Glucocorticoid Receptor Agonists to Improve the Productivity and Health of Early-Weaned Pigs: What is the Best Method of Delivery?

The purpose of the current study was to determine the best method of delivery for glucocorticoid receptor agonist (GRA) treatment. A total of 167 Pig Improvement Company (PIC) piglets (body weight (BW) 7.35 ± 1.24 kg) were weaned at 25.0 ± 0.81 days of age and randomly assigned to 14 treatment groups based on a 2 × 7 factorial arrangement with sex (gilts vs. barrows), in-feed antibiotic (ANT; 110 mg/kg in-feed tylosin), repeated intramuscular (I.M.) injection of GRA (two injections, 0.2 mg/kg BW dexamethasone (DEX)), low dose in-feed GRA (LF, 2.5 mg/kg diet DEX ), high dose in-feed GRA (HF, 5 mg/kg diet DEX), low dose in-water GRA (LW, 0.8 mg/L DEX ), high dose in-water GRA (HW, 1.6 mg/L DEX ), and no treatment control (CON) as the main factors. Body weight and feed intake were measured daily from days 0 to 7 and weekly from days 7 to 28 post-weaning. The interaction effect for average daily gain (ADG) was significant with gilts performing better in the I.M., ANT, and LF groups (p = 0.05). All treatment groups, with the exception of the HW group, had a higher ADG than the CON group. Gilts in the I.M., LF, and HF groups had the highest ADG compared to other treatment groups (p ≤ 0.05). Sex and the interaction between sex and treatments had no effect on the gain-to-feed ratio (G:F; p ≥ 0.21). All treatment groups had a higher G:F than the CON group (p ≥ 0.04). These results suggest that the low-dose, in-feed GRA treatment is the best GRA delivery method and is a suitable alternative to in-feed sub-therapeutic antibiotics.

The Effects of a Glucocorticoid Receptor Agonist (GRA) on the Immune Function, Nutrient Digestibility, and Wean-to-Finish Growth Performance of Early-Weaned Pigs.

This study assessed the viability of glucocorticoid receptor agonist (GRA) treatment as an alternative to in-feed antibiotics (ANT) in wean-to-finish pigs. A total of 209 piglets were assigned to eight treatments based on a factorial arrangement, with GRA (+ vs. -; dexamethasone, 0.2 mg/kg body weight, BW), ANT (+ vs. -; 110 mg/kg in-feed Tylosin) and sex (gilt vs. barrow) as the main factors. The serial slaughter technique and serial blood collection were performed on 115 pigs during the first week post-weaning to collect blood, tissue and ileal digesta samples. Fecal samples were collected to determine energy digestibility. In comparison to ANT, GRA more effectively improved the measures of systemic inflammation, protein utilization and recovery-associated biomarkers (p ≤ 0.05). Relative to the control group, GRA treatment improved (p ≤ 0.03) dietary nutrient digestibility relative to control pigs, which was comparable to ANT effects. Relative to the control group, all groups had a higher ADG and BW during the starter phase (p < 0.01). Similar to the ANT group, GRA improved the gain-to-feed ratio relative to the control group during the starter phase. Relative to control pigs, overall BW was higher in GRA and ANT pigs during the grow-to-finish phase (p < 0.01). Collectively, these results suggest that GRA injection improves the growth performance of newly weaned pigs by reducing weaning-induced inflammation and improving nutrient digestibility. GRA can be used as an alternative to in-feed ANT to mitigate the effects of weaning stress on pigs.

Effects of divergent selection for residual feed intake on nitrogen metabolism and lysine utilization in growing pigs.

