate to treat intestinal disease, the importance
of butyrate in maintaining gut health has also attracted signicant research attention to its application
for animal production, particularly as an alternative to in-feed antibiotics. Due to the difculties of using
butyrate in practice (i.e., offensive odor and absorption in the upper gut), different forms of butyrate,
such as sodium butyrate and butyrate glycerides, have been developed and examined for their effects on
gut health and growth performance across different species. Butyrate and its derivatives generally
demonstrate positive effects on animal production, including enhancement of gut development, control
of enteric pathogens, reduction of inammation, improvement of growth performance (including
carcass composition), and modulation of gut microbiota. These benets are more evident in young
animals, and variations in the results have been reported. The present article has critically reviewed
recent ndings in animal research on butyrate and its derivatives in regard to their effects and mech-
anisms behind and discussed the implications of these ndings for improving animal gut health and
production. In addition, signicant ndings of medical research in humans that are relevant to animal
production have been cited.
©2017, Crown copyright. Chinese Association of Animal Science and Veterinary Medicine. Production
and hosting by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction
Short-chain fatty acids (SCFA) are organic fatty acids with 1 to 6
carbons produced within the intestinal lumen by bacterial
fermentation of undigested dietary carbohydrates, and to a lesser
extent, dietary and endogenous proteins such as sloughed epithe-
lial cells and mucous, entering the colon (Topping and Clifton,
2001). The SCFA that are most abundant in the gastrointestinal
tract (GIT) are acetate, propionate, and butyrate. The production of
these SCFA allows the salvage of energy mainly from carbon sources
that are not digested in the small intestine. It has been estimated
that SCFA can contribute 5% to 15% of the total caloric requirements
of humans (Bergman, 1990).
Despite being the least abundant of the 3 primary SCFA listed,
butyrate is important as it is a major metabolite for the colonic
epithelial cells: as much as 90% of butyrate is metabolized by
colonocytes (Hamer et al., 20 08). Colonocytes are instrumental in
the absorption of water, sodium, and chloride from the intestinal
lumen. Butyrate has also been shown to have multiple benecial
effects in the GIT as well as the peripheral tissues, and acts
through multiple mechanisms, but many of them are related to
its regulatory effects on gene expression (Canani et al., 2011).
Butyrate is part of a class of epigenetic substances known as
histone deacetylase inhibitors (HDI). Histone deacetylases act by
*Corresponding author.
E-mail address: joshua.gong@agr.gc.ca (J. Gong).
Peer review under responsibility of Chinese Association of Animal Science and
Veterinary Medicine.
Production and Hosting by Elsevier on behalf of KeAi
Contents lists available at ScienceDirect
Animal Nutrition
journal homepage: http://www.keaipublishing.com/en/journals/aninu/
http://dx.doi.org/10.1016/j.aninu.2017.08.010
2405-6545/©2017, Crown copyright. Chinese Association of Animal Science and Veterinary Medicine. Production and hosting by Elsevier B.V. on behalf of KeAi Commu-
nications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Animal Nutrition 4 (2018) 151e159
removing the acetyl groups from lysine residues leading to the
formation of a condensed and transcriptionally silent chromatin.
TheHDIblockthisactionandcanresultinhyperacetylationof
histones, impacting a large amount of gene expression (Marks
et al., 2000).
The SCFA, including butyrate, possess antimicrobial activity, and
have been widely used as feed additives in an effort to control
pathogenic bacteria. Fatty acids and their monoglycerides have also
been shown to be effective in inhibiting bacterial growth (Kabara
et al., 1972; Thormar et al., 2006). Being supplemented into the
diets of newly hatched chicks, butyric acid signicantly reduced
Salmonella colonization in the ceca (Cox et al., 1994). In an in vitro
study by Namkung et al. (2011), butyric acid and its derivatives,
monobutyrin and a mix of mono-, di-, and tri-butyrin, were tested
for their antimicrobial activities at different concentrations against
Salmonella Typhimurium and Clostridium perfringens. They found
that Salmonella was best inhibited by butyric acid followed by
mono-butyrin, with tributyrin having minimal inhibition without
the addition of lipase, and that C. perfringens growth was attenu-
ated by both butyric acid and its glycerides in the same manner
(Namkung et al., 2011). Sodium butyrate supplementation in vitro
has been shown to induce the expression of host defence peptides,
including
b
-defensins and cathelicidins, in a variety of chicken cell
types, such as HD11 macrophage cells, primary monocytes, and
bone marrow cells, as well as jejunal and cecal explants (Sunkara
et al., 2011). Very recently, Rivera-Chavez et al. (2016) reported
that streptomycin treatment depleted commensal, butyrate-
producing Clostridia from the mouse intestinal lumen, leading to
decreased butyrate levels, increased epithelial oxygenation, and
aerobic expansion of Salmonella enterica serovar Typhimurium.
Epithelial hypoxia and Salmonella restriction could be restored by
tributyrin treatment.
There have been many investigations into the effects of buty-
rate supplementation into diets on animal performance, in addi-
tion to the studies of its potential applications in human health.
One of the major problems in the application of butyrate is the
difculty in handling. Butyrate has an offensive odor making it
unpleasant to work with, and can deter animals from consuming
feed with free butyrate incorporated. Moreover, free butyrate has
been shown to be largely absorbed in the upper GIT, meaning that
the majority would not reach the large intestine, including the
colon, where butyrate would exert its major functions (Pituch
et al., 2013). In this regard, butyrate glycerides, butyrate salts,
and different encapsulation techniques have been developed and
used in order to ease the handling and prevent the release of
butyrate in the upper GIT.
Butyrate glycerides, including mono-, di-, and tri-butyrin,
consist of a varied number of butyric acid molecules attached to
glycerol backbone. In the small intestine, the butyrate is liberated
from the glycerol through the action of lipase. In this form, the
butyrate is protected from absorption in the upper GIT. Sodium
butyrate is the sodium salt of butyric acid. It can be supplemented
freely to stimulate development in the upper GIT or in a protected
form, e.g., in a triglyceride matrix, to allow a slower release and
target the lower GIT.
