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. 2022 Nov 28;101:skac396. doi: 10.1093/jas/skac396

The effects of standardized ileal digestible His to Lys ratio on growth performance, intestinal health, and mobilization of histidine-containing proteins in pigs at 7 to 11 kg body weight

Yi-Chi Cheng 1, Hye-lim Lee 2, Yunil Hwang 3, Sung Woo Kim 4,✉
PMCID: PMC9838802  PMID: 36440959

Abstract

The objectives were to evaluate the effects of standardized ileal digestible (SID) His:Lys ratio above the current NRC requirement on growth performance, intestinal health, and mobilization of His-containing proteins, including hemoglobin, carnosine, and trypsinogen, in nursery pigs from 7 to 11 kg body weight (BW). Forty pigs (26 d of age; initial BW of 7.1 ± 0.5 kg) were allotted to 5 dietary treatments based on a randomized complete block design with sex and initial BW as blocks. Dietary treatments were supplemented with varying SID His to Lys ratios of 26%, 32%, 38%, 43%, and 49% and fed to pigs for 14 d (SID Lys = 1.22%). Feed intake and BW were recorded at d 0, 7, and 14 to measure growth performance. Blood samples were collected on d 12. Pigs were euthanized on d 14 to collect pancreas, longissimus dorsi muscles, mid-jejunum, and jejunal mucosa. Data were analyzed using the Proc Mixed of SAS. Growth performance was not affected, whereas varying SID His to Lys ratio affected hemoglobin (P < 0.05, max: 12 g/dL at 36%), immunoglobulin A (IgA, P < 0.05, min: 1.25 μg/mg at 35%) in jejunal mucosa, villus height (P = 0.065, max: 536 μm at 40%) in jejunum, trypsinogen (P = 0.083, max: 242 pg/mg at 41%) in pancreas, and carnosine (P = 0.051, max: 4.7 ng/mg at 38%) in muscles. Varying SID His to Lys ratios linearly increased (P < 0.05, from 1.95 to 2.80 nmol/mg) protein carbonyl in muscles and decreased (P < 0.05, from 29.1% to 26.9%) enterocyte proliferation. In conclusion, SID His to Lys ratio between 35% and 41% in diets fed to nursery pigs at 7 to 11 kg enhanced intestinal health and maximized concentrations of His-containing proteins, indicating that His-containing proteins are effective response criteria when determining His requirement.

Keywords: carnosine, growth performance, histidine, intestinal health, nursery pigs

The optimal standardized ileal digestible histidine to lysine ratio for pigs at 7 to 11 kg body weight is between 35% and 41% based on concentrations of histidine-containing proteins and intestinal health status.

Introduction

Histidine is the sixth limiting amino acid (AA) in typical diets fed to swine and may require supplementation in diets (NRC, 2012). Concentrations of His in diets should be at sufficient levels to prevent AA imbalance and reduction in growth, protein deposition, and intestinal enzymatic activities (Zhao et al., 2012; Cemin et al., 2018). Recommended standardized ileal digestible (SID) His to Lys ratio for pigs at 7 to 11 kg body weight (BW) from NRC (2012) is 34%, which was based on growth performance and plasma His concentration of pigs at 10 to 20 kg BW by Izquierdo et al. (1988). However, the weight range of pigs tested by Izquierdo et al. (1988) limits the applicability of His requirement for pigs at 7 to 11 kg body weight. Growth performance and plasma His concentration may not be the effective parameters to determine His requirement for nursery pigs due to the contribution of His from specific body proteins high in His, such as hemoglobin, carnosine, and pancreatic enzymes (Moro et al., 2020). In addition, Lys demand increased as genetics of pigs changed over 30 years to improve feed efficiency (Saintilan et al., 2014). Therefore, the AA requirement needs to be updated.

Hemoglobin contains 8% His and carnosine is a dipeptide composed of His and β-alanine (Nasset and Gatewood, 1954; Wu, 2020). Hemoglobin is a transport protein and the main component in red blood cells (RBC), enabling oxygen transport throughout the body. Histidine deficiency may reduce the formation of hemoglobin and thus decrease erythropoiesis due to hypo-responsiveness to irons as shown in growing and adult rats (Nasset and Gatewood, 1954; Clemens et al., 1984). Most carnosine is stored in muscles at 3 to 4 g/kg wet weight (Boldyrev et al., 2013). Haug et al. (2008) demonstrated that an increase of His at 1 g/kg diets increased the concentration of carnosine in muscles by 64%. Histidine deficiency may result in increased carnosine breakdown in muscles (Robbins et al., 1977; Kidd et al., 2021). Additionally, carnosine has antioxidative effects to prevent cells from oxidative damages by inactivating the production of reactive oxygen species (ROS) from fatty acids on cell membrane (Prokopieva et al., 2016; Thalacker-Mercer and Gheller, 2020). Palin et al. (2020) demonstrated that antioxidant enzymes, including superoxide dismutase and catalase, are enhanced by increasing carnosine in muscles in response to reduced cellular ROS.

