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Ionophores have limited effects on jejunal glucose absorption and energy metabolism in mice

Y. K. Fan^*,1, J. Croom, E. J. Eisen, H. R. Spires and L. R. Daniel

^* Department of Animal Science, National Chung Hsing University, Taichung 402, Taiwan; and Department of Poultry Science and and Department of Animal Science, North Carolina State University, Raleigh 27695-7608; and and 13201 Barkley Street, Leawood, KS 66209-3914

	Abstract

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Two experiments, Trial 1 (in vitro) and Trial 2 (in vivo), were conducted to examine the effects of ionophores, monensin, laidlomycin, and laidlomycin propionate on whole-animal O₂ consumption, organ weights, jejunal glucose absorption, and O₂ utilization, as well as growth, feed and water consumption, and feed efficiency. In Trial 1, 30 male Swiss-Webster mice, 8 wk old, were used to measure the in vitro effects of each of the ionophores at concentrations of 1.62 or 16.2 mM. Six combinations of three ionophores at two concentrations resulted in a total of eight treatments. All eight treatments were exposed to jejunal rings from a single mouse for a total of 30 observations per treatment. Jejunal rings were exposed to each ionophore treatment for 15 min. Laidlomycin propionate (16.2 mM) decreased (P < 0.02) glucose absorption, as estimated by H³-3-O-methyl glucose uptake compared with all other treatments, whereas laidlomycin propionate (1.62 mM) increased (P = 0.032) jejunal DM content compared with 16.2 mM laidlomycin propionate. In Trial 2, 40 5-wk-old mice were allotted into four treatments—control and 16.2 mM each of monensin, laidlomycin, and laidlomycin propionate—for a total of 10 observations per treatment. Ionophores were administered via the drinking water for 14 d. No ionophore treatment had any effect on whole-mouse O₂ consumption. Monensin increased (P = 0.004) stomach size and decreased (P = 0.049) the efficiency of BW gain compared with controls. Laidlomycin propionate decreased (P = 0.032) the percentage of whole jejunum oxygen consumption due to oubain-sensitive respiration compared with control. The efficiency of intestinal glucose absorption was not changed due to treatment in either trial. Under the conditions of these studies, monensin, laidlomycin, and laidlomycin propionate had minimal and inconsistent effects on jejunal function and energy utilization in mice. This investigation suggests that changes in the energetic requirements of animals treated with ionophores are not an issue in animal production.

Key Words: Absorption • Glucose • Intestines • Ionophores • Mice

	Introduction

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Polyether ionophores, such as sodium monensin and laidlomycin propionate, have been used to increase growth and feed efficiency in ruminants and poultry. Their mode of action in ruminants has been attributed to alterations in ruminal fermentation and the postruminal flow of nutrients (Spears, 1990; Bohnert et al., 2000). In poultry, they are used as coccidiostats (Daugschies et al., 1998; Vissiennon et al., 2000).

Monensin has no effect on glucose or AA transport in chickens (Riley et al., 1986). Nevertheless, monensin decreases oleic acid absorption in rat enterocytes (Hussenet et al., 1990) and prevents cholesterol uptake from cultured human intestine (Sviridov et al., 1993). Valinomycin, an ionophore, increases glucose uptake in mouse duodenum (Raja, et al. 1989).

There is only indirect data to suggest ionophores may alter intestinal cellular energetics. Exposure of the small intestine to monensin causes mitochondrial alterations in rat enteroctyes (Ellinger and Pavelka, 1984) and decreases intracellular transport in mouse intestine (Bennett et al., 1987). Monensin prevents the effects of amiloride on both glucose and dipeptide uptake in chicken enterocytes (Calongere et al., 1989).

The effects of ionophores on the rate of intestinal nutrient absorption have not been fully described. Besides, there is no direct information on the impact of ionophores on whole-animal and intestinal tissue energetics. These are of concern since the rate of nutrient absorption, as well as the energy expended by both the gastrointestinal tract and whole body, can dramatically affect performance of livestock (Croom, et al. 1993). Therefore, this study examined in vitro and in vivo effects of monensin, laidlomycin, and laidlomycin propionate on intestinal total, active, and passive glucose transports in mice. The effects of in vivo and in vitro ionophore exposure on whole-animal and/or intestinal tissue energy expenditures were directly examined also.

