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Organic Acids, with emphasis on
Benzoic Acid, to rationalize the use of
therapeutic antibiotics
María Alejandra Pérez-Alvaradoa, Jorge Cervantes Lópezb, José Antonio Cuarón Ibargüengoytiaa
Centro Nacional de Investigación Disciplinaria en Fisiología Animal, Instituto Nacional de Investigaciones Forestales,
Agrícolas y Pecuarias. Ajuchitlán, Municipio de Colón, Querétaro, México
a
b
DSM Nutritional Productcs México, S. A. de C. V. El Salto, Jalisco, México.
The herein discussion provides evidence and summarizes research
results (Pérez Alvarado et al., 2013) for the professional and sensible
use of antibiotics using Benzoic Acid (BA) to protect intestinal health
(microbial ecology) and the environment.
THE ANTIBIOTICS WORRIES
Reduction of antibiotics use in animal feed
demands substantial improvement of herd
health issues, but also sensible and professional
management of the antimicrobial drugs is
necessary to prevent the threats of antibiotic
resistance (Van Den Bogaard et al., 1999;
Collingnon, 2012). Antimicrobial drugs may be
used for effective therapeutic and prophylaxis
purposes, but the pulsing or continuous use of
antibiotics in-feed has been severely questioned,
besides public health issues, because of the
consequences in intestinal microbiota and the
gastrointestinal barrier harmonic function.
In Denmark, the European ban of antimicrobial
drugs in pigs’ feed resulted in a marginal
productivity loss in finishing pigs, but in worrying
losses in weanling pigs (including mortality)
which, in turn, increased the use of therapeutic
antibiotics (Who, 2003); currently in pigs,
therapeutic antibiotics are prescribed mostly
(>62%) for respiratory and enteric diseases and
the use of critically important antibiotics (for
humans), may reach an incidence as high as
34% (De Briyne et al., 2014), but also a vitiated
veterinary practice is to use as many antibiotics
as necessary to control prevalent farm diseases,
based in the proven clinical efficacy of the
antimicrobial, without consideration of the
animal systemic effects aside from the protection
that may be induced by the drug. Typically
prophylaxis of a respiratory problem goes in
hand with a diarrhea control antimicrobial and
little care is given to the continuity of the gut
microbioma and gastrointestinal tract barrier
function (Kim et al., 2012).
The Eubiotics concept -“… phases of medical
science and of medical service which go beyond
the prevention of disease and which foster as well
as advance the biologic growth, development and
well-being of the individual”- (Galdstone, 1944)
has opened several possibilities to cope with the
rational and sensible use of antibiotics, for which
organic acids are relevant tools (Cuarón, 2009).
ORGANIC ACIDS
Molecules dissociated in solution by release of protons give the acidic
condition; those carrying a carboxyl group (-COOH) are referred as
carboxylic acids, comprising the organic acids. The most commonly
used organic acids in pig feeding are short carbon chain length and
they may have one or more carboxyl groups, being all weak acids
(Mroz, 2003); these organic acids are naturally occurring in the body,
thus they are readily metabolized.
The short carbon chain length and acidic conditions favor the rapid
dissociation and absorption thru the gastrointestinal wall, implying
their possible effects limited to the small intestine. This is of clear
benefit in early weaned pigs compensating the transient shortage in
HCl production and the changing composition of gut microbiota, but
this may not be the case in older animals considering their digestive
physiology aptness and the feed ingredients buffering capacity. Thus,
proposed modes of action are a direct response to the molecules
dissociation and not directly to ingesta acidification, although
the consequent response abides gastric function, modification of
the intestinal microbiota, enhancement of endogenous enzyme
activity, the prompting of intestinal and pancreatic secretions
(counting the regulatory peptides and hormones), stimulation of cell
proliferation and differentiation at the intestinal wall and activation
of the intermediary metabolism, all of which are key issues in the
accounting of benefits from the application of organic acids in pig
feeding. As thought, a direct consequence of diet acidification is a
potential change of pH in the intestinal lumen to favor colonization
and proliferation of acid resistant bacteria, to result in a competitive
exclusion phenomenon (of potential pathogens), further,
undissociated organic acids diffuse through bacterial membranes,
originating cytosolic changes, altering bacterial enzymatic activity and
metabolic control. Thus the relatively low water solubility of BA is in
the benefit of intestinal activity prior absorption (Kluge et al., 2006;
Guggenbuhl et al., 2007; Siepmann and Siepmann, 2013).
Independently of their form, organic acids generally improve average
daily gain and feed efficiency of newly weaned pigs, but responses are
highly variable along with acid preparation, dose, feed composition,
stage of growth or physiological status, health and environmental
conditions; yet organic acids are deemed as good alternatives in health
protection and, perhaps, for growth promotion, but not substitutes to
antibiotics for therapeutic purposes (Partanen and Mroz, 1999).
