Evaluation of possible adverse effects in broiler chickens supplemented with ibuprofen or meloxicamABSTRACT
Antimicrobial Growth Promoters (AGPs) have been phased out due to their link to antibiotic resistance. While their exact mode of action remains unknown, they are thought to reduce inflammation in the gut. This study explored the safety and efficacy of two non-steroidal anti-inflammatory drugs (NSAIDs), ibuprofen (IBF) and meloxicam (MLX), as potential feed additives for broiler chickens. Chickens were divided into groups and fed diets supplemented with various doses of IBF or MLX for 42 days. Growth performance, blood parameters, and tissue health were monitored. While some minor changes in blood chemistry were observed, particularly a decrease in ALT levels and an increase in uric acid with IBF, these alterations were not considered clinically significant. Histopathological examination of vital organs revealed no signs of NSAID-induced damage. In conclusion, both IBF and MLX appear to be safe and well-tolerated as feed additives for broiler chickens, without negatively impacting growth performance or causing significant adverse effects.
Keywords:
growth promoter; feed additive; non-steroidal anti-inflammatory drugs; poultry
RESUMO
Os promotores de crescimento antimicrobiano (PCAs) foram proibidos devido à sua ligação com a resistência aos antibióticos. Embora seu modo exato de ação permaneça desconhecido, acredita-se que eles reduzam a inflamação no intestino. Este estudo explorou a segurança e a eficácia de dois anti-inflamatórios não esteroidais (AINEs), ibuprofeno (IBF) e meloxicam (MLX), como potenciais aditivos alimentares para frangos de corte. Os frangos foram divididos em grupos e alimentados com dietas suplementadas com várias doses de IBF ou MLX por 42 dias. O desempenho do crescimento, os parâmetros sanguíneos e a saúde dos tecidos foram monitorados. Apesar de algumas pequenas alterações na bioquímica sanguínea terem sido observadas, particularmente uma diminuição nos níveis de ALT e um aumento no ácido úrico no grupo IBF, essas alterações não foram consideradas clinicamente significantes. O exame histopatológico de órgãos vitais não revelou sinais de danos induzidos por AINEs. Em conclusão, tanto o IBF quanto o MLX parecem ser seguros e bem tolerados como aditivos alimentares para frangos de corte, sem impactar negativamente o desempenho do crescimento ou causar efeitos adversos significativos.
Palavras-chave:
promotor de crescimento; aditivo alimentar; anti-inflamatórios não esteroidais; frango de corte
INTRODUCTION
Antimicrobials have long been used as growth promoters (AGPs) in animal production, demonstrating benefits such as increased body growth and improved feed conversion, particularly for cattle, swine, and poultry (Jukes et al., 1950; Salinas-Chavira et al., 2009). However, due to concerns over the potential emergence of antibiotic-resistant bacterial strains in farm animals, AGPs have been banned in several countries (Vidovic and Vidovic, 2020).
Although AGPs have been widely used in poultry production with success for a long time, the exact mechanism by which they operate is still uncertain. One theory suggests that they interfere with bacterial metabolism, inhibiting their adhesion, reducing the release of toxins by pathogenic bacteria, and ultimately lowering the elicited immune response, thus mitigating local inflammatory processes. This results in improved absorption of nutrients and lower energy expenditure on immune responses. Other hypotheses suggest that AGPs protect nutrients from bacterial destruction and thin the small intestine villi, facilitating nutrient absorption, as well as reducing the incidence of subclinical intestinal infections (Plata et al., 2022). However, a well-supported and widely accepted proposition is that AGPs do not reduce infections due to their antibiotic character but rather work by directly inhibiting the intestinal inflammatory response, leading to improved nutrient absorption and enhanced zootechnical indices. This theory has been described in a review by Niewold (2007) and was investigated previously by our research group (Almeida et al., 2022; Di Gregorio et al., 2023). Considering this last theory, it is reasonable to wonder if nonsteroidal anti-inflammatory drugs (NSAIDs) may play a similar role as AGPs.
NSAIDs are widely used in both human and veterinary medicine. These drugs work by inhibiting the enzyme cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to prostanoids, including prostaglandins (PGs) and thromboxanes (TXs), which contribute to inflammatory processes. These mediators also play a role in regulating various physiological functions, such as gastric acid secretion, homeostasis, and renal functions. There are two types of COX: COX-1, a constitutively expressed enzyme associated with normal physiological function, and COX-2, whose expression is induced by various stimuli, including inflammatory cytokines (Stiller and Hjemdahl, 2022).