Histidine is an important AA in the catalytic triad of serine proteases, including trypsin, chymotrypsin, and elastase from the pancreas (Carter and Wells, 1988). The activities of pancreatic enzymes are highly related to the development of pancreas, which could in turn affect nutrient digestibility (Zhao et al., 2012). In addition, His can be decarboxylated to histamine, which has functions in digestion and inflammatory responses (Li et al., 2007). Histamine activates secretion of pepsinogen and hydrochloric acid for protein digestion (Tanaka et al., 2002). Otherwise, histamine can regulate innate and adaptive immune responses by activating histamine receptors (Son et al., 2005; Jiang et al., 2016). The deficiency of His may impair production of histamine, inhibit the differentiation of immune cells, and reduce secretion of digestive acids (Lee et al., 1981; Yoshikawa et al., 2014).

Dietary His not only affects protein synthesis for growth, but also plays functional roles in metabolic processes. Therefore, functional parameters are needed to be evaluated for a determination of the accurate His requirement. It is hypothesized that SID His to Lys ratio above the current NRC requirement may enhance growth performance, intestinal health, and maximize the levels of His-containing proteins, including carnosine, hemoglobin, and pancreatic trypsinogen. To test the hypothesis, the objectives were to evaluate the effects of SID His to Lys ratio above the current NRC requirement on growth performance, intestinal health, and availability of His-containing proteins in nursery pigs from 7 to 11 kg BW.

Materials and Methods

The experimental protocol was approved by the Institutional Animal Care and Use Committee of North Carolina State University.

Animals, experimental design, and diets

Forty nursery pigs (20 barrows and 20 gilts at 26 d of age) with an initial BW of 7.1 ± 0.5 kg were allotted to 5 dietary treatments (n = 8) in a randomized complete block design with initial BW and sex as blocks. Dietary treatments were supplemented with varying SID His to Lys ratios of 26%, 32%, 38%, 43%, and 49%. All essential AA met NRC (2012) requirements, except Lys. Crystalline amino acids from CJ BIO (Fort Dodge, IA) were supplemented in the basal diet, which was based on corn and soybean and was calculated to have a crude protein (CP) at 15% and sublimiting Lys at 1.22%. All experimental diets were sampled and sent to North Carolina Department of Agriculture (Raleigh, NC) for analysis of diet composition, including dry matter (method 930.15; AOAC Int. 2007), CP (method 990.0; AOAC Int. 2007), and ether extract (method 2003.06; AOAC Int. 2007) shown in Table 1. Diets were sent to CJ BIO (Seoul, South Korea) to analyze free AA without hydrolysis. All pigs were housed in individual pens and had ad libitum access to water and assigned experimental diets for 14 d.

Table 1.