A study was conducted to evaluate the effects of divergent genetic selection for residual feed intake (RFI) on nitrogen (N) metabolism and lysine utilization in growing pigs. Twenty-four gilts (body weight [BW] 66 ± 5 kg) were selected from generation nine of the low RFI (LRFI; n = 12) and high RFI (HRFI; n = 12) Iowa State University Yorkshire RFI selection lines. Six pigs from each genetic line were assigned to each of two levels of lysine intake: 70% and 100% of estimated requirements based on the potential of each genetic line for protein deposition (PD) and feed intake. For all diets, lysine was first limiting among amino acids. Using isotope tracer, N-balance, and nutrient digestibility evaluation approaches, whole-body N metabolism and the efficiency of lysine utilization were determined for each treatment group. No significant interaction effects of line and diet on dietary N or gross energy digestibility, PD, and the efficiency of lysine utilization for PD were observed. The line did not have a significant effect on PD and digestibility of dietary N and GE. An increase in lysine intake improved N retention in both lines (from 15.0 to 19.6 g/d, SE 1.44, in LRFI pigs; and from 16.9 to 19.8 g/d, SE 1.67, in HRFI pigs; P < 0.01). At the low lysine intakes and when lysine clearly limited PD, the efficiency of using available lysine intake (above maintenance requirements) for PD was 80% and 91% (SE 4.6) for the LRFI and HRFI pigs, respectively (P = 0.006). There were no significant effects of line or of the line by diet interaction on N flux, protein synthesis, and protein degradation. Lysine intake significantly increased (P < 0.05) N flux (from 119 to 150, SE 8.7 g/d), protein synthesis (from 99 to 117, SE 10.6 g of N/d), and protein degradation (from 85 to 100, SE 6.6 g of N/d). The protein synthesis-to-retention ratio tended to be higher in the LRFI line compared with the HRFI line (6.5 vs. 5.8 SE 0.62; P = 0.06), indicating a tendency for the lower efficiency of PD in this group. Collectively, these results indicate that genetic selection for low RFI is not associated with improvements in lysine utilization efficiency, protein turnover, and nutrient digestibility.

Immune system stimulation increases the irreversible loss of cysteine to taurine, but not sulfate, in starter pigs.

An isotope tracer study was conducted to evaluate the effects of immune system stimulation (ISS) on the irreversible loss of cysteine (Cys) to taurine (Tau) and sulfate (SO4), as well as glutathione (GSH) synthesis, during the fed state in pigs. We previously have reported that ISS increases plasma Cys flux and the GSH synthesis rate at the tissue and whole-body levels in growing pigs. Thus, the current article presents the data on the irreversible loss of Cys during ISS in pigs. Ten gilts (BW: 7.0 ±â€…0.12 kg) were feed restricted a sulfur amino acids (SAA) limiting diet and injected twice with either saline (n = 4) or increasing amounts of E. coli lipopolysaccharide (n = 6). The day after the second injection, a 5-h primed continuous intravenous infusion of 35S-Cys was conducted. ISS reduced plasma Cys and total SAA concentrations (16% and 21%, respectively; P < 0.05). However, ISS had no effect on the plasma concentrations of Tau and SO4, nor did it affect the appearance of 35S in plasma Tau, plasma SO4, urinary Tau, or urinary SO4 (P > 0.19). On a whole-body basis and including urinary excretion, ISS increased the appearance of 35S in Tau by 67% (P < 0.05), but tended to decrease the appearance of 35S in SO4 by 22% (P < 0.09). Overall, the current findings indicate that during ISS, decreased plasma SAA concentrations and increased plasma Cys flux are attributed in part to increased rates of Cys conversion to Tau, but not Cys catabolism to SO4. Thus, increased utilization of Cys for the synthesis of immune system metabolites, such as GSH and Tau, is likely the main contributor to increased Cys flux during ISS in pigs. In addition, the irreversible loss of Cys during ISS is small and has a minimal impact on the daily SAA requirements of starter pigs.

Immune System Stimulation Reduces the Efficiency of Whole-Body Protein Deposition and Alters Muscle Fiber Characteristics in Growing Pigs.

The effects of immune system stimulation (ISS), induced by repeated injection of Escherichia coli lipopolysaccharide, on the whole-body protein synthesis versus degradation rates, the efficiency of protein deposition (PD), and muscle fiber characteristics in pigs were evaluated. Twelve growing gilts were assigned to two levels of amino acid intake that was predicted based on the potential of each group's health status for PD and feed intake. Isotope tracer, nitrogen balance, and immunohistochemical staining techniques were used to determine protein turnover, PD, and muscle fiber characteristics, respectively. Protein synthesis, degradation, and PD were lower in immune-challenged pigs than in control pigs (p < 0.05). Strong tendencies for a higher protein synthesis-to-PD ratio (p = 0.055) and a lower protein synthesis-to-degradation ratio (p = 0.065) were observed in immune-challenged pigs. A decrease in muscle cross-sectional area of fibers and a shift from myosin heavy chain (MHC)-II towards MHC-I fibers (p < 0.05) were observed in immune-challenged pigs. These results indicated that ISS reduces PD not only by suppressing the whole-body protein synthesis and degradation rates, but also by decreasing the efficiency of PD in growing pigs. In addition, ISS induces atrophy in skeletal muscles and favors a slow-twitch oxidative fiber type composition.

Immune system stimulation increases the plasma cysteine flux and whole-body glutathione synthesis rate in starter pigs1.