Because of their antimicrobial activity, function as HDI, and ef-
fect on host immune response, butyrate and its derivatives are
considered to be potential substitutes for in-feed antibiotics for
animal production, as well as promising treatments for inamma-
tory bowel diseases in humans. This review will summarize and
critically evaluate previous studies on the effects of butyrate and its
derivatives on animal performance with the effects on human
health as a reference. In addition, their future applications in these
2elds, including both potential and challenges, will be discussed
along with connections between species.
2. Butyrate in the human colon
The importance of butyrate for human colon health has been
demonstrated in many studies with patients suffering from colon
inammatory diseases. The colonocytes of these patients present
with an impaired capacity to oxidize butyrate (Hamer et al., 2010;
De Preter et al., 2011). Through its function as an HDI, butyrate
can exert actions related to cellular homeostasis including
anti-diarrhetic, anti-oxidant, anti-carcinogenic, and anti-
inammatory functions (Williams et al., 2003; Mathew et al.,
2014; Jahns et al., 2015).
The absorption of butyrate has been shown to promote the
absorption of sodium, potassium, and water, the effects that give it
antidiarrheal properties (Ruppin et al., 1980). This is signicant as
diarrhea is a recognized complication in critically ill patients.
Additionally, patients with short bowel syndrome often experience
signicant loss of water and sodium due to the lack of absorption;
butyrate supplementation can improve this absorption and reduce
the requirement for intravenous electrolyte replacement
(Tappenden, 2010). Dysbiosis, a primary cause of diarrhea, is caused
by an antibiotic disturbance of the gut microbiota that suppresses
their fermentation and production of butyrate (Whelan and
Schneider, 2011). With the supplementation of ber into the diets
of jejunal feeding critically ill patients, an increase in butyrate-
producing bacteria was observed, and 75% of patients exhibited a
cessation of diarrhea (O'Keefe et al., 2011).
The anti-inammatory properties of butyrate have been shown
to be mediated by several mechanisms including: the reduction of
pro-inammatory cytokine expression (interferon gamma [IFN-
g
],
tumor necrosis factor-
a
[TNF-
a
], interleukin-1B [IL-1B], IL-6,IL-8),
the induction of IL-10 and transforming growth factor-B (TGF-B)
expression and signaling, the induction of nitric oxide synthase and
metalloproteinases, and the reduction of lymphocyte proliferation
and activation (Kyner et al., 1976; Segain et al., 2000; Matsumoto
et al., 2006; Meijer et al., 2010; Fung et al., 2012). The most stud-
ied anti-inammatory pathway of butyrate is via the inhibition of
nuclear factor kappa B (NF-kB). This pathway controls the expres-
sion of genes encoding pro-inammatory cytokines, inammation-
inducing enzymes, growth factors, heat shock proteins, and im-
mune receptors (Vinolo et al., 2011).
Several studies have linked impaired butyrate metabolism with
mucosal damage and inammation in patients with inammatory
bowel diseases including ulcerative colitis and Crohn's disease
(Roediger,1980; Den Hond et al., 1998; Duffy et al., 1998; De Preter
et al., 2011; Kovarik et al., 2011; De Preter et al., 2012; Morgan et al.,
2012), suggesting that treatments to increase butyrate in the GIT of
these patients can prove to be benecial. More data have indicated
that intestinal inammation also affects butyrate transport, and
thus its oxidation (Thibault et al., 2007). Various experimental
models have shown that monocarboxylate transporter 1 (MCT1)
transports butyrate into colonic epithelial cells (Tamai et al., 1995;
Ritzhaupt et al., 1998; Cuff et al., 2005), and that MCT1 down-
regulation is common in patients with ulcerative colitis (Thibault
et al., 2010; De Preter et al., 2011). Butyrate intake has shown a
positive effect in experimental studies on inammatory bowel
disease (Hamer et al., 2010; Komiyama et al., 2011; Vieira et al.,
2012), though clinical studies have shown inconsistent results
(Russo et al., 2012). Butyrate irrigation has been shown to improve
inammation symptoms in biopsies from inammatory bowel
disease patients; however, high concentrations are required to
illicit these improvements (Segain et al., 2000).
There are several mechanisms by which butyrate can control
oxidative stress. In a study with healthy human subjects, the
administration of a daily butyrate enema (10,000 mg/kg) for 2
weeks resulted in an increase in the anti-oxidant glutathione, and a
A. Bedford, J. Gong / Animal Nutrition 4 (2018) 151e159152
decrease in uric acid production compared to those without buty-
rate treatment (Hamer et al., 2009). However, when a similar study
was performed on patients with ulcerative colitis in remission,
butyrate showed only minor effects on inammatory and oxidative
stress parameters that seem to be dependent on the level of
inammation (Hamer et al., 2010). In vitro, physiological levels of
butyrate have been found to reduce H
2
O
2
-induced DNA damage,
increase catalase expression (one of the key defense systems
against oxidative stress), and reduce cyclooxygenase-2 (COX-2)
expression (an indicator of inammation) in human colonocytes
(Sauer et al., 2007). These results also support the potential of
butyrate in cancer treatment and prevention, as COX-2 over-
expression is found in colon tumors.
Butyrate has been linked to the prevention and inhibition of
colon carcinogenesis, largely through the increased intake of di-
etary ber, resulting in increased fermentation and butyrate pro-
duction (Trock et al., 1990; Howe et al.,1992; Bingham et al., 2003).
