key: cord-0008521-vk7kxnuq
authors: Argenzio, R.A.; Moon, H.W.; Kemeny, L.J.; Whipp, S.C.
title: Colonic Compensation in Transmissible Gastroenteritis of Swine
date: 2020-02-14
journal: Gastroenterology
DOI: 10.1016/s0016-5085(84)80165-1
sha: 8700a7f44f04113fef37c42756910cabd46cc0f0
doc_id: 8521
cord_uid: vk7kxnuq

Absorption of water and electrolytes by the small and large intestine was examined using a nonabsorbable marker technique in 3-day-old and 3-wkold pigs. One-half of the pigs in each group were orally infected with transmissible gastroenteritis virus; the remaining pigs served as controls. Threeday-old control pigs concentrated the nonabsorbable fluid marker twelve f old along the small and large intestine, indicating an efficiency of about 95% in absorption of the exogenous daily fluid load presented to the intestine. In contrast, the marker concentration in infected pigs showed no change whatsoever along either the small or large intestine, indicating a complete absence of net fluid absorption or secretion in these animals. Three-week-old control pigs concentrated the marker similarly to the 3-day-old group, with the bulk of the fluid absorption occurring in the small intestine. Infected pigs in the 3-wk-old group had marked net fluid secretion in the proximal small intestine, so that about twice the fluid load was presented to the large intestine of the 3-wk-old infected pigs as compared to the 3-day-old infected group. However, in contrast to the 3-day-old infected group, the large intestine of the 3-wk-old infected pigs increased fluid absorption some six times over the control, and this compensatory response prevented diarrhea in these older animals. Analysis of luminal contents indicated that in the older pigs, unabsorbed carbohydrate was almost completely fermented to short-chain fatty acids in the colon, whereas in the younger pigs the carbohydrate passed through the colon unchanged. These results demonstrate that development of microbial digestion, together with rapid short-chain fatty acid absorption, is a primary feature responsible for the colonic compensation in the older pigs with transmissible gastroenteritis.

Absorption of water and electrolytes by the small and large intestine was examined using a nonabsorbable marker technique in 3-day-old and 3-wkold pigs. One-half of the pigs in each group were orally infected with transmissible gastroenteritis virus; the remaining pigs served as controls. Threeday-old control pigs concentrated the nonabsorbable fluid marker twelvefold along the small and large intestine, indicating an efficiency of about 95% in absorption of the exogenous daily fluid load presented to the intestine. In contrast, the marker concentration in infected pigs showed no change whatsoever along either the small or large intestine, indicating a complete absence of net fluid absorption or secretion in these animals. Three-week-old control pigs concentrated the marker similarly to the 3-day-old group, with the bulk of the fluid absorption occurring in the small intestine. Infected pigs in the 3-wk-old group had marked net fluid secretion in the proximal small intestine, so that about twice the fluid load was presented to the large intestine of the 3-wk-old infected pigs as compared to the 3-day-old infected group. However, in contrast to the 3-day-old infected group, the large intestine of the 3-wk-old infected pigs increased fluid absorption some six times over the control, and this compensatory response prevented diarrhea in these older animals. Analysis of luminal contents indicated that in the older pigs, unabsorbed carbohydrate was almost completely fermented to short-chain fatty acids in the colon, whereas in the younger pigs the carbohydrate passed through the colon unchanged. These results demonstrate that development of microbial digestion, together with rapid short-chain fatty acid absorption, is a primary feature responsible for the colonic compensation in the older pigs with transmissible gastroenteritis.

Transmissible gastroenteritis (TGE) is a coronavirus infection of absorptive epithelial cells in the small intestine of pigs. The disease is characterized by atrophy of intestinal villi and acute diarrhea. Swine of all ages are susceptible to this infection. The case fatality rate approaches 100% in pigs that become infected during the first week after birth; however, it is comparatively low (:::;2%) in pigs that become infected when they are older (2:3 wk old). Villous atrophy and diarrhea are less severe and of shorter duration in older pigs than in newborn pigs. The reason for this age-dependent resistance is unclear; it has been ascribed, however, at least in part, to an accelerated rate of epithelial cell replacement in older pigs (1) (2) (3) . Normal newborn pigs require three times as long as normal 3-wk-old pigs to replace villous absorptive cells (4) . The comparatively shortlived villous absorptive cells of older pigs also tend to produce lower titers of TGE virus than those in newborn pigs. Villous absorptive cells destroyed by TGE virus are replaced by cells that migrate from the crypts before they are completely differentiated. Crypt epithelium and the incompletely differentiated cells covering atrophic villi are resistant to attack by the TGE virus (2, 3, 5) .

Previous studies on the pathophysiology of this disease have been limited to pigs >3 wk old and to isolated segments of small intestine or to in vitro mucosal sheets perfused with balanced electrolyte solutions (6) (7) (8) . These studies have shown that disaccharidase activity of the small bowel mucosa is reduced and that the operation of the coupled Na-glucose transport mechanism is impaired. Secretory function of the small bowel, however, appears to be intact. These results correlate well with the villous atrophy and crypt cell hyperplasia observed histologically.