Glutathione (GSH) is the major intracellular thiol that plays a role in numerous detoxification, bio-reduction, and conjugation reactions. The availability of Cys is thought to be the rate-limiting factor for the synthesis of GSH. The effects of immune system stimulation (ISS) on GSH levels and the GSH synthesis rate in various tissues, as well as the plasma flux of Cys, were measured in starter pigs fed a sulfur AA (SAA; Met + Cys) limiting diet. Ten feed-restricted gilts with initial body weight (BW) of 7.0 ± 0.12 kg were injected i.m. twice at 48-h intervals with either sterile saline (n = 4; ISS-) or increasing amounts of Escherichia coli lipopolysaccharide (n = 6; ISS+). The day after the second injection, pigs received a primed constant infusion of 35S-Cys (9,300 kBq/pig/h) for 5 h via a jugular catheter. Blood and tissue free Cys and reduced GSH were isolated and quantified as the monobromobimane derivatives by HPLC. The rate of GSH synthesis was determined by measurement of the specific radioactivity of GSH and tissue free Cys at the end of the infusion period. Plasma Cys and total SAA levels were reduced (16% and 21%, respectively), but plasma Cys flux was increased (26%) by ISS (P < 0.05). Immune system stimulation increased GSH levels in the plasma (48%; P < 0.05), but had no effect on GSH levels in the liver, small and large intestines, heart, muscle, spleen, kidney, lung, and erythrocytes. The fractional synthesis rate (FSR) of GSH was higher (P < 0.05) in the liver (34%), small intestine (78%), large intestine (72%), heart (129%), muscle (37%), and erythrocytes (47%) of ISS+ pigs compared to ISS- pigs. The FSR of GSH tended (P = 0.08) to be higher in the lungs (45%) of ISS+ pigs than in ISS- pigs. The absolute rate of GSH synthesis was increased by ISS (mmol/kg wet tissue/d ± SE, ISS- vs. ISS+; P < 0.05) in the liver (5.22 ± 0.22 vs. 7.20 ± 0.59), small intestine (2.54 ± 0.25 vs. 4.52 ± 0.56), large intestine (0.61 ± 0.06 vs. 1.06 ± 0.16), heart (0.21 ± 0.03 vs. 0.48 ± 0.08), lungs (1.50 ± 0.10 vs. 2.90 ± 0.21), and muscle (0.21 ± 0.03 vs. 0.34 ± 0.04), but it remained unchanged in erythrocytes, the kidney, and the spleen (P > 0.80). The current findings suggest that GSH synthesis is increased during ISS, contributing to enhanced maintenance sulfur amino acid requirements in starter pigs during ISS.

Immune system stimulation induced by porcine reproductive and respiratory syndrome virus alters plasma free amino acid flux and dietary nitrogen utilization in starter pigs1.

Changes in plasma free amino acid (AA) flux reflect the modification of AA metabolism in different metabolic states. Infectious diseases repartition AA away from protein retention toward processes involved in immune defense, thus impacting AA utilization in pigs. The current study sought to evaluate the effects of disease induced by a live pathogen on plasma free AA flux and whole-body nitrogen (N) utilization. Twenty gilts (BW 9.4 ± 0.9 kg) were surgically catheterized into the jugular vein, individually housed in metabolism crates, and feed-restricted (550 g/d). Intramuscular inoculation of a live field strain of porcine reproductive and respiratory syndrome virus (PRRSV) was used to induce disease. Whole-body N-balance was conducted across 3 d both before PRRSV inoculation (PRRSV-) and also after PRRSV inoculation (PRRSV+). At the end of each N-balance period, a bolus dose of a labeled [U-13C, U-15N]-AA mixture (Ile, Leu, Lys, Met, Phe, Thr, Trp, Val, and Gln) was infused intravenously, followed by serial blood collection for measurement of isotopic enrichment. A double exponential model was fitted with plasma enrichment data for each pig and each AA, and equation parameters were used to estimate plasma free AA flux and pool size. Apparent ileal digestibility (AID) of dietary N was determined using the slaughter technique and an indigestible marker. Blood chemistry, hematology, body temperature, and serum viremia indicated that PRRSV induced effective immune response in pigs (P < 0.05). Challenge with PRRSV reduced the AID of N (P < 0.05), but had no effect on apparent total tract digestibility of dietary energy (P = 0.12). Plasma flux (µmol/kg BW/h) for Met and Thr was increased by PRRSV infection (P < 0.05). A strong tendency of increased Val flux was observed in PRRSV+ pigs (P = 0.06). Infection with PRRSV increased the pool size for Lys, Met, Thr, Trp, Leu, Val, and Gln (P < 0.05). Collectively, these results suggest that PRRSV alters the utilization of dietary N and AA flux, as well as pool size, in growing pigs. The increase in Thr and Met flux in PRRSV+ pigs may be associated with enhanced utilization of these AA for the synthesis of immune system metabolites and increased catabolism of these AA. Thus, dietary Met, Thr, and Val requirements may increase in pigs infected with PRRSV, relative to the requirements for other AA.