A role for butyrate in colon cancer treatment has been supported by
the ndings of downregulated butyrate transporters (MCT1 and
sodium-coupled monocarboxylate transporter 1 [SMCT1]) in hu-
man colon cancer tissue (Lambert et al., 2002; Li et al., 2003),
resulting in reduced uptake and metabolism of butyrate in colo-
nocytes. Several rat models have been used to demonstrate a pro-
tective effect of butyrate on colorectal carcinogenesis (McIntyre
et al., 1993; Kameue et al., 2004; Bauer-Marinovic et al., 2006),
but direct evidence for a protective effect of butyrate on carcino-
genesis in humans is lacking. One study has investigated the rela-
tionship in humans between butyrate and G-protein-coupled
receptor GPR109A in the colon (Thangaraju et al., 2009). It was
found that butyrate binding to GPR109A can induce apoptosis in
colon cancer cells as well as blocking activation of the NF-kB
inammation pathway, potentially mediating inammatory
bowel disease (IBD). Butyrate has also been shown to enhance the
effects of anticancer drug therapy including vincristine, celecoxib,
cisplatin, and etoposide via its HDI activity, increasing the cyto-
toxicity of the drugs (Ramos et al., 2004; Kang et al., 2012;
Maruyama et al., 2012).
The overall aim for the use of butyrate in humans differs greatly
from that for animal production. Although the use of butyrate in
humans is desired mainly for the treatment of disease and in animal
production is for disease prevention and growth promotion, the
functions in enhancing GIT health, releasing stress, and controlling
inammation are commonly desired for both humans and animals.
Thus, the mechanisms of butyrate effects revealed by human
research can be valuable references to promote the research and
application of butyrate and its derivatives in animal production.
3. Butyrate supplementation in poultry
With the dramatic improvements in growth rate and feed
conversion in chicken production over the past 40 years, the
nutrition and health care of chickens are becoming more critical
and demanding (Yegani and Korver, 2008; Cooper and Songer,
2009). The nutritional and health status of birds is largely inu-
enced by their gut health, which affects digestion, absorption, and
metabolism of nutrients, as well as disease resistance and immu-
nity (Kelly and Conway, 2001; Yegani and Korver, 2008). There are a
number of disorders associated with the gut health of chickens,
including diarrhea, malabsorption syndrome, coccidiosis, and
necrotic enteritis (caused by an overgrowth of C. perfringens)
(M'Sadeq et al., 2015). In-feed butyrate has been studied as a
possible additive to combat GIT disorders, and ultimately enhance
chicken gut health and improve bird performance.
The rst week of a broiler chick's life is accompanied by many
changes in developmental processes, including changes in organ
growth patterns and development of immunocompetence (Nitsan
et al., 1991), which is critical for high producing broiler chickens.
Given the functions of butyrate and its derivatives, supplementa-
tion of these additives can be one effective approach to enhance
chicken gut development and health, including the development of
immunity, to possibly improve the quality of the chicken carcass. In
one previous study, Hu and Guo (2007) observed a dose response in
body weight gain to sodium butyrate at tested concentrations of
500, 1,000, and 2,00 0 mg/kg through 21 days of treatment. They did
not detect a signicant difference in the absorptive function of the
jejunum, but an increase in the concentrations of DNA, RNA, and
protein in the duodenal mucosa in response to increased sodium
butyrate levels was observed. This suggests that sodium butyrate
stimulated the growth of the duodenum, and was largely absorbed
here before entering the jejunum to exert its function. The authors
also found that the jejunal villus height to crypt depth ratio was
increased in a dose responsive action with dietary sodium butyrate
inclusion, which suggests improved digestive tract maintenance
and could be the reason behind the improved growth performance.
Nevertheless, it remains to be determined why this jejunal histo-
morphological improvement was not linked to an increased
absorptive function.
The effect of sodium butyrate supplementation on bacterial
infection in broilers has also been reported. One example is the
investigation by Fernandez-Rubio et al. (2009) into the effect of
feeding either free or partially protected sodium butyrate in vege-
table fats (both at 920 mg/kg) on Salmonella enteritidis colonization
in broilers. In their study, birds were challenged with Salmonella on
day 5 post-hatch and fecal shedding was assessed periodically from
day 6 through day 41. After 42 days, all birds were euthanized and
tissues were sampled for bacteriological analysis. They found that
both protected and free sodium butyrate were effective in reducing
Salmonella burden in birds from 27 days onward, with free butyrate
being more effective in the early stage of infection (at day 13) and
protected sodium butyrate having more effect in late stage infec-
tion (at day 41). Protected sodium butyrate was more effective at
preventing colonization in the crop and cecum, and infection in the
liver, compared to the free form. The growth performance of these
birds was not reported. These results suggest that the slow and
varied release of the protected sodium butyrate is possibly more
effective in preventing bacterial infection, as it is released and
active all along the digestive tract.
The effect of sodium butyrate on host-defense peptide (HDP)
expression and disease resistance has also been studied. In a study
reported by Sunkara et al. (2011), 5-day-old birds were separated
into 2 groups on diets with or without sodium butyrate (1,000 mg/
kg), and challenged with S. Enteritidis at 7 days of age. Sodium
butyrate supplementation resulted in a signicant decrease in S.
Enteritidis in the cecal digesta, and induced the expression of HDP
Avian beta-defensin 9 in the crop. Sodium butyrate has also been
shown to moderate the immune response of broiler chickens.
When supplemented with 1,000 mg/kg sodium butyrate, birds
challenged with Escherichia coli lipopolysaccharide (LPS) had a
reduced level of serum IL-6 and TNF-
a
, and increased serum su-
peroxide dismutase and catalase activities (Zhang et al., 2011). This
result agrees with the anti-inammatory effects observed in
humans, in which butyrate reduced proinammatory cytokine
expression (Segain et al., 2000). Also of interest, sodium butyrate
supplementation prevented a reduction in growth that was
observed in the control challenged birds. These protective attri-
butes of sodium butyrate support its potential inclusion as a sub-
stitute for antibiotics in broiler diets.
Sodium butyrate supplementation has also been applied to layer
hens, focusing on the enhancement of egg production and egg
characteristics. Nollet et al. (2014) tested different inclusion rates of
A. Bedford, J. Gong / Animal Nutrition 4 (2018) 151e159 153
sodium butyrate into the diets of layer hens. They found that the
highest inclusion level tested, 500 mg/kg, had no effect on the
average egg weight. However, lay efciency and feed conversion
were improved, as was the daily egg mass output in g/(bird$d).