However, some of the acids used have shown direct effects in the
animal (and not only in the intestine) and knowledge of their mode of
action has enlightened the control measures to ensure effectiveness.
Thus knowledge on the specific mode of action is necessary to
guarantee persistence and efficacy of the response, but seldom are
these changes highly correlated to the growth promotion response,
because of the inherent variation, but also, static measurements
do not describe the complex interactions in gut ecology. As the
presence of a pathogen does not imply disease, interactions of the
additives among microbes and between microorganisms and the
host are critical to understand sequels in health and protection
of the productive capacity of pigs. Particularly in terms of animal
performance, many clinical trials may show a clear microbiological
response in the intestine, but unaltered gain and feed efficiency,
consequently, effectiveness should not be implicit on the basis of the
microbial changes, potential pathogens activity is important, as much
as other factors permitting the expression of pathogenicity.
INTESTINAL MICROBIOTA
At the gastrointestinal level, organic acids presence may prevent the
proliferation of some bacterial strains and serotypes, to suppress their
growth or actively kill some; after dissociation ions may diffuse to act
in the bacterial cells organelles and interfere with RNA transcription
or DNA replication, thus affecting the bacterium functioning and
multiplication; the weakened cell results in a reduced anchorage
capacity to the mucosal surfaces, thus preventing intestinal antigen
aggression and parasitism, inducing greater susceptibility to disruption
and lysis (Varley, 2007). These effects are particularly significant in
anaerobic and gram negative prokaryotes, but the processes do not
affect acidifying bacteria of the lactobacillae and bifidae genera,
among others, thus helping in competitive exclusion. It also should
be considered the added value from the prevention of pathogens
shedding, reducing the impact of repetitive challenge in the population,
plus the extended benefits in public health (Creus et al., 2007).
In a dynamic study of the microbiota, using 16S rRNA gene based
PCR-denaturing gradient gel electrophoresis profiling, DNA sequencing
and real-time PCR techniques, it was found that time post-weaning
and dietary treatments (all, antibiotic, organic acids or herbal extracts)
resulted in a shift of the microbiota composition; time influenced
Clostridium, while additives increased Lactobacilae and acid related
bacteria (Gong et al., 2008). Studies like this give light in gut ecology,
but still the fate of potential pathogens challenge is unknown. Among
the few published results linking dynamic changes of the microbiota
and animal performance is the paper by Torrallardona et al. (2007);
they related the positive responses to BA in improved performance of
piglets to the greater ileal microbiota biodiversity. It happens that very
few dynamic studies have assessed the responses, within a controlled
pathogen challenge, to explain the inherent variability (Krause et al.,
1995; Fairbrother et al., 2005; Bhandari et al., 2008). The complexity
of the microbiota and of the microbes interaction with the host, play
a central role in the interpretation of results (Krause et al., 2006) in
consequence, also on the assurance of the response and given the
limited understanding on gut ecology and the effects of organic acids,
most of inferences on the application of these concepts must be
derived from empirical observations.
FIELD DATA IS CRUCIAL
In health and productive responses, live modeling is necessary
to describe specific effects, but well controlled field trials are
indispensable in the demonstration of product claims in a particular
environment, but very seldom these could be followed, notably if
a controlled infection is used as a research tool. Considering the
acute alterations in gut and immunological physiology after weaning,
duration of the experiments is of importance, particularly if growth
performance is to be accounted (Bhandari et al., 2008; Arthur et al.,
2008). A problem is that variation is enormously increased by disease,
hampering clear distinction of effects, but precise methodology
and statistical methods could be applied to assess deviation from
an expected value process aside from random process (De Vries
and Reneau, 2010). In a large isolation facility we have developed a
testing method, using field pathogenic strains of salmonella, to test
feed additives. Two abstracts are available in English (Martínez et al.,
2007a, b), but many clinical trials have been conducted over time.
The review by Mroz (2003) is important as the author established an
order of coliform bacteria killing potency of organic acids: propionic <
formic < butyric < lactic < fumaric < benzoic, which was almost identical
to the sequence found by Jensen et al., (2001) for salmonella in
slaughter pigs thus, it cannot be discarded that the organics acids also
controlled the pathogen, as simple changes in fermentation, increasing
volatile acid production in the gut are sufficient to alter microbial
ecology and survival of salmonella (Mikkelsen, 2004).