NSAIDs can act as nonselective inhibitors of cyclooxygenase. For example, ibuprofen (IBF) inhibits the activity of both COX-1 and COX-2. Alternatively, some NSAIDs, such as meloxicam (MLX), preferentially inhibit the activity of COX-2. The anti-inflammatory mechanism of a NSAID is responsible for its analgesic and antipyretic properties (Grosser et al., 2023).
Basic knowledge about the inflammatory process in birds, as well as the effect of NSAIDs on these animals, is still limited. To date, there have been few pharmacokinetic studies of anti-inflammatories in birds, and their use is generally based on empirical evidence (Baert and De Backer, 2003; Nakhaee et al., 2021). However, there is vast potential for their application, not only as growth promoters but also for the prevention of sudden death, ascites, and locomotion disorders, and the overall promotion of improved animal welfare in the poultry industry (Baert and De Backer, 2003).
Therefore, the objective of the present study was twofold: first, to evaluate the safety of giving IBF or MLX to broiler chickens for 42 days, and second, to estimate whether they have the potential to improve performance in broiler chickens, as observed with AGPs.
MATERIAL AND METHODS
The methodology was carried out in accordance with Almeida et al. (2022), as described below.
For the preparation of feed containing IBF or MLX, both drugs were added in their powdered form directly to the feed in the appropriate amount, resulting in a final concentration of 11.2mg of IBF per gram or 1.0mg of MLX per gram of feed. To establish this concentration, daily feed consumption was calculated over the broilers' growth period (Cobb-Vantress, 2018). Using these calculations, reverse dilution calculations were performed to formulate a more concentrated mixture known as a "premixture drug" (PMD), to be diluted later as the broilers’ diets. The final concentrations of IBF or MLX in PMD were determined spectrophotometrically (Thermo® brand UV‒vis spectrophotometer, model Evolution 201). The PMD of IBF or MLX was included in the basic broiler diets by geometric proportioning, performed with the aid of a Marconi horizontal mechanical mixer (Piracicaba, SP, Brazil, model MA 206/40).
The corn- and soybean-based isoenergetic diets were formulated according to the developmental stage of the birds, beginning with the starter diet, which was offered to broilers from Day 1, and progressing to the grower-finisher diet from the 22nd day onward. The diets were based on corn and soybean meal and were formulated to meet the nutritional and energy recommendations suggested by Rostagno et al. (2011). The components and nutritional levels of the two diets are described in Table 1. The anticoccidial agent Coxistac® was added to each diet according to standard procedures. In preparing the diets, components present in the lowest percentages were incorporated into a premix, which was homogenized in a Delta industrial mixer with a “Y” chamber (Research Triangle Park, NC, USA, model CTA4) and subsequently combined with the major dietary components in a Lucato horizontal mechanical mixer (Limeira, SP, Brazil, model W.17.250). Weekly calculations of PMD were performed, and the resulting amounts were incorporated into starter and grower-finisher diets to deliver treatment doses of 2.5, 5.0, and 10.0 mg IBF/kg BW or 0.1, 0.2, and 0.4 mg MLX/kg body weight (BW) per day. Calculations were based on the average BW and feed intake (FI) of the birds. The PMD was added “on top”.
The experiment was performed in the experimental houses of the poultry research laboratory of the Department of Animal Nutrition and Production (School of Veterinary Medicine and Animal Science, University of São Paulo, Pirassununga, SP, Brazil) located at 21°58’ S, 47°27’ W. One-day-old Cobb 500 male broiler chicks, vaccinated against Marek and Gumboro diseases, were obtained from a commercial hatchery. Chicks were housed from the 1st to the 21st day in stainless-steel/aluminum batteries (100 x 34 x 24cm L x W x H) arranged vertically and equipped with trough-type feeders, nipple drinkers and concealers. Broilers were transferred to another experimental house on the 22nd day, where they were kept individually in galvanized-steel wire cages (50 x 50 x 45cm) equipped with glass nipple drinkers. Management practices, environmental conditions and the lighting schedule followed the recommendations of the lineage manual (Cobb-Vantress, 2018). The birds received water and feed ad libitum, and the temperature and relative humidity of the broiler houses were monitored daily.
