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Article

Butyric Acid Is Synthesized by Piglets¹

^* Department of Pediatrics, The Ohio State University and ^** Children’s Research Institute, Columbus, OH 43205

²To whom correspondence should be addressed.

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
We hypothesized that there is no synthesis of butyric acid within organs or tissues not drained by the portal vein (PV). Two experiments were performed. In six piglets, the colonic vasculature was clamped (n = 4) or the entire colon resected while [1-¹³C]-butyric acid (99% enriched) was infused into a jejunal vein for 120 min; ¹³C enrichment of butyric acid was measured in the PV and carotid artery (ART) during the last 30 min of the infusion. In a second experiment, butyric acid tracer and unlabeled disaccharide were infused into the cecum for 120 min, and blood again was sampled from the PV and ART. For the four piglets studied during ligation of the colonic vasculature, the mean (±SD) ratio of the butyric acid enrichment in the ART to that in the PV (ART/PV) was 0.80 ± 0.05 (ART vs. PV, P = 0.002) and for all six piglets in expt. 1, the ART/PV ratio was 0.74 ± 0.1 (ART vs. PV, P = 0.001). The enrichment of butyric acid in the PV averaged 96.0% for the six studies, implying that splanchnic tissues other than the colon did not produce a substantial amount of butyric acid. For the second experiment, the ART/PV ratio was 0.80 ± 0.15 (ART vs. PV, P = 0.03). These studies provide the first evidence for endogenous synthesis of butyric acid by piglets.

KEY WORDS: • butyric acid • endogenous synthesis • fermentation • Sus scrofa • swine

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Butyric acid (BA)³ is a product of bacterial fermentation of carbohydrate in the rumen of multigastric animals and in the colon of omnivores such as humans (Annison and Armstrong 1970 , Cummings 1981 ). Perhaps stimulated by observations, albeit controversial, that colonic fermentation of fiber may inhibit promotion of colonic carcinogenesis (Fuchs et al. 1999 , Hassig et al. 1997 , Kritchevsky 1998 , Lupton 1995 , Newmark and Lupton 1990 , Potter 1999 ), a large body of literature has evolved concerning putative, antineoplastic effects of BA in cell culture (Hassig et al. 1997 , Whitehead et al. 1986 ). In particular, BA causes arrest of the cell cycle and induces terminal cellular differentiation of colonic adenoma and cancer cells presumably because it inhibits histone deacetylase (Archer et al. 1998 , Hassig et al. 1997 , Sakata 1987 , Singh et al. 1997 , Whitehead et al. 1986 ). In colonic adenoma or carcinoma cell lines, BA induces apoptosis (Hague et al. 1996 , 1997a and 1997b , Singh et al. 1997 ). BA also has a number of other potentially important, but diverse effects on protein synthesis (Kruh 1982 , Perrine et al. 1987 ), gene expression (Miller et al. 1998 , Perrine et al. 1993 ) and on viral transformation of cells (Kruh 1982 , Pouillart et al. 1992 ).

We have been using the piglet as a model for studying colonic fermentation and either mucosal injury or inflammation under conditions of severe carbohydrate malabsorption (Argenzio and Meuten 1991 , Harig et al. 1989 , Kien et al. 1999 ). Either an excess or deficiency in the supply of acetate, BA, or other short-chain fatty acids (SCFA) to the colonocyte may cause, respectively mucosal injury (Argenzio and Meuten 1991 , Butel et al. 1998 ) or inflammation (Harig et al. 1989 , Kien et al. 1999 ). Our group has been quantifying synthesis of BA and other SCFA in the colonic lumen since it is likely that the entry rate of SCFA into the colonic mucosa (not the small amount of SCFA remaining in the lumen) will determine intracellular effects (Kien et al. 1996 ). Moreover, the rate of synthesis of SCFA (intensity of fermentation) can be altered by dietary change or the use of probiotics or prebiotics (Flourie et al. 1993 , Fuller 1991 , Gibson and Roberfroid 1995 ). In order to extend our investigations of fermentation of sugars to studies of fiber and other complex carbohydrates, we wished to employ a simple isotope dilution model of BA production. This endeavor required us to determine, in two separate experiments outlined below, the quantitative importance (if any) of BA production by tissues or organs other than the colon, particularly the stomach and intestine of piglets.