Although such studies can elucidate abnormalities in epithelial ion transport mechanisms or mucosal enzyme activity, they do not account for the effect of digestive contents that may have a considerable impact on transmural ion and water transport in malabsorptive diseases. For example, it is assumed that unabsorbed carbohydrate, besides exerting an appreciable effective osmotic pressure in the small bowel, is rapidly fermented to short-chain fatty acids (SCF A) in the colon, thereby increasing further the osmotic driving force for net fluid secretion (9) . Alternatively, the colon may be compensating for small bowel malabsorption to some degree by rapidly absorbing these SCF A, as observed in human jejunoileal bypass patients (10) .

In TGE, neither morphological changes nor viral infection is observed in the colon and, thus, functional changes in the colon (if any) may be solely related to the abnormal contents presented to it from the small bowel. Therefore, the present study was undertaken to determine the significance of colonic function in this disease and if colonic function contributes to the age-dependent resistance observed both clinically and experimentally. A fluid marker technique was used which allowed the estimation of the effect of normal digestive components on net water movements in both the small and the large intestine.

Pigs Thirty-two hysterectomy-derived, colostrum-deprived, new born pigs were randomly assigned to two equal groups. One group was designated 3-day-old pigs and the other designated 3-wk-old pigs. Eight pigs were selected randomly from each group to be infected. All pigs were raised in the laboratory in isolation to prevent inadvertent exposure to the virus.

Pigs were fed 100 ml of sterilized cow's milk [supplemented with vitamins, minerals, and eggs (11) ] twice a day into which was incorporated the water-soluble marker polyethylene glycol-4000 (PEG) at a concentration of 5 gIL. Pigs maintained for 3 wk were also given 15 ml of a ground, grain-based pig starter ration twice a day beginning at week 2, and this was increased to 30 ml by week 3. Feed intake was restricted to insure complete consumption of the meal. Both control and infected pigs readily consumed the total amount of feed given at each feeding.

Steady-state marker conditions were approximated as described by Hamilton and Roe (12) . On the day of necropsy, the daily feedings were divided into eight equal GASTROENTEROLOGY Vol. 86, No.6 portions and fed at hourly intervals for 3 h and at 30-min intervals for a remaining 2 h. Although Hamilton and Roe (11) had established that a relatively constant concentration of PEG was obtained by 5 h with this schedule by means of a fistula near the ligament of Treitz, it was questioned whether or not steady-state marker conditions would be obtained throughout the digestive tract, especially in the more distal segments. We define the steady state as a constant perfusion of PEG in amount (CV) per unit time (t) throughout the digestive tract, where C is PEG concentration and Vis volume flow. Then, CjV/t = CoValt, where i and 0 refer to the input and output, respectively, to any segment of the digestive tract. Therefore, the flow rate past a sampling point is Volt = Cj V/Cot. These conditions imply that in the steady state, C and V must be constant in any given segment as a function of time. In order to test the assumption that relatively stable PEG concentrations were obtained in each segment, preliminary experiments were conducted with control pigs of each age group. These pigs were fed their meals according to the above schedule and were necropsied in groups of three at 3, 4, 5, and 6 h following the initial morning feeding. This procedure permitted examination of the change in marker concentrations with time in various segments of the bowel. These studies showed that relatively constant marker concentrations were established by 5 h in all segments of the tract examined (see Results), and, therefore, 5 h appeared sufficient to approximate steady-state conditions in the main experiment. The constancy of V is only assumed, but appears reasonable in view of the small, frequent feedings.

The virus preparation was from the same stock as used previously (3) . Pigs in the 3-day-old group were infected intragastrically on day 3 with 5 ml of a 1: 20,000 dilution of the stock virus suspension containing 1.5 x 10 6 plaque-forming units (PFU)/ml. Pigs in the 3-week-old group were given 12 ml of the same dilution of virus on day 21 to compensate for their greater body weight.

The 3-day-old pigs were randomly assigned to necropsy at days 5 and 8 for controls and days 6 and 7 for infected animals. Three-week-old pigs were necropsied on days 23 and 26 for controls and days 24 and 25 for infected animals.

Pigs were killed with pentobarbital Na and the stomach and intestinal sites were immediately ligated. These sites included the stomach, two equal lengths of small intestine, the cecum plus the first loop of spiral colon, and the remainder of the colon. Two 10-cm segments of small intestine were fixed in situ by injecting a 10% formalin solution intraluminally. These segments were from sites located 1 m distal to the ligament of Treitz and 1 m proximal to the ileocecal junction. Segments of cecum and colon were also fixed in 10% formalin. Formalin-fixed segments were embedded in paraffin, cut into sections 7 Mm thick, and examined with a light microscope equipped with an ocular micrometer. Five well-oriented villi from each segment of small intestine were measured to determine mean villous height for the jejunum and ileum in each pig. Muscosal depth was measured in the cecum and colon of all pigs (five measurements per site per pig).