	Materials and Method

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Animal Care and Diet
Swiss-Webster male mice, born within a 3-d period of time, were used. The mice were weaned at 3 wk. After weaning, mice were housed in pairs in polypropylene cages in a climatically controlled room (23°C; 65% relative humidity) with a 12-h light/dark illuminating schedule beginning at 0700. Mice had free access to drinking water and pelleted Rodent Laboratory Chow #5001 (Purina Mills, Inc., St. Louis, MO). Mouse care was in accordance with the guidelines of the Institutional Animal Care and Use Committee of North Carolina State University (02-022-A).

Experimental Design
A randomized complete block design was used for two trials. The objective of Trial 1 was to determine whether short-term in vitro exposure to various ionophores exert effects on jejunal oxygen consumption and glucose uptake. In Trial 1, 30 male Swiss-Webster mice, 8 wk old, were used to measure the in vitro effects of monensin, laidlomycin, and laidlomycin propionate at concentrations of 1.62 or 16.2 mM. Six combinations of three ionophores at two concentrations resulted for a total of eight treatments. All of the ionophores were dissolved in 0.5% ethanol. This, in addition to the blanks (media with no 0.5% ethanol excipient) and controls (media with 0.5% excipient), resulted in a total of eight treatments and 30 observations per treatment. All eight treatments were tested on jejunal tissue from each mouse. Jejunal tissue from individual mice were placed in all eight treatment media, two pieces for each treatment medium, for 15 min before oxygen consumption and glucose absorption measurements. For each of the eight treatments, the average of two pieces of jejunal tissue from each mouse was regarded as an experimental unit and each mouse was regarded as a block.

In Trial 2, the effects of consumption of various ionophores on growth, feed intake, organ weight, whole-body respiration, jejunal respiration and glucose uptake were investigated. Twenty cages, each containing two mice (BW average 28.4 ± 1.08 g), were randomly allotted to four treatments (10 mice per treatment). An adjustment period of 3 d was allowed before treatment periods commenced. Treatments were control (0.5% ethanol [ETOH] which served as the common excipient for all the ionophores), 16.2 mM/L laidlomycin, 16.2 mM monensin, and 16.2 mM laidlomycin propionate in the drinking water. Ionophore treatments were placed into the drinking water to eliminate the possibility of any refusal of the mice to consume an ionophore-supplemented feed. Mice were treated for 2 wk, from 5 to 7 wk of age. The ionophore concentrations used were selected based on the results of Trial 1 and designed to approximate a similar exposure of the enterocytes to the ionophore concentrations used in Trial 1, taking into account the average water intake calculated for the mice during the pretrial period, as well as the concentration of ionophores in the drinking water. The daily consumption of laidlomycin, monensin or laidlomycin propionate for each mouse was 109, 122, or 108 µmol, respectively.

Cage was regarded as the experimental unit from which performance data, such as BW gain, feed consumption, and water consumption were collected. The individual mouse, however, was regarded as the experimental unit on all other variables measured since the data were collected on the basis of each individual mouse for these variables.

Whole-Body Oxygen Consumption
Whole-body O₂ consumption and mouse activity were measured as described previously by Fan et al. (1996). Mice were placed in an O₂-ECO system (Columbus Instruments Int., Columbus, OH) to measure whole-body O₂ consumption rate 3 d prior to the end of Trial 2 (d 11 of experiment). Oxygen consumption measurements were initiated after the mouse was placed into the measuring chamber for 1 h to allow for behavioral adjustment. Behavioral activity of the mouse in the chamber during the measurement period was monitored using an apparatus with infrared beam sensors. Whole-body O₂ consumption was measured twice for two 12-min periods, consecutively, and the average value used. Body weight of each mouse was measured immediately after repeated measurements of whole-body O₂ consumption.

Jejunal Tissue Preparation
After an overnight fast, mice were killed by cervical dislocation and BW were recorded. The small intestine was removed from the body cavity by an abdominal incision along the mid-line and cut at the pylorus and ileocecal valve. The small intestine was placed in a petri dish with ice-cold HEPES buffer (pH 7.4, 25 mM HEPES, 4.8 mM KCl, 140 mM NaCl, 2.5 mM CaCl₂, 1.2 mM MgSO₄, 1.2 mM KH₂PO₄/L) and mesentery and fat deposits were detached. In Trial 1, the small intestine was placed on a wax pan and two adjacent segments of the mid-jejunum were removed at its midsection for glucose transport and respiration measurements. In Trial 2, the small intestine was gently blotted dry, weighed, and its unstretched length recorded. Three adjacent 6-cm sections of the mid-jejunum were removed for glucose uptake assay, O₂ consumption and biochemical analyses. All sections used for biochemical analysis were stored at -20°C.