Composition of experimental diets

Item SID1 His to Lys ratio, %
26 32 38 43 49
Feedstuff, %
 Corn grain 59.8 59.7 59.7 59.6 59.5
 Whey permeate 10.0 10.0 10.0 10.0 10.0
 Soybean meal 12.5 12.5 12.5 12.5 12.5
 Bakery meal 10.0 10.0 10.0 10.0 10.0
 Poultry fat 1.80 1.80 1.80 1.80 1.80
 L-Lys HCl (Lys) 0.94 (0.79)2 0.94 (0.69) 0.94 (0.76) 0.94 (0.67) 0.94 (0.78)
 L-Met 0.38 (0.42) 0.38 (0.39) 0.38 (0.40) 0.38 (0.37) 0.38 (0.39)
 L-Thr 0.43 (0.40) 0.43 (0.36) 0.43 (0.38) 0.43 (0.43) 0.43 (0.43)
 L-Val 0.38 (0.39) 0.38 (0.38) 0.38 (0.37) 0.38 (0.39) 0.38 (0.39)
 L-Trp 0.10 0.10 0.10 0.10 0.10
 L-His 0.03 (0.03) 0.10 (0.10) 0.17 (0.17) 0.24 (0.25) 0.31 (0.34)
 L-Phe 0.28 (0.33) 0.28 (0.31) 0.28 (0.32) 0.28 (0.31) 0.28 (0.31)
 L-Ile 0.26 (0.26) 0.26 (0.25) 0.26 (0.24) 0.26 (0.26) 0.26 (0.26)
 L-Leu 0.34 (0.38) 0.34 (0.35) 0.34 (0.36) 0.34 (0.36) 0.34 (0.36)
 Dicalcium phosphate 1.60 1.60 1.60 1.60 1.60
 Limestone 0.73 0.73 0.73 0.73 0.73
 Vitamin premix3 0.03 0.03 0.03 0.03 0.03
 Mineral premix4 0.15 0.15 0.15 0.15 0.15
 Salt 0.25 0.25 0.25 0.25 0.25
Calculated composition
 DM5, % 90.0 90.0 90.0 90.0 90.0
 ME6, kcal/kg 3,442 3,442 3,441 3,441 3,440
 NE7, kcal/kg 2,636 2,636 2,635 2,635 2,635
 CP8, % 14.8 14.9 15.0 15.2 15.3
 SID Lys, % 1.22 1.22 1.22 1.22 1.22
 SID Met + Cys, % 0.74 0.74 0.74 0.74 0.74
 SID Trp, % 0.22 0.22 0.22 0.22 0.22
 SID Thr, % 0.79 0.79 0.79 0.79 0.79
 SID Val, % 0.86 0.86 0.86 0.86 0.86
 SID Ile, % 0.69 0.69 0.69 0.69 0.69
 SID Leu, % 1.35 1.35 1.35 1.35 1.35
 SID Phe, % 0.79 0.79 0.79 0.79 0.79
 SID His, % 0.32 0.39 0.46 0.53 0.60
 Ca, % 0.80 0.80 0.80 0.80 0.80
 STTD9 P, % 0.40 0.40 0.40 0.40 0.40
Analyzed composition, %
 DM 90.4 90.4 90.1 90.3 90.2
 CP 14.1 14.1 14.6 14.5 14.4
 EE10 4.76 4.59 4.67 4.66 4.68
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1 SID, standardized ileal digestible.

2 The data in parentheses indicate the analyzed free AA composition.

3 The vitamin premix provided the following per kilogram of complete diet: 6613.8 IU of vitamin A acetate, 992.0 IU of vitamin D3, 19.8 IU of vitamin E, 2.65 mg of vitamin K, 0.03 mg of vitamin B12, 4.63 mg of riboflavin, 18.52 mg of D-pantothenic acid, 26.45 mg of niacin, and 0.07 biotin.

4 The trace mineral premix provides the following per kilogram of complete diet: 33.0 mg Mn as manganous oxide, 109.5 mg of Fe as ferrous sulfate, 109.5 mg of Zn as zinc sulfate, 16.5 mg of Cu as copper sulfate, 0.3 mg of I as ethylenediamine dihydroiodide, and 0.3 mg of Se as sodium selenite.

5 DM, dry matter.

6 ME, metabolizable energy.

7 NE, net energy.

8 CP, crude protein.

9 STTD, standardized total tract digestible.

10 EE, ether extract.

Growth performance and fecal score

The body weight and feed intake were measured on d 0, 7, and 14 to calculate ADG, ADFI, and G:F. Fecal scores were recorded on every even day from d 2 to 14. Fecal scores were based on 1 to 5 scale following Cheng et al. (2021): 1) very hard and dry stool, 2) firm stool, 3) normal stool, 4) loose stool, and 5) watery stool with no shape.

Sample collection

Two blood samples (7 mL) were collected from the jugular vein of all pigs on d 12 into vacutainers with anticoagulant (BD Diagnostics; Franklin Lakes, NJ). At the end of the experiment (d 14), all pigs were euthanized by a captive bolt gun followed by exsanguination to collect tissues from the pancreas, longissimus dorsi muscles (25 to 30 g from the left side of carcass at the last rib position), and mid-jejunum (4 m after the pyloric duodenal junction). Pancreas and longissimus dorsi muscles were wrapped using aluminum foil and immediately frozen in liquid nitrogen, and then stored at -80 °C for further analyses. Jejunal tissues were placed in 50 mL falcon tubes with 40 mL of 10% buffered formaldehyde for 48 h. The jejunal mucosa was collected into 2 mL microcentrifuge tubes and immediately frozen in liquid nitrogen, and then stored at −80 °C for analyses of immune status and oxidative stress markers.