To eliminate any potential for feed contamination, experiments involving MLX and IBF were conducted separately, one at a time. A total of eighty broilers were used and distributed into 2 completely randomized designs: i) four groups (n = 10/group) comprising a control group administered feed without IBF and three treatment groups administered feed containing 2.5, 5.0, or 10.0mg of IBF/kg; and ii) four groups (n = 10/group) comprising a control group administered feed without MLX and three treatment groups administered feed containing 0.1, 0.2, or 0.4mg of MLX/kg BW. A cage with one broiler was considered the experimental unit, and each bird was monitored from the first to the forty-second day of life. Each group received the control or NSAID-supplemented starter diet daily from Days 1 to 21 and the control or NSAID-supplemented grower-finisher diet daily from Days 22 to 42. FI values were assessed daily, and body weight gain (BWG) was measured individually every 3 days. Blood was collected from broilers on Days 21 and 42 by puncturing the ulnar vein and was transferred to tubes containing the anticoagulant EDTA for hematological evaluations or to tubes without EDTA for the assessment of biochemical parameters. On the 42nd day, birds were euthanized by cervical dislocation, and tissue samples were taken for histopathological evaluations.
The FI value equaled the difference between the weight of the day's ration and the amount remaining from the previous day. BWG was evaluated as the difference between the final and initial BW values of broilers over the specified time interval. The feed conversion ratio (FCR) was defined as the quotient of BWG/FI.
Red and white blood cell counts (RBCs and WBCs, respectively) were performed manually using a Neubauer chamber with blood samples diluted 1:100 in 0.1% toluidine blue solution. Differential WBCs (eosinophils, basophils, heterophils, lymphocytes, and monocytes) were obtained by examining 100 WBCs on Wright’s-stained blood smears under an optical microscope with a 100X objective. Hematocrit values were determined using the microhematocrit method with the capillary tube centrifuged for 5 min at 1200 x g, and the results are expressed as percentages. The hemoglobin concentrations were determined according to the cyanmethemoglobin technique using Bioclin test kits (Quibasa, Belo Horizonte, MG, Brazil). Mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC) were calculated.
Serum samples were stored at -20 °C in microtubes until analysis of the biochemical parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), glucose (GLU), uric acid (UA), and creatinine (CR). Analyses were performed using commercial kits from Bioclin in accordance with the recommendations of the manufacturer, with readings recorded on a CELM automatic spectrophotometer (Companhia Equipadora de Laboratorios Modernos, São Caetano do Sul, SP, Brazil, model SBA 200).
Tissue samples were collected from the crop (ingluvies), gizzard, pro-ventricle, small intestine (jejunum, duodenum and ileum), large intestine (cecum), liver and kidney of three euthanized 42-day-old broilers randomly selected from each group of each drug. The samples were fixed in 10% buffered formaldehyde and processed according to routine protocols. Sections (5 μm) were stained with hematoxylin and eosin and examined under an optical microscope. Lesions were classified as mild, moderate, or severe according to their intensity and as focal, multifocal, or diffuse based on their distribution.
Individual chicks were considered the experimental unit for all analyzed variables. Statistical analysis was performed with GraphPad Prism 5.00( software (GraphPad Software, Inc., San Diego, CA, USA), with a significance level set at P<0.05. The results are presented as the average followed by its standard error (mean ± SEM). All data were tested for normal distribution and homogeneity of variances. For parametric data, analysis of variance was used followed by the Dunnett post hoc test. In cases where homoscedasticity was not verified, the Kruskal‒Wallis analysis of variance was used followed by the Dunn test.
RESULTS
The BW, BWG, FI and FCR of the birds that received IBF or MLX (Table 2 and Table 3, respectively) were not significantly different between the groups treated with different drug doses and their respective control groups (P>0.05).
Growth performance of broilers treated from the 1st to the 42nd day of life with non-supplemented feed (control group) and feed containing different doses of ibuprofen (Mean ± SEM)
Growth performance of broilers treated from the 1st to the 42nd day of life with non-supplemented feed (control group) and feed containing different doses of meloxicam (Mean ± SEM)
Table 4 presents the serum biochemistry results of broiler chickens treated with IBF. At 21 days of age, a statistically significant reduction in ALT was observed in broilers treated with all doses of IBF when compared to the control group (P<0.0001). Additionally, birds treated with 5.0 and 10.0 mg/kg IBF exhibited an increase in uric acid levels (P<0.0001).