Jejunal Glucose Transport Assay
The jejunal tissue sections used for the glucose uptake assay were cut into groups of eight 1-mm wide rings using an aluminum device that holds six single-edged razor blades evenly spaced at 1-mm intervals. The jejunal rings were immediately submerged in HEPES buffer at room temperature until determination of glucose transport rate. Jejunal glucose transport was estimated following the procedure of Black (1988) as modified for mouse tissue (Bird et al., 1994a; Fan et al., 1996). This technique measures the tissue accumulation of H³-3-O-methyl glucose (3OMG) in the presence and absence of phlorizin, an inhibitor of the intestinal Na⁺-dependent glucose transporter, SGLT1. Total, active, and passive glucose transport rates were expressed as µmol glucose/(min•g of jejunum).

Jejunal Tissue Oxygen Consumption
Jejunal segments were prepared by rinsing in ice-cold media 199 (Sigma Chemical Co., St. Louis, MO; 11 g of M199, 5.96 g of HEPES and 0.36 g of NaHCO₃ in 1.0 L of H₂O, pH 7.4) to remove digesta residue and dividing into four 20- to 40-mg intact pieces. The remaining tissue samples were gently scraped of mucosa with the edge of a glass microscope slide, leaving the jejunal muscularis externa and serosa. The serosa was cut into four 20- to 40-mg pieces, and the individual pieces were placed in incubation chambers fitted with an O₂ electrode in 4 mL of M199 and constantly stirred at 37°C. The rate of O₂ uptake of either jejunal intact tissue or jejunal serosa tissue was measured using an O₂ monitor as described by McBride and Milligan (1985). The O₂ consumption rate of intestinal mucosa was estimated using the difference between the O₂ consumption rate of intact jejunal tissue and that of the serosa. Oxygen consumption rates of jejunal intact tissue and serosal tissue attributable to Na⁺/K⁺-ATPase and cytoplasmic protein turnover were measured by the differences of O₂ consumption in the presence and absence of ouabain and cycloheximide (Sigma Chemical Co.), respectively.

Mucosal Biochemical Analyses
Jejunal segments were thawed and rinsed in ice-cold 0.9% NaCl (wt/vol), blotted dry, weighed, and the mucosa gently removed by scraping with the edge of a glass microscope slide. The remaining muscularis externa and serosa were weighed and the proportion of mucosa calculated by difference. Dry matter of jejunal mucosa, serosa, or intact tissue was determined by drying at 80°C in a forced-air oven for 48 h. Mucosal DNA content was measured using 20 mg of scraped mucosa. After homogenizing (Techmar Company, Cincinnati, OH) for 30 s in cold buffer (2.5 mL; pH 7.4, 10 mM Tris, 1 mM EDTA, and 1 M NaCl), the DNA content of the mucosal homogenate was measured by using a TKO 100 fluorimeter (Hoefer Scientific Instruments, San Francisco, CA), which utilizes calf thymus DNA as a standard. Mucosal protein content was measured using 20 mg of scraped mucosa. After homogenizing for 30 s in 2.5 mL of ice-cold NaCl (2 g/L) protein in the mucosal homogenate was precipitated by addition of trichloroacetic acid (100 g/L) and subsequently centrifuged at 800 x g for 15 min at 4°C. The resulting protein pellet was resuspended in 2 mL of NaCl solution (2 g/L, wt/vol) and total protein determined by measuring the absorbance of bicinchoninic acid complexed with Cu⁺ at 550 nm (Pierce Biochemicals, Rockford, IL). Bovine serum albumin was used as the standard.