Hematology and plasma urea nitrogen

Whole blood with EDTA was sent to Antech Diagnostics (Cary, NC) for complete blood count including hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean corpuscular volume, platelet count, RBC, white blood cell count, lymphocytes, monocytes, and neutrophils as described by Weaver et al. (2013). Plasma samples were obtained after centrifugation (3,000 g for 15 min) at 4 °C to obtain supernatant for plasma urea nitrogen (PUN) analysis using Urea Nitrogen Colorimetric Detection Kit (EIABUN, BioAssay Systems, Hayward, CA) following Shen et al. (2012). The working range of standards was 0 to 50 mg/dL. The absorbance was measured at 520 nm. The standard curve was used to calculate the concentration of urea. The concentration of urea divided by 2.14 was the concentration of PUN.

Immune status, oxidative stress, carnosine, and trypsinogen

One gram of jejunal mucosa and muscle samples were mixed with 2 mL PBS solution into new 5 mL ­polypropylene tubes. Mucosa and muscle samples were homogenized (Tissuemiser, Thermo Fisher Scientific) for 30 s on ice, withdrawn into new 2 mL microcentrifuge tubes, and centrifuged at 13,500 g for 10 min (MiniSpin, Eppendorf; Hamburg, Germany). Four hundred mg of frozen pancreas samples were with 2 mL protein extraction reagent. To make 10 mL protein extraction reagent needs 4 mL 0.8% NaCl, 4 mL 0.01 mol/L Sucrose, 1 mL pH 7.4 0.01 mol/L Tris–HCl, and 1 mL 0.0001 mol/L EDTA-2Na. Pancreas samples were homogenized for 30 s on ice, withdrawn into new 2 mL microcentrifuge tubes, and centrifuged at 12,500 g for 10 min. All supernatant was collected and stored at −80 °C until further analyses.

The concentrations of total proteins in mucosa, pancreas, and muscle samples were measured by following instructions of Pierce BCA Protein Assay Kit (#23225, Thermo Fisher Scientific) as described by Cheng et al. (2022). The concentration of total protein was described as mg/mL. It was used to normalize the concentration of interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α), immunoglobulin A (IgA), immunoglobulin G (IgG), and malondialdehyde (MDA), protein carbonyl (PC), carnosine, and trypsinogen.

The concentration of IL-6 in jejunal mucosa was measured by following instructions of the Porcine IL-6 DuoSet ELISA Kit (DY686, R&D Systems, Minneapolis, MN) as described by Duarte et al. (2021). The concentration of IL-6 was described as ng/mg of protein. The concentration of IL-8 in jejunal mucosa was measured by following instructions of the Porcine IL-8/CXCL8 DuoSet ELISA Kit (DY535, R&D Systems) as described by Moita et al. (2021). The concentration of IL-8 was described as ng/mg of protein. The concentration of TNF-α in jejunal mucosa was measured by following instructions of Porcine TNF-α DuoSet ELISA Kit (DY690B, R&D Systems) as described by Holanda et al. (2021). The concentration of TNF-α was described as pg/mg of protein. The concentration of IgA in jejunal mucosa was measured by following instructions of the pig ELISA kit (#E101-102, Bethyl Laboratories; Montgomery, TX) as described by Kim et al. (2019). The concentration of IgA was described as μg/mg of protein. The concentration of IgG in jejunal mucosa was measured by following instructions of the pig ELISA kit (E101-104, Bethyl Laboratories) as described by Xu et al. (2022). The concentration of IgG was described as μg/mg of protein. The concentration of MDA in jejunal mucosa and muscle samples was measured by following instructions of OxiSelect TBARS MDA Quantitation Assay Kit (#STA-330, Cell Biolabs, Inc., San Diego, CA) as described by Zhao and Kim (2020). The concentration of MDA was described as nmol/mg of protein. The concentration of PC in jejunal mucosa and muscle samples was measured by following instructions of OxiSelect Protein Carbonyl ELISA Kit (STA-310, Cell Biolabs, Inc) as described by Deng et al. (2022). The concentration of PC was described as nmol/mg of protein. The concentration of carnosine in muscle samples was measured by following instructions of the Carnosine ELISA Kit (NBP2-75013, MyBioSource, San Diego, CA) as described by Shi et al. (2014). The concentration of carnosine was described as ng/mg of protein. The concentration of trypsinogen in pancreas was measured by following instructions of the Porcine trypsinogen ELISA Kit (MBS2612343, MyBioSource). The concentration of trypsinogen was described as pg/mg of protein.