Additionally, inclusion levels over 100 mg/kg reduced the per-
centage of eggs having egg bending, indicating stronger shells
(Nollet et al., 2014). In another study with layer hens, the effect of
the addition of 2,000 mg/kg sodium butyrate on laying perfor-
mance, with or without phytase in the diet (500 U/kg), was
investigated (Vieira et al., 2011). Contrary to the previous study,
they did not observe any changes in egg production, egg charac-
teristics, or calcium balance with the addition of sodium butyrate.
Further research thus appears to be required to determine if so-
dium butyrate supplementation is benecial for laying hens, and
how the observed affects in broiler chickens can be exploited for
egg production.
As with encapsulated sodium butyrate, butyrate glycerides
have been used in an effort to target butyrate release in the lower
GIT. Interested in their effect on small intestine morphology and
growth performance, Antongiovanni et al. (2007) tested a buty-
rate glyceride mix (mono-, di-, and tri-glycerides) at 4 different
levels (2,000, 3,500, 5,000, and 10,000 mg/kg) into the diets of
broiler chickens. Birds treated with the butyrate glyceride mix had
a higher live weight at slaughter, and an improved feed conversion
rate. Additionally, birds receiving the lowest inclusion levels of
butyrate glycerides (2,000 mg/kg) had shorter villi, longer
microvilli, and deeper crypts in the jejunum, a sign in increased
cell turnover (Zhang et al., 2005). This result is similar to what was
observed in birds supplemented with sodium butyrate, suggesting
that both butyrate derivatives are effe ctive in promoting intes tinal
development (Hu and Guo, 2007). With a mixture of butyric acid
glycerides (mono-, di-, and triglycerides) fed at 2,000 or
4,000 mg/kg, Leeson et al. (2005) observed no change in ADG, but
treatment birds had signicantly improved breast muscle and
carcass weight. Further, upon challenge with coccidiosis, butyrate
glyceride supplemented birds showed improved growth post-
challenge compared to unsupplemented birds (Leeson et al.,
2005). In agreeance with Leeson et al. (2005), one of our studies
investigating the effects on broiler performance of SILO Health
104 (a butyrate glyceride product, claimed by the manufacture to
contain 65% monobutyrin, 5% dibutyrin, and 30% a mix of mono-
and diglycerides of lauric, caprylic, capric, and propionic acids)
showed an increase in relative breast muscle weight (to body
weight) in a dose responsive manner (y¼18.428 þ0.000450x;
P¼0.0074) to the increase of SILO Health 104 supplementation
from 500 to 3,000 mg/kg, although ADG was unaffected (unpub-
lished data). Additionally, across multiple studies, we have
observed a decrease in relative abdominal fat weight with the
supplementation of either monobutyrin (Bedford et al., 2017a),
tributyrin (Bedford et al., 2017b), or their mixture (Yin et al., 2016)
at tested concentrations. These results, to be discussed in the
following section, provide additional evidence on the benecial
effects of butyrate glycerides on the performance, carcass traits,
and gut morphology of broiler chickens.
More recent studies have been performed in an attempt to
determine the mechanism of action behind the effects of butyrate
glycerides on broiler chickens. One effort was to elucidate the
pathways related to energy expenditure and lipid metabolism that
are affected by butyrate glyceride supplementation, Yin et al.
(2016) performed RNA-seq analysis on the liver and jejunum
from broilers treated with butyrate glycerides. In these birds,
RNA-seq analysis revealed 79 and 205 differentially expressed
genes (DEG) in the jejunum and liver, respectively. Further, 255
and 165 treatment specically expressed genes (TSEG) were found
in butyrate glyceride birds in the jejunum and liver, respectfully.
Among these genes, bioinformatic analysis determined a signi-
cant enrichment of DEG and TSEG involved in the biological
processes for reducing synthesis, storage, transportation and
secretion of lipids in the jejunum, and enhancing the oxidation of
ingested lipids and fatty acids in the liver. In particular, tran-
scriptional regulators of thyroid hormone responsive (THRSP)and
early growth response gene-1 (EGR-1)aswellasseveralDEG
involved in the peroxisome proliferator-activated receptors
(PPAR) signaling pathway were signicantly affected by dietary
intervention of butyrate glyceride for lipid catabolism. Also in this
study, serum triglycerides and total cholesterol were lowered in
butyrate glyceride birds. Fatty acid synthase levels were lowered
in the serum, liver and adipose tissue of butyrate glyceride fed
birds, while lipoprotein lipase was decreased in the jejunum, liver
and adipose of the same birds. These results suggest that the
reduced body fat deposition observed was due to the regulation of
gene expression inuenced by butyrate glycerides and provide a
valuable reference for future studies on the regulation of ingested
energy distribution and how it can be used to improve animal
production.
Following the study by Yin et al. (2016),Bedford et al. (2017b)
investigated the effects of tributyrate glycerides on the perfor-
mance of 2 different broiler strains (Ross 308 and Ross 708).
Although no overall changes in average daily gain or feed ef-
ciency were observed, tributyrate glyceride supplementation
signicantly lowered abdominal fat deposition, as well as fat
deposition in the breast muscle in both strains compared to
control birds. Supporting the changes in lipid metabolism, sig-
nicant differences in the expression of hepatic sterol regulatory
element-binding protein 1, peroxisome proliferator-activated re-
ceptor alpha, and ATP citrate lyase were observed between trib-
utyrate glyceride treated birds and controls. Very recently, Yang
et al. (unpublished data) investigated butyrate glycerides-induced
changes in the chicken intestinal microbiota and serum metabo-
lites as well as their links via pyrosequencing of bacterial 16S rRNA
genes and nuclear magnetic resonance (NMR)-based metab-
olomics analysis. They found that dietary treatment with butyrate
glycerides did not affect overall diversity of the intestinal micro-
biota, but altered its composition. Bacillus was the only genus in
the ileal microbiota that was signicantly modulated by butyrate
glyceride supplementation. In contrast, there were several
changes in the cecal microbiota composition, including a group of
butyrate-producing bacteria (Subdoligranulum). In particular,
Bidobacterium demonstrated a considerable increase in not only
the abundance but also the species diversity upon dietary inter-
vention with butyrate glycerides. The NMR-based analysis also
revealed changes in serum concentrations of metabolites,
including those of bacteria-derivation, such as choline, glycer-
ophosphorylcholine, dimethylamine, trimethylamine,
trimethylamine-N-oxide, lactate, and succinate (Nicholson et al.,
2012). The coincidence of the shift in the cecal microbiota
composition, particularly the increase in the abundance and
species diversity of Bidobacterium, with elevated serum con-
centrations of choline metabolites suggests a contribution from
intestinal bacteria to lipid metabolism/energy homeostasis in
broilers, which may have partially contributed to the decrease in
abdominal fat deposition described above. These ndings can
improve our understanding of the molecular mechanisms un-
derlying the effect of butyrate on chicken performance.