Calculations and Statistical Analyses
The ouabain- and cycloheximide-sensitive proportions in jejunal tissue respiration were calculated by subtraction of total jejunal tissue respiration from that inhibited by ouabain and cycloheximide. Glucose active transport was calculated as the difference between 3OMG accumulation in the media with and without phlorizin. Glucose passive transport was calculated as the difference of 3OMG accumulation in the media in the presence of phlorizin incubated at both 37°C and at 4°C. The apparent energetic efficiency of active glucose transport of intact intestinal tissue (nmol ATP expended/nmol glucose uptake; APEE) was calculated assuming 5 nmol of ATP synthesized per nmol of O₂ consumed (Gill et al., 1989) divided by active glucose transport (Bird et al., 1994c).

The data were analyzed using the GLM procedure of SAS (SAS Inst., Inc., Cary, NC), and ANOVA was used to examine the significance of treatment effects. Effects of the ionophores were tested using the residual error mean square as the denominator to calculate the F-value. For each measured variable in Trial 1 and Trial 2, the ionophore effects were considered statistically significant at P < 0.05. Pairwise comparisons of means were conducted using Tukey’s test with a minimum significant difference (Steel and Torrie, 1980). Pearson’s product-moment correlations between variables were pooled using the within-treatment sums of squares and crossproducts from the ANOVA feature of SAS.

	Results

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Trial 1
The effects of in vitro exposure of mouse jejunal tissue to a media blank, excipient, or 1.62 and 16.2 mM laidlomycin, monensin, and laidlomycin propionate on oxygen consumption rate and DM content are presented in Table 1. No differences were noted between the blank and 0.5% ETOH (wt/vol) control excipient. Hence, in subsequent tables, values for the blank have been omitted. None of the ionophores had any short-term effect on tissue O₂ consumption compared with control incubations. Laidlomycin propionate at 1.62 mM increased (P = 0.032) jejunal DM content compared to the 16.2 mM level. There were no differences between the effects of laidlomycin propionate and any other treatment.

	Discussion

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These data suggest that under the conditions of the in vitro study, laidlomycin propionate may have had adverse effects on the metabolic function of jejunal enterocytes. It is possible that the actions of this ionophore in an in vitro setting, removed from the normal homeostatic controls of an intact gastrointestinal tract, could have resulted in changes in cellular homeostasis so as to disrupt Na⁺-dependent glucose transport. It is unknown why this particular ionophore would decrease jejunal glucose uptake in vitro when no changes were observed with the other ionophores. The age of the mice used in the two trials could have accounted for the differences in effect of laidlomycin propionate on jejunal tissue function in the two trials. Scrutiny of the data, however, suggests this is not the case. The 8-wk-old mice used in Trial 1 were mature with a fully developed ability to absorb glucose from the jejunum (Bird et al., 1994b). Exposure of jejunal tissue at the higher concentration of laidlomycin propionate in Trial 1 resulted in decreased active uptake of glucose. The 5-wk-old mice used in Trail 2 have more immature gastrointestinal tracts as measured by their ability to absorb glucose (Bird et al., 1994b). Mice younger than 2 mo of age have lower rates of jejunal glucose transport. Hence, one would expect that the magnitude of effects of ionophores on glucose transport, if present, would be greater in the older mice used in Trial 2 (Bird et al., 1994b).

Laidlomycin and laidlomycin propionate had virtually no effect on any of the parameters studied in vivo compared to controls in Trial 2. Monensin decreased BW gain and BW gain efficiency (Table 3). This is similar to the report by Todd et al. (1984) that mice fed diets containing monensin at concentrations between 37.5 and 300 ppm for 3 mo had reduced BW gain. Additionally, Spinosa et al. (1999) reported that female rats exposed to monensin in utero exhibited delayed functional and physical development during the neonatal period.

Whole-body O₂ consumption, glucose absorption, and the APEE of jejunal glucose absorption were unaltered. This lack of effect on glucose transport is consistent with that reported by Riley et al., (1986) in the chicken. It is unclear how the failure of monensin to alter these physiological parameters could be associated with decreased growth and feed conversion. It cannot be attributed to the decreases in feed consumption as reported in cattle fed ionophores (Baile et al., 1979), since no differences in feed consumption were noted between any of the ionophore treatments and the control. It is possible that these changes in growth parameters and organ weights are through mechanisms independent of the gastrointestinal.