	MATERIALS AND METHODS

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Animal care.

This study involved Yorkshire/Hampshire pigs (aged 23–30 d) which were either completely sow-reared until the day of study (n = 2) or were fed sow’s milk replacement formula (Ross Products Division of Abbott Laboratories, Columbus, OH) from about the age of 10 d. Each of the tracer studies described here was conducted while the piglets were anesthetized with isoflurane, after sedation was attained using a combination of tiletamine HCL and zolazepam HCl (7.5 mg/kg i.m., Telazol; Fort Dodge Laboratories, Fort Dodge, IA) and xylazine (5 mg/kg, i.m., Rompun; Bayer Corp., Shawnee Mission, KS). Each piglet was studied in the fed state although the two sow-reared piglets (expt. 1A) no longer had access to food for about 3 h before the study. The study was approved by our institution’s animal use and care committee.

Experimental design.

Two experiments were conducted. In expt. 1, in six piglets (aged 23–30 d), the vasculature of the large intestine ("colon"), which includes the cecum, was clamped (expt. 1A, n = 4), and two of these piglets had the entire colon (including cecum) resected (expt. 1B, n = 2). Then, after obtaining baseline samples of blood for BA enrichment from the portal vein (PV) and carotid artery (ART), a primed, constant infusion of [1-¹³C]-butyrate (99% enriched) was administered via a jejunal vein for 120 min (Isotec,, Miamisburg, OH) (2.24 µmol · kg^-1 · min^-1; Prime/min Infusion Rate: 20:1). At 90, 100, 110 and 120 min after commencing the tracer infusion, blood samples for BA enrichment again were obtained from the PV and ART.

Previous studies have shown that infusion of tracers into a jejunal vein prevents "streaming" of tracer into the PV, which could prevent mixing with unlabeled BA (Myers et al. 1991 ). Nevertheless, in order to verify that streaming of tracer did not account for our results in expt. 1, we measured enrichment of BA in the PV and ART during expt. 2 which was also conducted to study the rate of synthesis of BA via lactose or lactulose fermentation (data specific to this goal are not shown in this paper). In expt. 2, BA tracer and unlabeled BA can mix both in the cecal lumen as well as within the cecal mucosa. Thus, there should be no streaming of tracer into the PV during expt. 2. In expt. 2, seven studies in six piglets (aged 24–30 d) were conducted in which [1-¹³C]-butyrate (2.29 µmol · kg^-1 · min^-1; prime/min infusion rate: 20:1) and either unlabeled lactose (21 or 42 mg/min, n = 4) or lactulose (42 mg/min, n = 2) were infused into the cecum of pigs for 120 min. The colon (including cecum) and its vasculature were left intact. As in expt. 1A, blood samples for BA enrichment were obtained from the PV and ART prior to commencing the tracer infusion and at 90, 100, 110 and 120 min.

Measurement of BA enrichment.

BA enrichment (moles percentage excess, MPE) was measured using a previously described assay (Powers et al. 1995 ).

Statistics.

Values are expressed as mean ± SD Statistical comparison of BA enrichment in the PV and ART was conducted using a paired t test; statistical significance was indicated by an = 0.05.

	RESULTS

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Experiment 1 (Table 1 ).

For the four piglets studied while the colonic vasculature was clamped (expt. 1A), the ratio of BA enrichment in the ART to that in the PV ranged from 73 to 84% (mean = 80%). BA enrichment in the ART (76.0 ± 7.2 MPE) also was 80% of the mean for the PV (95.3 ± 4.0 MPE). In the two piglets which had the cecum and colon resected, ART enrichment was 60.8 MPE in both and was 96.2 and 98.0 in the PV. For the entire six piglets studied in expt. 1, BA enrichment in the ART (70.9 ± 9.6) was 74% of that in the PV (96.0 ± 3.3)(ART vs. PV, P = 0.001) (Fig. 1 ).

View larger version (17K): [in this window] [in a new window]   Figure 1. Comparison of arterial (ART) and portal venous (PV) enrichment of butyric acid in piglets in expts. 1 and 2 (*P = 0.001; **P = 0.03). In expt. 1, the colonic vasculature was clamped (n = 4) or the entire colon (including cecum) was resected (n = 2), and [1-13C]-butyric acid was infused into a jejunal vein. Mean moles per cent enrichment (MPE) of butyric acid was significantly higher in the PV compared to the ART (*P = 0.001). In expt. 2, [1-13C]-butyric acid was infused into the cecum along with unlabeled lactose or lactulose. Isotopic enrichment of butyric acid was significantly higher in the PV compared to the ART (**P = 0.03).