In the broiler duck, the addition of sodium butyrate into the
basic ration at 350, 700, and 1,050 mg/kg was reported to improve
feeding efciency in a dose responsive manner, compared to the
control group of ducks (Liu et al., 2011). The 2 higher butyrate
concentration groups had increased average daily gains compared
to control birds. In addition to the growth parameters, they
A. Bedford, J. Gong / Animal Nutrition 4 (2018) 151e159154
investigated the effect of sodium butyrate supplementation on the
fecal content of the ducks in regards to pollutants. Sodium butyrate
at 700 mg/kg was the best at reducing the levels of total nitrogen,
total phosphorus, and ammonia nitrogen in the feces. These envi-
ronmental parameters that have not been considered in relation to
butyrate supplementation in any other study, but could be an
additional, area of interest for future butyrate research in animal
production.
4. Butyrate supplementation in pigs
The weaning transition is a critical time period for piglets.
Shifting from liquid to solid feed, changes in environment, and
mixing with new pen mates are stressful, often resulting in a post-
weaning growth lag. A signicant factor in this growth lag is the
underdeveloped GIT due to early weaning, leading to the inability
to properly digest and absorb nutrients. There have been many
studies investigating different strategies and feed additives,
including SCFA, to ease the transition of piglet weaning (Ravindran
and Kornegay, 1993; Lalles et al., 2007; de Lange et al., 2010; Heo
et al., 2013; Thacker, 2013).
Early studies on the inclusion of organic acids in the diets of
weaned pigs have demonstrated that their inclusion can improve
growth performance, and increase digestibility of the diet
(Falkowski and Aherne, 1984; Henry et al., 1985). A further study
on the role of butyrate in the intestinal metabolism was reported
by Piva et al. (2002a). In the study, 6-week-old piglets were
divided into 2 groups fed an antibiotic-free conventional diet with
or without the inclusion of sodium butyrate (800 mg/kg) (Piva
et al., 2002a). Piglets fed sodium butyrate had a signicantly
higher ADG after 14 days of treatment compared to control pigs,
but this advantage did not carry through to 35 days of treatment.
It is proposed that this occurs due to the fact that butyrate has a
positive effect on cell proliferation of the intestinal epithelium,
which is of greater biological value in the early weaning period
when the small and large intestine are rapidly increasing in size
(Sakata and Setoyama, 1997). Additionally, pigs fed the sodium
butyrate diet had an increased feed intake compared to control
pigs through 35 days of treatment. The study by Sakata and
Setoyama (1997) suggests that sodium butyrate could encourage
solid feed intake, although the benecial effects may not be car-
ried through to growth performance over time, and perhaps an
earlier addition of butyrate to the diets may illicit increased
benecial responses. A later study by the same group included
sodium butyrate into the diets of 32-day-old weaned piglets at
1,000, 2,000, or 3,000 mg/kg for 6 weeks (Biagi et al., 2007). No
signicant differences were observed between treatments in
growth performance, intestinal morphology, or intestinal micro-
biota throughout the trial. Authors indicated that the lack of
response in these parameters may have been due to a different
dietary composition or gut maturation status compared to the
previous a trial, in which they did observe changes in growth
performance. Nonetheless, differences were observed in the
cecum of sodium butyrate fed animals, including increased cecal
pH, increased cecal chime ammonia concentration, and increased
cecal isobutyric acid concentration. These results suggest that
sodium butyrate can inuence the activity of the cecal microbiota
and may present a possibility to negate the negative effects of
early weaning through the manipulation of energy sources in the
hindgut.
Targeting the small intestine and lower GIT may be advanta-
geous in weaned piglets to help stimulate intestinal development,
improve digestive capabilities, and prevent post-weaning diar-
rhea. Mallo et al. (2012) compared the effects of the inclusion of
encapsulated sodium butyrate and monobutyrate glycerides on
21-day-old weaned piglets. They observed no differences in
growth performance, but higher concentrations of butyric acid
and VFA in the colon in encapsulated sodium butyrate fed animals
compared to monobutyrate glyceride fed animals. This result
suggests that certain encapsulation techniques could facilitate an
easier release of butyric acid than from monobutyrate glycerides,
allowing more butyric acid to reach the distal GIT. When sup-
plemented into articial milk formulas of 2-week-old piglets for 7
days, sodium butyrate (3,000 mg/kg) was shown to increase crypt
depth, villi length, and mucosa thickness in the jejunum and
ileum compared to unsupplemented pigs (Kotunia et al., 2004). By
further investigating the increased gut maturation, Mazzoni et al.
(2008) supplemented sodium butyrate (3,000 mg/kg) to piglets
through the suckling (days 4 to 28), weaning (day 28), and/or
postweaning period (days 29 to 40). Sodium butyrate supple-
mentation increased parietal cell number. In particular, after
weaning the supplementation specically increased the number
of enteroendocrine and somatostatin positive cells in the oxyntic
mucosa, in addition to the increase of gastric mucosa thickness
(Mazzoni et al., 2008). This effect on increasing the mucosa
thickness was also previously observed in the jejunum, ileum,
colon, and cecum of piglets given a cecal infusion of butyrate (Kien
et al., 2007). These studies show the potential proliferative effects
of butyrate on the porcine GIT.