In the analyses carried out at 42 days of age, an increase (P<0.05) in serum LDH activity was observed in birds treated with 5.0 mg/kg IBF, a decrease (P<0.05) in ALP activity was observed in birds treated with the lowest dose of this NSAID, and once again, a statistically significant increase in uric acid levels was observed in broilers treated with doses of 5.0 (P<0.05) and 10.0 mg/kg (P<0.001) IBF.
Regarding the blood counts (Table. 5), at 21 days of age, only a statistically significant reduction (P<0.05) in the eosinophil count was observed in broiler chickens treated with 5.0 mg/kg when compared to the control group. At 42 days of treatment, a statistically significant reduction in the total WBC count (P<0.01) was observed in broilers treated with 10 mg/kg IBF, and a significant reduction in the MCHC count (P<0.05) was observed in broilers treated with 5 mg/kg IBF. A statistically significant reduction in heterophil count (P<0.05) in the groups treated with 2.5 and 10.0 mg/kg IBF when compared to the results of the control group was also seen.
Regarding the biochemical profile of birds treated with MLX (Table 6), at 21 days, a decrease in ALT was seen in all groups of birds treated with MLX (P<0.0001), while ALP levels increased in the group treated with 0.1mg/kg when compared to the control group (P<0.01). The 0.2mg/kg group had decreased glucose levels (P<0.001), and the 0.4mg/kg treated group had increased creatinine levels (P<0.0001) compared to the control group. A decrease in UA (P<0.0001) was seen in all three treated groups. At 42 days, no biochemical differences were found.
As for the blood cell count (Table 7) of the broilers treated with MLX, at 21 days there was a statistically significant decrease in hemoglobin (P<0.05) and in MCHC (P<0.05) in the group treated with 0.4mg/kg. However, at 42 days, there were no statistically significant differences (P>0.05) between the groups of animals in any parameter evaluated.
Only minor histological changes were observed in the tissues collected from broilers treated with IBF or MLX. In the proventriculus and gizzard tissues, multifocal inflammatory infiltrates of moderate to severe intensity were observed in the groups that received 2.5 or 5.0mg/kg IBF. In the intestines, mild to moderate multifocal inflammatory infiltrates were observed in the animals treated with IBF. In the animals treated with MLX, the gizzard tissues presented moderate infiltration at doses of 0.2 and 0.4mg/kg MLX. In the animals treated with 0.2mg/kg MLX, moderate infiltrates in the intestine were also observed. In both IBF and MLX experiments, there was no evidence of any of the usual harmful side effects attributed to NSAIDs, including erosive damage and upper gastrointestinal bleeding.
DISCUSSION
The use of NSAIDs in poultry farming for the therapeutic purpose of painful, inflammatory, or antipyretic conditions is very uncommon (Nakhaee et al., 2021). However, some studies have shown that the use of these drugs in commercial birds has produced some encouraging results for the poultry industry. As an example, there are beneficial effects against coccidiosis when IBF and clopidol are combined in broilers (Hafeez et al., 2021), and there is a reduction in the inflammation process induced by E. coli lipopolysaccharide in broilers treated with MLX (Nakhaee et al., 2021). Regarding studies on the potential use of NSAIDs for a long time as performance enhancers, the findings in the literature are even more scarce. The potential NSAIDs that would be candidates for use in poultry production must have basic characteristics such as low cost, capability of being incorporated into animal feed with pharmaceutical-grade quality and fundamentally low toxicity.
It is very well established that the main cause of observed interspecies differences in drug response arises from species variability in pharmacokinetics (i.e., absorption, distribution, metabolism, and elimination), such differences being most common and of greatest magnitude when functions are phylogenetically divergent between species (Toutain et al., 2010). Moreover, although all NSAIDs share a common mechanism of action, i.e., inhibiting COX enzymes (Grosser et al.; 2023), the affinity of the drug to the enzymes varies greatly between species (Lees et al., 2004). In this manner, the beneficial effects of an NSAID for a particular animal species (in this case, chickens) depend on the dose and duration of administration. However, the use of these compounds may also cause toxic effects, such as gastrointestinal complications, nephrotoxicity, and hepatotoxicity.