However, besides the obvious inferences from the acidification power
of the acids and their mixtures, different acids result in differential
responses from specific functions: some are normally important
contributors of “dietary” energy (e.g., acetates, propionates, lactates),
or improve nutrients utilization (by enzymatic induction at the upper
digestive tract); others further acidify additional tissues, (e.g., renal
and urinary tract portions from hipuric acid derived from benzoates)
or down regulate bacterial metabolic functions (Kristensen et al.,
2009), or the induction of cell differentiation and apoptosis of
undifferentiated cells, as it has been demonstrated for butyric acid
(Castillo et al., 2006; Sengupta et al., 2006).
Thus, dietary additions of organic acids are effective in the protection
of intestinal health and are true alternatives to antibiotics as
prophylactics, but very seldom they can prevent the use of antibiotics
as therapeutic agents; different organic acids have dissimilar effects
on bacterial growth or on the bacteriostatic or bactericide effects.
BENZOIC ACID IN PROTECTION
OF PIGS’ PRODUCTIVITY AND
THE ENVIRONMENT
To challenge the drop of antibiotics in presence of BA (5 kg/ton.), a
commercial feeding program was chosen in an area of high incidence
of PRRS, circovirus and associated infections, notably Haemophillus,
Mycoplasma. Antibiotics routinely used at the time (with the
justification of protecting pigs from diseases of the respiratory and
intestinal syndromes), were: during the first 21 post-weaning days,
Amoxicillin hydrate (200 ppm), Enramycin (10 ppm), Lincomycin
hydrochloride (44 ppm) and Spectinomycin sulphate (44 ppm); from
day 22 to day 42 post-weaning, Tiamulin hydrogenated fumarate (100
ppm) and Chlorotetracycline (300 ppm) were used, and antibiotics
were withdrawn thereafter. The dietary inclusion of BA was to remove
all antibiotics, except for Amoxicillin during the first 21 post-weaning
days. Details in diets composition is in the original publication (PérezAlvarado et al., 2013) and results are summarized for the BA effects for
an experimental farm (Tables 1 and 2, Figure 1) and in a commercial
setting, where disease signs were evident (Table 3).
The use of BA was effective in protecting pigs’ performance upon
withdrawal of antibiotics, provided that the main pathogen was
controlled. Because of variation, piglets body weight were different
(P<0.03) only at 42d post-weaning, the BA effect in the pattern of
response for the first 21d is difficult to explain, but it cannot be
completely attributed to an antimicrobial effect in the gut, since
the enteric problems were quite located and were attributed as a
sequel of a respiratory problem. It cannot be inferred either, the
physiological consequences given that the feed intake was practically
the same (Ravindran and Kornegay, 1993; Amezcua et al., 2007). In
addition, whenever antibiotics are used as growth promoters, for
instance, beyond their therapeutic effects, the typical response of
susceptible animals was higher than those resistant, which result
in some improvements in the Coefficients of Variation (CV); the CV
demeanor was practically the same. Then, the only explanation of the
response to the BA may be in the animal welfare and it is suggested
a probable involvement of the membrane immunity, potentially given
the diminishing of the consequences of the inflammatory response
(Casula et al., 2002; Brahmachari et al., 2009)
The results from reducing the antibiotics load in feed for piglets in the
commercial farm and in presence of respiratory syndrome signs are
summarized in Table 3. In general, no differences were found (P>0.15)
in none of the response criteria, and then the use of Enramycin,
Lincomycin and Spectinomycin sulphate, in excess of Amoxicillin
hydrate in Phases 1 and Phase 2 feeds could have been discarded in
this farm with the use of BA. Therefore, BA seems to be an effective
resource for the control of infectious problems (“opportunistic”) of
intestinal course. However, the inference should be limited to the
necessary effectiveness of the diagnosis of the problems found in
each farm and the decision of using effective therapeutic antimicrobial
drugs. However, this inference is somehow confounded since no
observations have been taken from a treatment with no antibiotics, or
only with Amoxicillin and no BA. These results suggest the necessity to
investigate the possible interaction between the BA and the intestinal,
saprophyte and enterotoxigenic, microbiota; at the same time that
is impossible infer the probable additive effects between the BA and
Amoxicillin or any other antibiotic. It is apparent, at least, that the
use of these two drugs is compatible and that BA may moderate the
consequences of the antibiotic alteration of the microbiota.
It is apparent that BA is an effective resource to protect the growth
of piglets at weaning, and to reduce variation in live body weight at
the end of finishing period. Besides, BA is an alternative to the use
of antibiotics. However, more field research is needed to sustain the
mode of action, being possible, among others, the modification of
the intestinal microbiota and it is suggested the possibility of mucosal
immunity modification. Benzoic acid is a resource for the protection of
the environment since it prevents NH3 emissions.