There have also been studies on the effects of dietary supple-
mentation of tributyrate glycerides on the growth, intestine
development, and immune function of weaned piglets. Tributyrate
glycerides (10,000 mg/kg) with a sweetener (lacticol, 3,000 mg/kg)
has been shown to improve the average daily gain of piglets
through 42 days of age when supplemented from weaning (d 28)
onwards (Piva et al., 2002b). Intrauterine growth restriction (IGR), a
common problem in animal production and a recognized issue in
human health, is a condition where a fetus is growing at an
abnormally slow rate inside the womb, leading to the risk of health
problems during gestation, delivery, and after birth (Wang et al.,
2008). When supplemented to piglets suffering from IGR, tribu-
tyrate glyceride was shown to improve body weight, as well as
increase spleen and small intestine development compared to
unsupplemented IGR piglets (Dong et al., 2016). In addition, trib-
utyrate glyceride supplementation was shown to reduce the
expression of pro-inammatory cytokines and improve tight
junction formation in the colon, a benet to intestinal health
(Tugnoli et al., 2014). Recently, Hou et al. (2014) reported that
tributyrate glyceride supplementation (1,000 mg/kg) was able to
alleviate intestinal injury, possibly by inhibiting apoptosis, pro-
moting tight-junction formation, and activating EGFR signaling, in a
study with the porcine model of ulcerative colitis. These results
support the previously discussed benets of butyrate for the
treatment of intestinal disease in humans. Tributyrate glycerides
appear to be an option for relief of digestive dysfunctions, as well as
mediating immune response and improving growth performance
in swine.
The term boar taint refers to an off-putting odor and taste that
can be evident during the cooking or eating of pork from non-
castrated male pigs. It is caused by the accumulation of andros-
tenone and skatole in the fat of these pigs: androstenone is pro-
duced in the testes, whereas skatole is produced by intestinal
bacteria then absorbed (Deslandes et al., 2001). Increased skatole
formation has been linked with debris from cell apoptosis. In-
testinal butyrate has been shown to decrease apoptosis, leading to
the studies to determine whether butyrate has an effect on skatole
formation and tissue accumulation (Hass et al., 1997; Mentschel
et al., 2001). Barrows fed diets containing resistant potato
starch, a substrate known to increase butyrate formation in the
colon, were found to have signicantly increased butyrate and
A. Bedford, J. Gong / Animal Nutrition 4 (2018) 151e159 155
decreased rates of apoptosis in the colon (Govers et al., 1999;
Topping and Clifton, 2001; Claus et al., 20 03). Consequently,
skatole was decreased in both the feces and blood plasma, and the
concentration of skatole in the fat tissue was below the detection
limit (0.8 ng/g), a signicant reduction compared to control pigs
(167 ng/g) (Claus et al., 2003). These decreased levels suggest
potential for butyrate in lessening boar taint and improving the
sensory quality of pig meat.
Early studies on monobutyrate glycerides have revealed a
unique function that is relevant to animal production. The 1-
Butyryl-glycerol (monobutyrate glyceride) is a simple lipid
secreted by adipocytes showing angiogenic activity when tested
in the chick chorioallantoic membrane assay (Dobson et al., 1990;
Wilkison et al., 1991). The biosynthesis of monobutyrate glycer-
ides is tightly linked to lipolysis associated with changes in blood
ow (Ailhaud et al., 1992). Moreover, synthetic monobutyrate
glycerides have shown the same spectrum of biological activities
as the adipocyte-derived factor monobutyrate glyceride (Wilkison
and Spiegelman, 1993). The 2 types of monobutyrate glycerides,
a
-
monoglyceride and
b
-monoglyceride, originate from dietary
sources or tributyrate glyceride digestion, and are transported
into the blood stream from the small intestine. Absorbed mono-
butyrate glycerides can stimulate the growth of endothelial cells
in the development of new blood vessels, which are required for
the development of any new tissue under normal or pathological
conditions. Thus, monobutyrate glycerides may represent a ther-
apeutic opportunity for stimulating the growth of intestinal tissue
through its angiogenic activity in food-producing animals, espe-
cially when there are wounds or damages in the intestinal
epithelia. Nonetheless, further studies are required to conrm the
concept on the potential effects of monobutyrate glyceride in
poultry and pigs.
5. Butyrate supplementation in ruminants
Sodium butyrate is found in the milk of most animals, with
the exception of sow milk (Alais, 1984), and is naturally found in
the forestomach of ruminants. An early study by Sander et al.
(1959) showed that the administration of a sodium butyrate
solution (100,000 mg/kg) directly into the rumen of cannulated
calves for the rst 11 weeks after weaning (at 2 to 5 weeks of
age) resulted in an increased rate of rumen papillae development
(Sander et al., 1959). This is the only study using such a high
inclusion level, perhaps owing to the fact that it was one of the
rst butyrate studies and the dosage was likely desired to
maximize the chance of observing a response. Similar results
were observed with adult sheep, in which sodium butyrate (2 g/
kg body weight per day) administered intraruminally for 6 days
resulted in increased rumen epithelium development (Sakata
and Tamate, 1978).
Volatile fatty acids, including butyrate, have been established
to be signicant factors in the postnatal development of the
ruminal epithelium (Sakata and Tamate, 1978). The rumen
epithelium is responsible for many important physiological func-
tions including absorption, transport, and SCFA metabolism
(Graham and Simmons, 2005). Improving the rumen epithelium
development could lead to enhanced animal performance, espe-
cially in early life.