In this way, one preliminary and mandatory step to study the effectiveness of IBF and MLX as performance enhancers is to evaluate the safety of prolonged use of these drugs in birds. It is crucial to the study design that the drug be administered accurately to achieve the intended target dose (mg/kg). For this purpose, it is fundamental to verify the stability of the drug in the vehicle of administration, such as feed, drinking water, or gavage. In fact, a prior study of NSAIDs in birds conducted by our research group (Almeida et al., 2022) has already found that potential variations in clinical manifestations observed in chickens could be attributed to ignoring this factor, which may even result in contradictory results with the same NSAID. For example, considering acetylsalicylic acid (ASA), two studies reported a positive effect on chicken growth when 0.2% or 0.3% ASA was administered in food (Glick, 1963; Oluyemi and Adebanjo, 1979). Al-Mashhadani et al. (1988) confirmed this beneficial effect in chickens fed a diet supplemented with 0.05 or 0.1%; however, these same authors verified that feed addition of 0.15% ASA decreased the weight gain in treated chickens. Along the same lines, Nakaue et al. (1967) noted a significant decrease in live body weights of broiler chickens fed at a level of 0.60% or 0.90% ASA for four weeks, and no effect on chick body weight was noted when ASA was fed at a level of 0.30%. Thus, the present study took precautions to ensure that the drugs were incorporated into the feed at the appropriate and intended concentrations through pharmacotechnical formulation. Additionally, to ensure that the chickens received the correct dosage, they were housed separately, and their intake was closely monitored.
The administration of IBF or MLX to chickens resulted in sporadic variations in their zootechnical performance, which did not significantly affect their total FI, BWG or FCR. These outcomes are important since they demonstrate that prolonged usage of these NSAIDs did not induce weight loss, lethargy, or reduced appetite in the chickens. These observations align with prior studies indicating that the use of MLX or IBF for avian therapy is well tolerated at doses similar to those used here, without exhibiting any adverse effects common to this class of drugs (Paul-Murphy and Ludders, 2001).
It is important to emphasize that the present study is a preliminary step that aims to evaluate the safety of prolonged use of these drugs in birds. To evaluate the potential of IBF and MLX to replace antimicrobials as growth promoters, a different design is needed, with a more extensive sample size and more repetitions to better assess the zootechnical parameters. Future studies conducted by our group will focus on zootechnical evaluation and will include a positive control group (i.e., animals treated with “classical” AGPs used in poultry farming) to compare the efficacy of NSAIDs with that of antimicrobials.
In the hematological evaluation, prolonged exposure to IBF did not produce consistent alterations in the parameters at the end of the study, though slight but significant decreases in total leukocytes and heterophils were observed at Day 42 in the group with the highest dose of IBF. It is worth mentioning that although they were significantly reduced, the values are easily within the normal range (Carpenter, 2010), which may only suggest a probable beneficial anti-inflammatory action within the birds, since no other significant changes were observed in this group. Poźniak et al. (2012) reported a similar situation when evaluating increasing doses of another NSAID, ASA. They also observed a slight but significant decrease in WBC count.
In serum biochemistry, the decrease in ALT activity in the groups treated with IBF on the 21st day is not a consistent finding per se, considering that i) this change was not maintained until the 42nd day; ii) the clinical condition of the birds was compatible with good health throughout the entire study; iii) on histopathology there is no evidence of loss of hepatocyte mass (such as fibrosis); and iv) the specificity of ALT in birds is very low (Lumeij, 2008), making interpretation difficult. Thus, the present evaluation showed that IBF is not hepatotoxic at the doses used. In fact, a study conducted by Ghodasara et al. (2014) revealed that only concentrations above 2000 ppm (corresponding to approximately 250 mg/kg IBF) were able to promote hepatotoxicity. However, studies in mammalian species have shown that a decrease in ALT is common in individuals with renal impairment, with the presence of uremia and depletion of vitamin B6, a necessary cofactor for ALT metabolism. Furthermore, the interaction between NSAIDs and vitamin B6 can impede its absorption in the body and potentially interfere with its metabolism (Chang et al., 2013). Unlike in mammals, uric acid is the main excretion product of nitrogen metabolism in avian species, and its increase may suggest renal dysfunction (Lumeij, 2008). In the present study, uric acid levels were what most grabbed our attention, as they were increased under the two highest doses of IBF on the 21st and 42nd days. Since one of the main toxic effects associated with NSAIDs in humans and animals is renal effects (Modi et al., 2012), it is possible to presume that the alteration in this biochemical parameter could be the earliest sign of IBF toxicity. However, a search in the literature did not reveal any study associating these NSAIDs with nephrotoxicity in birds; in contrast, Ghodasara et al. (2014) showed that chicks receiving approximately 2000 ppm IBF for 21 days did not display alterations in any biochemical parameters.