Intestinal morphology and crypt cell proliferation

Two sections of mid-jejunum were cut into cassettes and sent to North Carolina State University College of Veterinary Medicine Histopathology Lab for immunohistochemistry staining with Ki-67 assay. One slide is represented by a pig. Pictures were taken using an Olympus CX31 microscope (Tokyo, Japan) and Infinity Analyze and Capture software (Lumenera Corporation; Ottawa, Canada). Well-shaped 20 villus and corresponding crypts were taken from each slide with the magnifying at ×40 to measure villus height (VH), crypt depth (CD), and villus height to crypt depth (VH:CD) ratio using the Infinity Analyze and Capture software (Lumenera Corporation). The lengths of 25 well-shaped crypts were taken from each slide with the magnifying at ×100 and cropped to calculate the ratio of Ki-67 positive cells in a crypt of the mid-jejunum by operating the program called ImageJS (http://imagejs.org). The percentage of Ki-67 positive cells was an indicator of the enterocyte proliferation rate in the crypt (Chen et al., 2017; Duarte et al., 2019).

Statistical analysis

Data were analyzed by SAS 9.3 (SAS Inc, Cary, NC) using the Mixed procedure. The experimental units were pigs housed individually. Initial BW (light and heavy) and sex (gilts and barrows) were considered as blocks. Dietary treatments were defined as fixed effects and blocks were random effects. The LSMEANS procedure was used to calculate mean values for all treatments as described by Holanda et al. (2020). Contrasts were preplanned to assess the effects of SID His to Lys ratio for linear and quadratic responses using Proc NLMIXED in SAS. The fecal score data was performed by using Kruskal–Wallis Test with Dwass, Steel, Critchlow-Fligner Method option for pairwise two-sided multiple comparison analysis following Guo et al. (2015). Statistical significance was P < 0.05 and 0.05 ≤ P < 0.10 was considered as tendency.

Results

Growth performance and fecal score

Increasing SID His to Lys ratios did not affect the growth performance (Table 2) or fecal score (Table 3).

Table 2.

Growth performance of pigs fed diets with varying standardized ileal digestible (SID) His to Lys ratio

SID His to Lys ratio, % P-value
0.26 0.32 0.38 0.43 0.49 SEM Linear Quadratic
BW, kg
 d 0 7.2 7.1 7.1 7.1 7.1 0.5 0.840 0.713
 d 7 8.9 8.9 8.9 8.9 8.6 0.6 0.609 0.102
 d 14 11.0 11.8 11.4 11.4 11.0 0.8 0.744 0.223
ADG, g
 d 0–7 241 245 257 255 213 26 0.568 0.267
 d 7–14 312 413 366 359 339 33 0.976 0.106
 Overall 276 329 311 306 276 26 0.778 0.104
ADFI, g
 d 0–7 353 378 372 389 337 41 0.877 0.414
 d 7–14 543 700 639 627 641 62 0.477 0.282
 Overall 448 539 506 508 489 47 0.703 0.288
G:F
 d 0–7 0.69 0.68 0.73 0.67 0.65 0.05 0.616 0.462
 d 7–14 0.57 0.60 0.58 0.58 0.54 0.04 0.537 0.420
 Overall 0.61 0.62 0.63 0.61 0.58 0.03 0.439 0.415
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Table 3.

Fecal score of pigs diets with varying standardized ileal digestible (SID) His to Lys ratio

SID His to Lys ratio, %
26 32 38 43 49 SEM P value
d 2 2.9 3.1 3.0 2.8 3.0 0.1 0.861
d 4 3.0 3.0 3.0 2.7 3.0 0.1 0.785
d 6 2.7 3.0 3.0 3.0 3.0 0.1 0.392
d 8 2.7 3.0 2.8 3.0 2.7 0.1 0.399
d 10 2.9 3.0 2.9 2.7 3.0 0.1 0.373
d 12 2.9 2.9 2.9 2.8 2.9 0.1 0.153
d 14 3.1 2.9 2.9 2.9 3.0 0.1 0.875
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Hematology

Increasing SID His to Lys ratios had quadratic effects (P < 0.05; Table 4) on hematocrit (maximum 41% at SID His:Lys 36%), RBC (maximum 6.9 × 106 cells/μL at SID His:Lys 37%), and hemoglobin (maximum 12 g/dL at SID His:Lys 36%; Figure 1). Increasing SID His to Lys ratios tended to have quadratic effects (P = 0.065) on the number of neutrophils (maximum 7.3 × 103 cells/μL at SID His:Lys 41%).

Table 4.