Flavomycin is a phosphoglycolipid antibiotic that has been used
exclusively and extensively as an antimicrobial agent and growth
promoter in livestock production (Edwards et al., 2005). A study by
Guilloteau et al. (2009) investigated the effect of replacing a-
vomycin (16.5 mg/kg) with sodium butyrate (3,000 mg/kg) in the
diets of milk fed calves from 12 days of age to slaughter. They found
that compared to controls, calves supplemented with sodium
butyrate had signicantly improved body weight, average daily
gain, and feed conversion ratio from 60 to 124 days of age
(Guilloteau et al., 2009). Enterocyte proliferation in the upper
jejunum and duodenal villi height were also improved in sodium
butyrate calves. Additionally, sodium butyrate enhanced the levels
of heat shock proteins (HSP) 27 and 70 in the abomasum and colon,
and expression of insulin-like growth factor 1 (IGF-1) receptors in
the jejunum compared with the action of avomycin. As the
removal of avomycin resulted in substantial modulation of the
intestinal microbiota, the increase of these HSP could be related to
the change of microbiota composition, and have a protective effect
on the GIT. Increased expression of the receptors suggests that IGF-
1 was likely one mediator of the observed growth effects, along
with the improved GIT development.
For economic reasons, the early weaning of calves from whole
milk or a milk replacer as early as 3 or 4 weeks of age is often
practiced. This transition requires the rapid development of the
GIT, especially the rumen, as it directly affects solid feed intake,
and thus, the growth and health of calves post-weaning
(Greenwood et al., 1997; Baldwin et al., 2004). Prior to weaning,
the choice of supplied liquid feed determines the growth and
health of the animal, and therefore the success of the transition
onto solid feed including rumen development (Khan et al., 2007).
It has been shown that the use of milk replacer instead of whole
milk as a liquid feed slows the small intestine development, which
impairs performance, decreases solid feed intake, and in turn,
slows rumen development (Blattler et al., 2001; Gorka et al.,
2011b). One previous study investigated the effect of feeding
calves whole milk, milk replacer, or milk replacer supplemented
with sodium butyrate (3,000 mg/kg) on rumen development in
calves (Gorka et al., 2011b). Results from the study showed that
feeding calves milk replacer instead of whole milk from 5 to
26 days of age slowed down small intestine development, and
negatively affected the metabolic status of the animals. However,
the addition of sodium butyrate stimulated small intestine
development and partially negated the negative effects of milk
replacer on rumen development. A further study by the same
group investigated the addition of sodium butyrate into the milk
replacer (at 3,000 mg/kg), as well as into the dry starter mixture
(at 6,000 mg/kg), offered to calves from the trial's onset (Gorka
et al., 2011a). They found that the addition of sodium butyrate
to both the milk replacer and the starter mixture had a positive
effect on rumen development, indicated by an increased per-
centage of the whole stomach weight and increased papillae
length and width. Furthermore, both body weight gain and gen-
eral calf health were improved by the addition of sodium butyrate.
Tributyrate glycerides have also been studied as an additive in
milk replacer for calves and was shown to modulate glucose
and insulin dynamics when supplemented at 3,000 mg/kg from
12 days of age, but did not increase growth performance (Araujo
et al., 2013). These studies indicate that butyrate derivatives
could be particularly benecial in improving rumen development
and easing the weaning transition of calves.
A recent shift in lamb production to an intensive fattening
system means that in some countries, lambs are fed a high
concentrate diet from 2 weeks of age to assure fast growth and high
productivity (Cavini et al., 2015). Failing to adapt to this sudden
dietary change can lead to complications such as inadequate rumen
development and slow growth. Cavini et al. (2015) investigated the
effect of incorporating sodium butyrate (3,500 mg/kg) into the
concentrate diet during suckling, weaning, or both, on lamb growth
performance and rumen characteristics. They found that sodium
butyrate supplementation during the suckling period led to sig-
nicant increases in hot carcass weight and dressing percentage,
without having an effect on rumen characteristics. However,
A. Bedford, J. Gong / Animal Nutrition 4 (2018) 151e159156
sodium butyrate supplementation during the fattening period had
no signicant effects. There have been limited studies investigating
the inclusion of butyrate derivatives into ovine diets; more research
is required to determine if a similar result as observed in calves
could be achieved.
6. Major benets and potential cross species effects
The main common thread with the supplementation of butyrate
and its derivatives across animal production species is their benet
on the development of the GIT, including improved morphology
and cell proliferation, thus on animal gut health. The result of these
improvements is often associated with an observed increase in
growth performance, including changes in carcass composition,
although it may depend on the age of the animals. Thus, earlier
supplementation may result in a better chance for observed
improvements.
Butyrate supplementation has shown potential for alleviating
the symptoms of inammatory bowel diseases in human patients,
most notably through the inhibition of inammatory pathways via
the inhibition of NF-kB. Although the application of butyrate de-
rivatives in feed for animal productionis mainly subtherapeutic, and
not intended for disease treatment, this anti-inammatory response
was also observed in broiler chickens and weaned piglets, which is
one of expected properties for the alternatives to antibiotics in feed.
The theme of butyrate being an alternative to antibiotics is evidently
strong within the studies using food-producing animals. This is
especially apparent in the studies where the use of a butyrate de-
rivative is used as a direct replacement for an antibiotic, but also
observed in studies where butyrate-fed animals are challenged with
a pathogen. Thus, butyrate and its derivatives can be expected to
have a role in the post-antibiotic era of animal production.
7. Conclusions
The work completed thus far with butyrate and its derivatives in
feed for animal production has laid a foundation for future studies,
as well as for the extension of application. The various reported
benecial effects, such as antimicrobial and anti-inammatory ac-
tivities, enhancement of growth performance (including carcass
composition) and gut tissue development/maturation, and modu-
lation of immune response and intestinal microbiota, grant buty-
rate and its derivatives the potential to develop into valuable
supplements across species and as an alternative to in-feed anti-
biotics for animal production. Although the benets in human
health applications show its promise in the treatment of disease,
such as IBD, the positive effects of different forms of butyrate on
multiple food-producing animal species demonstrate its ability to
be a diverse product for livestock production. Given that the ben-
ets appear to be more evident in young animals, it is important to
maximize the potential of butyrate and its derivatives from young
to adult animals.
Acknowledgments
This work was supported by Agriculture and Agri-Food Canada
and Canadian Poultry Research Council through the Poultry
Research Cluster Program (AAFC J-000264). Andrea Bedford was a
NSERC Visiting Fellow to Canadian Federal Government
Laboratories.