Histopathological evaluation presented no specific changes in any of the tissues studied in either group. Thus, broilers treated or not treated with IBF showed the usual inflammatory infiltrate in the gastrointestinal tract of commercial birds. Despite the clear increase in uric acid levels in birds, no signs of kidney injury were observed in the histopathology of animals treated with IBF. A study on the toxicity of IBF found that administering this NSAID at a dose 25 times higher than the highest dose used in this study for 21 consecutive days resulted in only slightly enlarged and pale liver in some birds and no clinical signs of renal toxicity (Ghodasara et al., 2014).
Considering that the main mechanism of action of IBF is the nonselective, reversible inhibition of the cyclooxygenase enzymes COX-1 and COX-2, when IBF impairs the activity of both enzymes, it can cause a decrease in renal blood flow, a decrease in glomerular filtration rate, and renal tubular toxicity (Weir, 2002). In fact, many studies in humans (Shao et al., 2021) and some animal species (Modi et al., 2012) have shown nephrotoxicity caused by IBF. Therefore, additional investigation is needed to determine whether IBF has potential nephrotoxic effects in broiler chickens.
In the MLX experiment, no consistent alterations in the hemogram were detected between the different groups. It has been reported in the literature that the chronic use of NSAIDs in humans promotes a decrease in hemoglobin concentration (Bao et al., 2018). In the present study, although a slight decrease in hemoglobin in birds receiving the highest dose of MLX on the 21st day was detected, the values were within the normal reference range (Carpenter, 2010), and this alteration was not maintained until the 42nd day, even with the uninterrupted use of MLX.
In the MLX biochemical assessment, although a decrease in ALT and an increase in creatinine levels was detected on the 21st day, these alterations were not observed at the end of the study. Additionally, as there were no changes in AST, LDH, or uric acid - which are considered more sensitive and specific markers for assessing liver and kidney injury in birds - the changes found are not considered relevant. GLU levels at 21 days did not reveal any consistent changes that could be attributed to the toxic effects of MLX. Histopathology confirmed the absence of changes observed in the biochemical evaluation, as no specific histopathological changes were detected regardless of the tissue or group.
Regarding the reduction of the ALT enzyme observed in both NSAID studies, although it cannot be correlated with a hepatotoxic effect, as stated above, since the other biochemical parameters related to liver evaluation showed no alteration and the histopathological study did not reveal liver damage in birds subjected to the two different NSAID treatments, it should be kept in mind that other studies, using different NSAIDs, have also reported changes in ALT levels in chicks. In this sense, Poźniak et al. (2012), administering doses of 200 and 400 mg/kg of both ASA and sodium salicylate, noted decreased ALT activity. Likewise, Di Gregorio et al. (2023) observed the same alteration after administering doses of 30 and 90mg/kg sodium salicylate for 42 days. Even with other studies indicating a reduction in ALT levels when administering NSAIDs, little has been discussed about the reasons behind this phenomenon. The initial safety evaluation studies of NSAIDs conducted by our group were designed to address these possibilities. Future research will be designed to better understand this phenomenon and its potential impacts on other parameters that will be investigated.
CONCLUSIONS
All doses of IBF and MLX studied here were well tolerated by the birds up to 42 days of age, with no impairment of zootechnical parameters such as weight gain, feed consumption, and feed conversion. Caution should be taken when using IBF as a potential substitute for AGPs, as there are indications of incipient renal alterations.
ACKNOWLEDGMENTS
The authors wish to express their gratitude to co-workers for technical collaboration. This research was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior [CAPES grant number 1723701/2017]; and the Fundação de Amparo à Pesquisa do Estado de São Paulo [FAPESP grant number 2018/19474-6 and fellowship 2019/07151-0]. The authors affirm that the funding bodies played no role in the study design, the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.
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