	DISCUSSION

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Our original hypothesis behind this study was that the only source of BA synthesis was production of BA via fermentation in the gastrointestinal tract, particularly the colon. If this hypothesis were true, then tracer entering the liver via the PV would not be further diluted by unlabeled BA, and the enrichment of BA in the PV would not be different from that in the ART (our null hypothesis). That is, much of the unlabeled and labeled BA could be removed on first pass through the liver, but the isotopic enrichment of BA would not be affected unless there was an additional source of unlabeled BA entering the peripheral circulation besides that entering the liver via the PV. Using two paradigms, we have ruled out this null hypothesis. These data provide the first evidence for BA synthesis by mammalian tissues other than lactating mammary glands of goats (Nandedkar et al. 1969b ) or rabbits (Nandedkar and Kumar 1969a ). This discovery raises the possibility that some of the previously described effects of BA in cultured colon adenoma or carcinoma cells may have relevance to other tissues (Archer et al. 1998 , Hassig et al. 1997 , Kruh 1982 , Miller et al. 1998 , Perrine et al. 1993 , Perrine et al. 1987 , Pouillart et al. 1992 , Sakata 1987 , Singh et al. 1997 , Whitehead et al. 1986 ).

From the PV enrichments ranging from 95.7–98.0 measured in five of six piglets in expt. 1, we determined that there was little, if any, BA production by splanchnic tissues other than the colon. The lower BA enrichment observed in the PV of pigs in expt. 2 is a function of the production of unlabeled BA from the cecal fermentation of lactose or lactulose. Thus, these studies show that during acute anesthesia, very little BA is produced by the stomach or small intestine of the piglet or via fermentation in the lumens of these organs. This finding has potential importance in the application of a simple, single tracer model for measuring BA production via fermentation. By sampling BA enrichment in the PV, it is possible to estimate production of BA from diets containing variable amounts of fermentable carbohydrate without being confined to using isotopically-labeled sugars (Kien et al. 1996 ).

Lymphatic absorption of BA from the colon or direct transport of BA from the colon via systemic veins could explain, in theory, the results of expt. 1A, if the lymphatic drainage of the cecum and colon were not completely ligated along with the venous drainage. Based on dissection of a pig cadaver, we did not identify systemic veins draining the colon. Moreover, we found no evidence in the literature that lymphatic drainage of the cecum or colon plays an important role in transport of BA after absorption. A recent paper (Lai and Ney 1998 ) suggested that BA from butterfat is not appreciably transported from the intestine via the lymph in rats. However, lymphatic or systemic vein transport of BA could not explain the results in expt. 1 since we observed almost no dilution of our BA tracer in the PV; that is, to us, it does not seem plausible that even under conditions of acute anesthesia, a large amount of stomach- or small intestine-derived BA would reach the systemic circulation directly without any reaching the PV. Transport of BA via the lymphatics from the cecum, where much of the fermentation to BA may occur, could not explain the results of expt. 1B since lymph ducts in the cecum and colon were removed. Lymphatic transport of cecum-derived BA could not explain the results of expt. 2 since the enrichment of the BA formed in the cecum would be the same whether it was transported via the PV or via the lymphatics, unless synthesis of unlabeled BA occurred in piglet tissues. This mechanism for explaining our results in expt. 2 might be more plausible if less enriched or unenriched BA were transported from the distal colon by the lymphatics because this could result in lower enrichment in the systemic circulation than in the PV. That is, one might conjecture that BA formed in the distal colon might not have mixed completely with the tracer. Our results in expt. 1B oppose this hypothesis since we observed an even lower ratio of BA enrichment (ART/PV) in this Experiment (0.62 and 0.63)(Table 1) than the mean of this ratio in expt. 2 (0.8). Thus, it does not seem likely that lymphatic transport of BA accounts for our data.