Hematology (d 12) in plasma of pigs fed diets with varying standardized ileal digestible (SID) His to Lys ratio

Item1 SID His to Lys ratio, % P value
26 32 38 43 49 SEM Linear Quadratic
HCT, % 39.0 39.1 41.0 40.7 36.8 0.8 0.264 0.001
MCH, pg 17.4 17.8 17.4 17.6 17.1 0.5 0.469 0.479
MCHC, g/dL 29.8 30.4 29.6 29.6 29.6 0.3 0.353 0.710
MCV, fL 58.6 58.9 58.8 59.5 57.6 1.5 0.727 0.480
PLT, 103 cells/μL 0.43 0.48 0.50 0.53 0.41 0.05 0.116 0.178
RBC, 106 cells/μL 6.56 6.65 7.03 6.78 6.43 0.16 0.789 0.011
WBC, 103 cells/μL 16.6 17.5 19.5 20.6 18.8 1.6 0.162 0.322
LYM, 103 cells/μL 8.9 10.8 11.1 10.7 11.2 1.1 0.151 0.364
MONO, 103 cells/μL 0.49 0.57 0.63 0.85 0.60 0.10 0.116 0.178
NEU, 103 cells/μL 5.16 6.15 6.28 8.89 5.69 0.79 0.176 0.065
PUN, mg/dL 7.73 8.59 8.56 9.35 9.22 0.74 0.135 0.696
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1HCT, hematocrit; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PLT, platelet count; RBC, red blood cell count; WBC, white blood cell count; LYM, lymphocytes; MONO, monocytes; NEU, neutrophils; PUN, plasma urea nitrogen.

Figure 1.

Figure 1.

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Hemoglobin (HGB) in plasma of pigs fed diets with varying standardized ileal digestible (SID) His to Lys ratio. Quadratic model: y = −0.005x2 + 0.320x + 6.250, R2 = 0.18, P < 0.05 (overall model), 0.014 (x2), 0.019 (x), and 0.012 (intercept), x = SID His to Lys ratio (%), y = HGB (g/dL).

Immune status, oxidative stress, carnosine, and trypsinogen

In the jejunal mucosa, increasing SID His to Lys ratios had a quadratic effect (P < 0.05; Table 5) on the concentration of IgA (minimum 1.25 μg/mg of protein at SID His:Lys 35%). In muscles, increasing SID His to Lys ratios linearly increased (P < 0.05) the concentration of PC and tended to have quadratic effects on concentrations of MDA (P = 0.095; minimum 48 nmol/mg of protein at SID His:Lys 38%) and carnosine (P = 0.051; maximum 4.7 ng/mg of protein at SID His:Lys 38%; Figure 2). In the pancreas, increasing SID His to Lys ratios tended to have a quadratic effect (P = 0.083) on the concentration of trypsinogen (maximum 242 pg/mg of protein at SID His:Lys 41%; Figure 3).

Table 5.

Immune status, oxidative stress markers, carnosine, and trypsinogen in the jejunal mucosa, longissimus dorsi muscles, and pancreas of nursery pigs fed diets with varying standardized ileal digestible (SID) His to Lys ratio

SID His to Lys ratio, % P value
26 32 38 43 49 SEM Linear Quadratic
Jejunal mucosa, amount/mg of protein
 TNF-α1, pg 1.02 1.00 1.26 1.15 1.21 0.14 0.237 0.737
 IL-62, ng 17.0 26.8 28.6 20.9 17.5 5.4 0.830 0.108
 IL-83, pg 0.33 0.46 0.40 0.43 0.41 0.10 0.526 0.589
 IgA4, μg 1.68 1.44 0.99 1.86 2.15 0.27 0.159 0.034
 IgG5, μg 0.91 0.93 0.78 0.96 1.11 0.16 0.437 0.375
 PC6, nmol 2.19 2.69 2.56 2.43 2.22 0.44 0.897 0.414
 MDA7, nmol 0.39 0.35 0.50 0.36 0.45 0.05 0.363 0.882
Longissimus dorsi muscles, amount/mg of protein
 PC, nmol 1.95 2.32 2.32 2.34 2.80 0.34 0.006 0.743
 MDA, nmol 0.57 0.53 0.43 0.54 0.54 0.05 0.715 0.095
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1 TNF-α, tumor necrosis factor-alpha.

2 IL-6, interleukin 8.

3 IL-8, interleukin 6.

4 IgA, immunoglobulin A.

5 IgG, immunoglobulin G.

6 PC, protein carbonyl.

7 MDA, malondialdehyde.

Figure 2.

Figure 2.