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Table 1. Growth performance, pigs fed with or without Benzoic acid, during 42 days post-weaning.
Benzoic acid (BA), kg·t-1
0
5b
SDc
BA
P<
Observations, na
18
18
Initial weight (weaning), kg
6.13
6.09
1.095
0.92
Weight at 21d post-weaning, kg
10.39
11.15
1.524
0.15
Weight at 42d post-weaning, kg
21.44
23.45
2.653
0.03
Avg. Feed intake, 7d, kg·d-1
0.13
0.15
0.028
0.21
1
Avg. Feed intake, 21d, kg·d-
0.28
0.29
0.041
0.26
Avg. Feed intake, 42d, kg·d-1
0.54
0.55
0.066
0.43
Avg. weight gain, 7d, kg·d-
0.08
0.14
0.054
0.001
Avg. weight gain, 21d , kg·d-1
0.20
0.24
0.037
0.004
Avg. weight gain, 42d, kg·d-1
0.36
0.41
0.043
0.002
Gain/Feed,7d
0.59
0.94
0.374
0.008
Gain/Feed, 21d
0.74
0.82
0.122
0.04
Gain/Feed, 42d
0.68
0.74
0.056
0.002
1
Pens of 5 pigs per pen (i.e. 90 per treatment) wean at 21 days of age.
Control (mixed antibiotics) = 0; 5 = BA doses in substitution of antibiotics.
c
SD = Standard deviation; squared root of the mean squared error.
a
b
Table 2. Some wastewater traits, from pens of pigs fed with or without Benzoic acid 42 days post-weaning. Samples were collected from Nalgene
jars were wastewater was allowed to ferment.
Benzoic acid (BA), kg·t-1
0
5b
SDc
BA
P<
Observations, na
18
18
pH, 7d
7.25
6.71
0.236
0.001
pH, 14d
7.47
6.24
0.245
0.001
pH, 21d
7.69
5.66
0.200
0.001
pH, 42d
8.00
5.48
0.110
0.001
Total N 7d, mg·L-1
7.00
7.40
0.285
0.007
Total N 14d, mg·L-1
9.13
9.58
0.416
0.03
Total N 21d, mg·L-1
14.72
15.36
0.659
0.02
Total N 42d, mg·L-1
15.36
16.08
0.627
0.02
Ammonia N 7d, mg·L-1
3.70
3.18
0.173
0.001
Ammonia N 14d, mg·L-1
4.82
4.12
0.258
0.001
Ammonia N 21d, mg·L-1
7.69
6.61
0.409
0.001
Ammonia N 42d, mg·L-
8.89
8.33
0.352
0.003
1
Pens of 5 pigs per pen (i.e. 90 per treatment) wean at 21 days of age.
Control (mixed antibiotics) = 0; 5 = BA doses in substitution of antibiotics.
c
SD = Standard deviation; squared root of the mean squared error.
a
b
Figure 1. Dispersion of pigs’ body weight at 147 days of age in response to the previous use to antibiotics or Benzoic acid.
120
115
110
105
Body weight, kg
100
95
90
85
80
75
70
65
60
55
50
Control
Benzoic acid
Each dot represent one pig, the middle line represent the overall mean and others one standard deviation (S) over or under the mean.
Table 3. Growth performance and total coliforms count in pigs fed a mix antibiotics diet or Benzoic acid.
Variable
Control
BA
20
20
Initial body weight, kg
6.06
5.86
0.522
Avg. Feed intake, 7d, kg·d-1
0.13
0.14
0.012
Avg. Feed intake, 28d, kg·d-1
0.37
0.36
0.013
Avg. Feed intake, 49d, kg·d-1
0.48
0.47
0.016
Avg. weight gain, 7d, kg·d-1
0.11
0.11
0.021
Avg. weight gain, 28d, kg·d-1
0.33
0.34
0.015
Avg. weight gain, 49d, kg·d-1
0.38
0.38
0.053
Gain/Feed, 7d-1
0.77
0.72
0.166
Gain/Feed, 28d-1
0.88
0.97
0.040
Gain/Feed, 49d-1
0.80
0.84
0.049
Mortality rate at 49d, %
4.98
2.60
1.592
Coliforms, log10 cfu·g-1, 7d
9.03
9.13
0.221
Coliforms, log10 cfu·g-1, 28d
5.53
6.77
0.657
Coliforms, log10 cfu·g-1, 49d
5.88
5.90
0.292
Observations, na
SEM
Observation of a commercial farm showing respiratory and intestinal diseases sings. Control = Therapeutic program with intensive use
of antibiotics; BA = Benzoic acid (5 kg/ton.). There were no differences between treatments (P>0.15).
a
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