Obviously, using an isotope dilution technique, we can not differentiate BA released into the circulation by lipolysis vs. de novo synthesis. However, much of the BA produced in the rumen or colonic lumen is metabolized by gut tissue or the liver (Reilly and Rombeau 1993 ). The adipose tissue lipids and milk fat of the pig do not contain BA, and the liver mainly synthesizes palmitic acid (Gurr 1992 , Jensen 1995 ). Moreover, the formula-fed animals in our study had access to food just prior to our study, and the sow-reared piglets theoretically had access to milk up to 3 h before our study. Nevertheless, confirmation of these findings might include studies of the transfer of ¹³C label from palmitate to BA or the use of deuterated glycerol infusions to rule out substantial lipolysis induced by anesthesia. At any rate, further exploration of how endogenous synthesis is affected by diet or metabolic state (including anesthesia) is beyond the scope of this report, which is mainly intended to suggest that the phenomenon exists.

This study was not designed to quantify the amount of BA produced by endogenous tissues. Using stable isotopes, the rate of production of a compound like BA is estimated from the ratio of the rate of infusion of the isotope divided by the isotopic enrichment with a downward connection for the non-negligible contribution to production by the tracer itself (Kien et al. 1996 ). A maximum rate of BA synthesis could be calculated for expt. 1A from the data and the rate of tracer infusion into the jejunal vein (0.64 µmol · kg^-1 · min^-1). However, based on assumptions about the uptake of BA by the liver (Bergman and Wolff 1971 ), the rate of endogenous BA synthesis is probably 15% of this value or 0.09 µmol · kg^-1 · min^-1. This is ~7% of the molar dose of BA used to stimulate fetal globulin synthesis in patients (Perrine et al. 1993 ). On the other hand these tracer studies measure only the entry rate of unlabeled BA into the circulation. BA synthesized within cells could have biological effects within such cells and in theory could be oxidized without coming into equilibrium with the tracer. Regardless of the validity of such an estimate, the important point is that endogenous BA synthesis is apparently taking place in this model.

Bacteria such as Clostridia or Escherichia coli species synthesize BA via an acyl-CoA transferase (Gottschalle 1979 , Sramek and Frerman 1975a and 1975b ) which obviates the type of futile pathway characteristic of acetate synthesis in mammals (Buckley and Williamson 1977 , Knowles et al. 1974 , Pethick et al. 1981 ). However, in lactating goat mammary glands, BA is synthesized via fatty acid synthestase from malonyl-CoA and acetyl-CoA (Nandedkar et al. 1969b ). In contrast, in lactating rabbit mammary glands, crotonyl-CoA is formed from acetyl-CoA via a reversal of ß-oxidation, and then BA is synthesized from crotonyl-CoA by fatty acid synthetase (Lin and Kumar 1971 , Nandedkar and Kumar 1969a ). If other tissues synthesize BA by analogous pathways as those in lactating mammary glands, one might speculate that BA would be formed in tissues which are capable of active ß-oxidation of fatty acids and which also contain fatty acid synthetase (e.g., liver).

In summary, this study presents evidence that BA is produced in the piglet by tissues not drained by the PV. Different tracer methodology coupled with chronic colectomy or bowel sterilization could be used to further establish the actual rate of entry of BA into the peripheral circulation. Clearly, additional research would be needed to determine whether BA synthesis is affected by nutritional and metabolic status, whether its synthesis is subjected to any form of metabolic regulation, and whether gene transcription, cellular differentiation, proliferation, apoptosis or protein synthesis change in response to alterations in BA synthesis. However, since BA has intriguing effects on these molecular processes and since it is a compound that might have been present in primitive multicellular organisms evolving from bacteria, it is intriguing that BA may be synthesized endogenously and thus could have had regulatory effects on cell biology at an early stage of evolution.

	ACKNOWLEDGMENTS

 
We acknowledge the technical assistance of Jonathan Lash, the statistical assistance of John Hayes and the editorial assistance of Rita Porter.

	FOOTNOTES

 
¹ This project was supported by grants from the Crohn’s and Colitis Foundation of America, Inc., and the Children’s Research Institute. Experimental formula was provided by Ross Products Division of Abbott Laboratories.

³ Abbreviations used: ART, artery; BA, butyric acid; MPE, moles per cent excess; PV, portal vein; SCFA, short-chain fatty acid(s).

Manuscript received June 18, 1999. Initial review completed July 19, 1999. Revision accepted November 3, 1999.

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