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The concentration of carnosine in muscles of pigs fed diets with varying standardized ileal digestible (SID) His to Lys ratio. Quadratic model: y = −0.005x2 + 0.380x − 2.480, R2 = 0.09, P = 0.051 (overall model), 0.063 (x2), 0.062 (x), and 0.495 (intercept), x = SID His to Lys ratio (%), y = carnosine (ng/mg of protein).

Figure 3.

Figure 3.

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The concentration of trypsinogen in pancreas of pigs fed diets with varying standardized ileal digestible (SID) His to Lys ratio. Quadratic model: y = −0.22x2 + 18.14x − 131.10, R2 = 0.15, P = 0.083 (overall model), 0.091 (x2), 0.066 (x), and 0.455 (intercept), x = SID His to Lys ratio (%), y = trypsinogen (pg/mg of protein).

Intestinal morphology and crypt cell proliferation

Increasing SID His to Lys ratios tended to have a quadratic effect (P = 0.065; Table 6) on VH (maximum 536 μm at SID His:Lys 40%) and linearly decreased (P < 0.05) the enterocyte proliferation.

Table 6.

Intestinal morphology and crypt cell proliferation of pigs fed diets with varying standardized ileal digestible (SID) His to Lys ratio

SID His to Lys ratio, % P value
26 32 38 43 49 SEM Linear Quadratic
VH1, μm 481 523 541 518 517 18 0.234 0.065
CD2, μm 238 240 253 239 244 12 0.747 0.308
VH:CD ratio3 2.06 2.20 2.14 2.17 2.13 0.12 0.763 0.872
Ki-67+4, % 29.1 29.0 26.9 26.7 26.9 0.8 0.011 0.242
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1 VH, villus height.

2 CD, crypt depth.

3 VH:CD ratio, villus height to crypt depth ratio.

4 Ki-67+, crypt cell proliferation rate of the proliferating cells to the number of epithelial cells in a crypt.

Discussion

The SID His to Lys ratio covered between 26% and 49% in the current study. Previous studies have shown that His deficiency at SID His to Lys ratio 20% and 24% decreased growth performance (Gloaguen et al., 2013; Cemin et al., 2018), whereas growth performance is not affected by SID His to Lys ratio from 26% to 49% in the current study as described by Wessels et al. (2016) and Cemin et al. (2018). Deficiency of AA in diets can cause AA imbalance and consequently reduce protein synthesis (Kino and Okumura, 1987), however, growth performance was not affected by varying SID His to Lys ratio in the current study possibly because endogenous His from mobilization of hemoglobin, carnosine, and trypsinogen may be utilized by nursery pigs until endogenous His is depleted. A short experimental period could also be a potential reason for lacking growth response. A large scale feeding study can properly valid growth performance responses. Although the growth performance was not affected, the changes in concentrations of endogenous sources of His, including hemoglobin, carnosine, and trypsinogen, were observed.

Histidine is not only an essential AA for growth and protein synthesis, but also plays a vital role in the metabolic system. Histidine is involved in the formation of a catalytic triad for serine peptidases that play an essential role in maintaining pH and synthesis of enzymes in the pancreas (Carter and Wells, 1988). The synthesis of pancreatic enzymes is affected by the available amino acid pool in the pancreas (Snook, 1965). In the current study, the maximum concentration of pancreatic trypsinogen was observed with supplementing SID His to Lys at 41% in diets in agreement with Zhao et al. (2012), who reported that increasing dietary His at 0.8% resulted in the maximum concentration of digestive enzymes and growth of pancreatic development in fish. However, limited studies have investigated whether the level of dietary His could affect pancreatic enzymes in pigs.

Hemoglobin is composed of 4 peptide chains (α and β) and a heme iron. Histidine is located at the distal part of α and β peptide chains and bound to the heme iron (Kovalevsky et al., 2010). Compared to hemoglobin, carnosine has a higher metabolic priority and thus His from hemoglobin would be mobilized more effectively than carnosine for His needs (Clemens et al., 1984). Carnosine is made of 3 ionizable groups, including a carboxyl group, amino group from β-alanine, and imidazole ring from His (Tanokura et al., 1976). Carnosine is abundant in mammal skeletal muscles and acts on histamine receptors, which can enhance or reduce digestive process (Caruso et al., 2019; Wu, 2021). Clemens et al. (1984) demonstrated that the deficiency of His in rat diets resulted in degradation of hemoglobin and carnosine to release His for synthesis of protein or other His-containing compounds in tissues. Excessive dietary His reduced copper and zinc in plasma resulting in hypercholesterolemia that increased inflammation (Moro et al., 2020; Collado et al., 2021). In the current study, the concentrations of hemoglobin and carnosine would be maximized as supplanting SID His to Lys ratio from 36% to 38%. This indicated that deficiency and excess of SID His to Lys ratio may increase metabolic cost and consequently damage in health and growth (Moro et al., 2020).