Immune system stimulation induced by Escherichia coli lipopolysaccharide alters plasma free amino acid flux and dietary nitrogen utilization in growing pigs.

Changes in plasma free AA flux reflect the modification of AA metabolism in different metabolic states. Immune system stimulation (ISS) in growing pigs may redistribute AA from protein retention towards processes involved in the immune response, thus impacting AA utilization. The aim of the current study was to evaluate the effect of ISS on whole-body nitrogen (N) utilization and the kinetics of plasma free AA. Ten gilts (BW 9.4 ± 1.1 kg) were surgically fitted with jugular vein catheters, individually housed in metabolism crates, and feed-restricted (550 g/d). Repeated intramuscular injections of increasing amounts of Escherichia coli lipopolysaccharide (LPS) were used to induce ISS (30 and 36 µg/kg BW, given 48 h apart). Whole-body N-balance was determined for 3-d before ISS (ISS-) and 3-d during ISS (ISS+). At the end of each N-balance period, a bolus dose of labeled [U-13C, U-15N]-AA mixture (Ile, Leu, Lys, Met, Phe, Thr, Trp, Val, and Gln) was infused intravenously, followed by serial blood collection for determination of isotopic enrichment. A double exponential model was fitted with plasma enrichment data for each pig and each AA, and equation parameters were used to estimate plasma-free AA flux and pool size. Apparent ileal digestibility (AID) of N was determined using the slaughter technique and an indigestible marker. Blood samples were collected before and 76-h after the initiation of ISS and assayed for hematology and blood chemistry. Body temperature (BT) was monitored during the course of study. Blood chemistry, hematology, and BT results indicated that LPS induced effective ISS in pigs (P < 0.05). ISS tended to reduce N retention (P = 0.09) and the N retention-to-N intake ratio (P = 0.08). Apparent total tract digestibility of dietary energy and AID of N were reduced by ISS (P < 0.05). Plasma flux (µmol/kg BW/h) for Ile and Phe was reduced by ISS (P < 0.05). Strong tendencies for decreased Lys flux and N retention were observed in ISS pigs (P < 0.10). ISS increased the pool size for Leu but reduced the pool size for Ile (P < 0.05). Collectively, these results suggest that ISS alters the utilization of dietary N and AA flux, as well as pool size in growing pigs. The decrease in Lys, Phe, and Ile flux during ISS may be attributed to a reduction in whole-body protein synthesis or decreased catabolism of these AA. Relative to other AA, dietary Lys, Phe, and Ile requirements may decrease in ISS pigs.

Immune system stimulation increases dietary threonine requirements for protein deposition in growing pigs.

Previous studies have reported an increase in the utilization of threonine (Thr) during immune system stimulation (ISS). However, increased utilization of an AA during ISS may not reflect an increased dietary requirement, as endogenous sources may supply AA to meet the need for enhanced utilization. The current study evaluated the impact of ISS on components of dietary Thr requirements, i.e., maintenance requirement and the efficiency of Thr utilization. Thirty-nine gilts (initial BW 32 ± 2.1 kg) of commercially relevant genetics were individually housed in metabolism crates and fed one of six experimental diets in which Thr was the first limiting among other AA. Three levels of dietary Thr were tested within each ISS group: 70%, 90%, and 110% of daily Thr requirements, which were estimated based on the potential of each ISS group for protein deposition (PD). Following adaptation to the experimental diets, pigs from each dietary treatment group were injected with either increasing amounts of Escherichia coli lipopolysaccharide (ISS+; 25 and 35 µg/kg BW) or saline (ISS-). Injections were given 48-h apart and whole-body nitrogen balance was measured for 72-h following the first injection. Body temperature (BT) was monitored and blood samples were collected 24 h after initiation of ISS and evaluated for measures of blood chemistry. Blood chemistry and BT results indicated an effective ISS in pigs (P < 0.03). Threonine intake increased PD in a linear fashion in both ISS groups (P < 0.01). The marginal efficiency of standardized ileal digestible (SID) Thr utilization for PD, represented by the slope, was not affected by ISS. However, ISS substantially increased the extrapolated maintenance SID Thr requirements, represented by the intercept at zero PD (ISS- vs. ISS+, -11.2 vs. -56.3 SE 13.2; P < 0.05). Collectively, our results indicated that the physiological changes associated with ISS increased the dietary SID Thr requirements for PD due to an increase in maintenance requirements.