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A. Bedford, J. Gong / Animal Nutrition 4 (2018) 151e159 159
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... These results agreed with previous studies (Sun et al. 2021;, and were probably elucidated by the observed ability of GOD to enhance intestinal antioxidant property that could benefit intestinal morphological structure in piglets (Wen et al. 2020). Alternatively, under GOD catalysis, the production of gluconic acid and/or its conversion product butyric acid favored the development and repairing of intestinal epithelial cells (Bedford and Gong 2018;Ząbek et al. 2020), thus leading to improvements in intestinal morphology of piglets. It seemed that the enhancements in intestinal absorption and barrier functions arising from improvements in intestinal morphology in GOD-fed piglets could contribute to the observed reduction of diarrhea rate. ...
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Poultry production has undergone a substantial increase compared to the livestock industries since 1970. However, the industry worldwide is now facing challenges with the removal of in-feed antibiotics completely or gradually, as the once well-controlled poultry diseases have re-emerged to cause tremendous loss of production. Necrotic enteritis (NE) is one of the most important diseases which costs the industry over two billion dollars annually. In this paper, we review the progress on the etiology of NE and its control through dietary modifications, pre- and probiotics, short chain fatty acids, and vaccination. The other likely measures resulted in the most advances in the toxin characterization are also discussed. Vaccine strategies may have greater potential for the control of NE mainly due to clearer etiology of NE having been elucidated in recent years with the identification of NetB toxin. Therefore, the use of alternatives to in-feed antibiotics with a better understanding of the relationship between nutrition and NE, and limiting exposure to infectious agents through biosecurity and vaccination, might be a tool to reduce the incidence of NE and to improve gut health in the absence of in-feed antibiotics. More importantly, the combinations of different measures may achieve greater protection of birds against the disease. Among all the alternatives investigated, prebiotics, organic acids and vaccination have shown improved gastrointestinal health and thus, have potential for the control of NE.
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The mammalian intestine is host to a microbial community that prevents pathogen expansion through unknown mechanisms, while antibiotic treatment can increase susceptibility to enteric pathogens. Here we show that streptomycin treatment depleted commensal, butyrate-producing Clostridia from the mouse intestinal lumen, leading to decreased butyrate levels, increased epithelial oxygenation, and aerobic expansion of Salmonella enterica serovar Typhimurium. Epithelial hypoxia and Salmonella restriction could be restored by tributyrin treatment. Clostridia depletion and aerobic Salmonella expansion were also observed in the absence of streptomycin treatment in genetically resistant mice but proceeded with slower kinetics and required the presence of functional Salmonella type III secretion systems. The Salmonella cytochrome bd-II oxidase synergized with nitrate reductases to drive luminal expansion, and both were required for fecal-oral transmission. We conclude that Salmonella virulence factors and antibiotic treatment promote pathogen expansion through the same mechanism: depletion of butyrate-producing Clostridia to elevate epithelial oxygenation, allowing aerobic Salmonella growth.
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Background: The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis result from alterations in intestinal microbes and the immune system. However, the precise dysfunctions of microbial metabolism in the gastrointestinal microbiome during IBD remain unclear. We analyzed the microbiota of intestinal biopsies and stool samples from 231 IBD and healthy subjects by 16S gene pyrosequencing and followed up a subset using shotgun metagenomics. Gene and pathway composition were assessed, based on 16S data from phylogenetically-related reference genomes, and associated using sparse multivariate linear modeling with medications, environmental factors, and IBD status. Results: Firmicutes and Enterobacteriaceae abundances were associated with disease status as expected, but also with treatment and subject characteristics. Microbial function, though, was more consistently perturbed than composition, with 12% of analyzed pathways changed compared with 2% of genera. We identified major shifts in oxidative stress pathways, as well as decreased carbohydrate metabolism and amino acid biosynthesis in favor of nutrient transport and uptake. The microbiome of ileal Crohn's disease was notable for increases in virulence and secretion pathways. Conclusions: This inferred functional metagenomic information provides the first insights into community-wide microbial processes and pathways that underpin IBD pathogenesis.
Article
Intrauterine growth restriction (IUGR) neonates suffer from growth restriction. Tributyrin (TB), a pro-drug of butyrate, can facilitate the growth of animals. This study was to investigate the effects of TB supplementation on the growth of IUGR neonatal piglets. Sixteen IUGR and 8 NBW (normal body weight) neonatal piglets were chosen, weaned at 7th day and fed basic milk diets (NBW and IUGR group) or the basic diets supplemented with 0.1% tributyrin (IT group, IUGR piglets fed with tributyrin) until day 21 (n = 8). The body weights of the piglets on days 0, 7, 10, 14, 17, and 20 were measured. The digestive enzyme activity, intestinal morphology, immunoglobulin levels and gene expression of IgG, FcRn and GPR41 in the small intestines were analyzed. The body weights of the piglets in the IUGR and IT group were similar, and both were lower than the NBW group on days 10 and 14. However, after day 17, the IT group exhibited improved (P < 0.05) body weights compared to that of the IUGR group. The piglets were sacrificed on day 21. Compared with the NBW piglets, IUGR impaired the development of immune organs and small intestines, impaired the intestinal villus morphology, decreased (P < 0.05) most of the tested intestinal digestive enzyme activities, decreased (P < 0.05) the ileal sIgA and IgG levels, and down-regulated (P < 0.05) the intestinal IgG and GPR41 expression. Piglets in the IT group exhibited a better-developed (P < 0.05) spleen and small intestines, improved intestinal villus morphology, increased (P < 0.05) intestinal villus surface areas, enhanced (P < 0.05) digestive enzyme activities, and up-regulated (P < 0.05) expression of IgG and GPR41 mRNA compared to those of the IUGR group. TB supplementation improves the growth and the intestinal digestive and barrier functions in IUGR piglets during the suckling period. Copyright © 2015. Published by Elsevier Ltd.