Some changes were noted between different dosages of the same ionophore as well as between different ionophores. In vitro, 1.62 mM of laidlomycin propionate increased jejunal DM content compared to 16.2 mM laidlomycin propionate. In vivo, total and horizontal movements were greater in laidlomycin propionate fed mice compared with mice fed laidlomycin. To our knowledge, ionophores have no known effects on the central nervous system. Most studies on ionophore toxicity describe detrimental effects on skeletal muscle, liver, and the heart (Mollenhauer et al., 1981; Todd et al., 1984; Novilla et al., 1991).

Laidlomycin propionate fed mice had a smaller percentage of total jejunal oxygen consumption that was oubain sensitive as compared with monensin fed mice. One would expect that, because of their affinity for various electrolytes and their abilities to facilitate transmembrane ion flux, ionophores might change the intracellular ionic milieu and organelle function in such a manner as to affect consistent alterations in absorptive function. Monensin, one of the most commonly used ionphores in animal production, can alter the sodium gradient across the plasma membrane of the Swiss 3T3 cell and stimulate the Na⁺/K⁺ pump (Smith and Austic, 1980). Lichtshtein et al. (1979) reported that the membrane potential of mouse neuroblastoma—rat glioma hybrid NG 108-15 cells increase 20 to 30 mV when exposed to monensin. Monensin inhibits glucose and L-lactate uptake in the ruminal bacteria Streptococcus bovis as well as Na⁺-dependent serine uptake (Wampler et al., 1998). Additionally, previous studies have noted that short-term exposure of the rat intestine to monensin causes alterations in enterocyte mitochondria in both the proximal and distal small intestine (Ellinger and Pavelka, 1984). Similarly, Bennett et al. (1987), found that in addition to alterations in enterocyte mitochondrial cisternae, short-term culture of mouse intestine resulted in decreased intracellular transport and insertion of glycoproteins into the apical membranes of mucosal cells. If these changes in cellular function occurred in the present study, they had little impact on the overall ability of the mouse intestine to absorb glucose.

The lack of effect of ionophores on gut energetics and glucose absorption may also provide insight regarding the effects of the authocthonous and allocthonous populations of intestinal microorganisms on intestinal physiology. Gaskins (2001) has recently proposed that authocthonous bacteria, introduced via probiotic feed supplements, may increase energy expenditures in the intestinal tract, hence increasing the maintenance requirement of the animal. He proposed that this is due to the promotion of the formation of protective mucous secretions by elements of the intestinal epithelium. Although in the present study we did not examine the effects of ionophores on intestinal microbial numbers, monensin and laidlomycin propionate are known to have antimicrobial activity on gram-positive organisms within the intestinal tract and rumen (Wampler et al., 1998; Butaye et al., 2001). It would seem that if the ionophores used in the present study reduced the number of intestinal microorganisms, there would have been less intestinal mucous secretion and jejunal energy utilization would have been lower than those of control animals. One should note, however, that the lack of difference in total intestinal and whole-body O₂ utilization between the control- and the ionophore-treated mice may have been due to the limited antimicrobial spectrum of the ionophores used. Thus, possible alterations in the energy utilization by intestinal tissue by both authocthonous and allocthonous microorganisms cannot be ruled out by the results of this study.

The present study examined the effects of three ionophores, sodium monensin, laidlomycin and laidlomycin propionate, on jejunal function both in vivo and in vitro, as well as animal growth, whole-body energetics and jejunal glucose absorption and energy utilization. When taken as a whole, the data gathered in the present trials failed to describe any large, consistent effects of monensin, laidlomycin, or laidlomycin propionate on jejunal function in mice under the conditions studied.

	Implications

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The data presented in the present study indicate that the use of ionophores is not associated with consistent alterations in the absorptive function or energetics of the intestinal tract or the whole body. These findings are significant, in that the beneficial effects associated with the use of ionophores attributed to their alterations of ruminal and gastrointestinal microbial fermentation in ruminants, as well as to specific enteric antimicrobial activities in poultry, cannot be excluded. Furthermore, the data presented herein do not support recent suggestions that allocthonous or autocthonous bacterial populations exert a measurable effect on the energy consumption of the intestinal tract and whole body of healthy animals.

¹ Correspondence—phone: 886-4-2285-3748; fax: 886-4-2286-0265; E-mail: ykfan{at}dragon.nchu.edu.tw.

Received for publication December 13, 2002. Accepted for publication May 14, 2003.

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