Oxidative stress is induced by ROS, which can damage cellular integrity and functions and increase secretion of pro-inflammatory cytokines (Hussain et al., 2016). Malondialdehyde is a marker of polyunsaturated fatty acids attacked by ROS and PC directly oxidizes AA residues in protein (Dalle-Donne et al., 2003; Fang et al., 2007). In skeletal muscles, the maximum concentrations of carnosine and minimum concentrations of MDA in muscles were observed as supplementing SID His to Lys ratio at 38% in nursery diets. The result may indicate that supplementing appropriate levels of His in diets could reduce oxidative stress due to antioxidant effects from His by interacting with hydroxyl radical and singlet oxygen (Wade and Tucker, 1998). In addition, carnosine has ability to scavenge ROS by generating a charge-transfer complex to react with free radicals (Boldyrev et al., 2013; Palin et al., 2020). Previous study reported that His efficiently reduces ROS and thus reduces MDA, PC, and pro-inflammatory cytokines (Jiang et al., 2016), whereas the concentration of PC was increased in the current study.

Histamine, converted by His and carnosine by histidine decarboxylase (HDC), can stimulate gastrin for protein digestion (Tanaka et al., 2002). Gastrin is produced by G cells and secreted by parietal cells in the fundic region of the stomach to affect feed intake (Saqui-Salces et al., 2012; Bohler et al., 2019). Lee et al. (1981) demonstrated that supplementing His increased HDC in the stomach converting His to histamine and further stimulating gastrin secretion. However, feed intake of pigs was not affected by varying SID His to Lys ratio in this study. On the other hand, histamine interacts with the immune system by activating innate and adaptive immune responses (O’Mahony et al., 2011). In the intestinal mucosa, histamine as a neurotransmitter is secreted by mast cells to regulate cytoplasmic pH, water secretion, and tight junction permeability (Wouters et al., 2016). Histamine receptors on immune cells have also been shown to influence cytokine secretion (O’Mahony et al., 2011). In the current study, no changes were observed in concentrations of pro-inflammatory cytokines in jejunal mucosa by varying SID His to Lys ratio in nursery diets. Otherwise, as supplementing SID His o Lys ratio at 35%, the concentration of IgA was reduced in jejunal mucosa, indicating SID His to Lys ratio at 35% could reduce T helper 1 cells activation and subsequent inflammation.

In conclusion, the SID His to Lys ratio between 35% and 41% in the nursery diets fed to pigs at 7 to 11 kg BW maximized concentrations of His-containing proteins, including hemoglobin and carnosine, and trypsinogen in pancreas. In addition, SID His to Lys ratios between 35% and 41% enhanced intestinal health by reduced IgA, reduced enterocyte proliferation, and increased villus height in the jejunum. This study suggests a slightly greater SID His to Lys ratio than NRC (2012) based on growth performance and plasma His. Growth performance did not respond to His deficiency due to compensation of His from His-containing proteins and potentially due to a short experimental period. This study indicates that hemoglobin, carnosine, and trypsinogen are effective response criteria when determining His requirement.

Acknowledgments

This work is/was supported by the USDA National Institute of Food and Agriculture (Hatch #02893), North Carolina Agricultural Foundation (Raleigh, NC, USA), and CJ BIO (Seoul, South Korea).

Glossary

Abbreviations

AA

amino acid(s)

BW

body weight

CP

crude protein

IgA

immunoglobulin A

IgG

immunoglobulin G

IL-6

interleukin 6

IL-8

interleukin 8

MDA

malondialdehyde

PC

protein carbonyl

RBC

red blood cells

ROS

reactive oxygen species

SID

standardized ileal digestible

TNF-α

tumor necrosis factor-alpha

VH

villus height

Contributor Information

Yi-Chi Cheng, Department of Animal Science, North Carolina State University, Raleigh, NC 27695, USA.

Hye-lim Lee, CJ Cheiljedang, Seoul, 04560, South Korea.

Yunil Hwang, CJ Cheiljedang, Seoul, 04560, South Korea.

Sung Woo Kim, Department of Animal Science, North Carolina State University, Raleigh, NC 27695, USA.

Conflict of Interest Statement

H. Lee and Y. Hwang are employed by CJ Bio, Seoul, South Korea. All other authors have no conflict of interest.

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