Intestinal contents were collected from each ligated segment and the pH was measured immediately. A portion of contents was centrifuged at 20,000 rpm and the supernatant was collected, diluted 1: 5 with distilled water, and frozen. The remainder was frozen immediately and was pooled from all pigs in the group. The small intestine was ground and virus titer was determined, as previously described (3) .

Diluted samples were analyzed for PEG by the method of Hyden (13) , osmolality by freezing-point depression, Na and K by flame photometry, and CI by the method of Schales and Schales (14) . Pooled samples were thawed, mixed, centrifuged at 4°C, and analyzed for total carbohydrate (15) and for volatile fatty acids by gas chromatography (16) .

Small intestinal tissue from all control pigs was negative for TGE virus. Pigs exposed to virus at day 3 and necropsied 3 and 4 days after being infected had virus titers of 4.07 ± 2.7 (SE) x 10 5 PFU/ml of intestinal homogenate. Three-week-old pigs also necropsied 3 and 4 days after being infected displayed significantly lower virus titers of 4.45 ± 2.6 x 10 4 PFU/ml of homogenate, even though these pigs were inoculated with 2.5 times the dose given to the 3-day-old group.

Results of the histopathologic studies of intestinal mucosa, expressed as villous length (jejunum, ileum) or mucosal depth (cecum, colon), are shown in Figure 1 . Three-day-old pigs exposed to the virus had marked villous atrophy of the jejunal and ileal mucosa with a mean villous length of <25% of the control tissues (Figures 1 and 2) . The degree of villous atrophy was remarkably constant with little variation among pigs. The mucosal depth of the cecum and colon of exposed pigs, however, was unaffected, nor were there any other morphological alterations seen in these tissues when compared to the controls.

In contrast, the height of jejunal and ileal villi in the 3-wk-old infected group was not significantly different from that in the control group (p > 0.10).

Large variations were present in the jejunum of these (Figure 2 ). Such variation in older pigs has been demonstrated previously and was expected. However, no correlation between the degree of villous atrophy and virus titer was present. As in the 3-day-old group, there were no structural alterations of the cecum and colon in the older pigs.

Preliminary experiments. The PEG concentration in the various segments of the digestive tract examined as a function of time are shown in Figure  3 . Although large individual variation was present, relatively stable PEG concentrations were obtained for the young pigs by 5 h after the initial morning feeding. Large individual variation was also present in the older pigs; however, changes in PEG concentration with time for each site were nonsignificant. Inasmuch as large changes in PEG concentration between certain segments were obtained, it appeared reasonable to expect that changes in various segments of the bowel as a result of the infection could be established with confidence using the 5 allowed the number of pigs to be increased in each group from 3 to 8, thus reducing the error due to individual variation. However, it should be emphasized that large errors are possible with the present method. The overall variation in PEG concentration among the pigs in a given segment approached ± 34% and was as high as ± 60% in the distal colon. Coupled with this, a variation as high as ±20% could be expected from non-steady-state conditions, lead-ing to an overall uncertainty in estimating the net flow of water in control segments of ±40%. We also assume a relatively constant marker release from the stomach and a regular propulsion of marker through the small intestine; conditions which may very well be altered in infected animals . Nevertheless, the use of this method allowed a noninvasive and more physiologic examination of net water movement in the entire digestive tract and, thus, would be more suitable for assessing the effect of normal digestive components on net water movement than the conventional perfusion methods.

Control and infected pigs. The concentration of PEG in the various segments of the gastrointestinal tract is shown in Figure 4 . The marker was concentrated fivefold by the time ingesta reached the ileum in 3-day-old control pigs, and was further concentrated in the large intestine to a value nine times that found in gastric contents. In striking contrast, no change in PEG concentration was observed along the entire gastrointestinal tract in the 3-day-old pigs with TGE.

Similar data recorded for the 3-wk-old group are shown in the lower portion of Figure 4 . Again, the control pigs concentrated the marker severalfold during passage along the small and large intestine. The infected pigs were unable to concentrate the marker in the small intestine to the same degree; however, unlike the 3-day-old group, the large intestine of these 3-wk-old infected pigs did concentrate the nonabl3orbable marker.

Examination of the relative PEG concentrations along the gastrointestinal tract may be quantitatively misleading, because a small change in marker con~ centration in the upper tract, where the flow rate is high, indicates relatively large volume changes. Conversely, although the marker is concentrated severalfold in the distal colon, very little net movement of water may actually be present. Therefore, the data are replotted in Figure 5 as the percentage of fluid COLONIC FUNCTION IN TGE 1505 intake passing the midpoint of each of the gastrointestinal segments listed. In expressing the data in this manner, we must assume that a steady state in regard to feed and PEG intake is present. Although we are aware that we have not proven this assumption, the large differences in marker concentration observed between individual segments and between control and infected pigs should allow an estimate of the relative quantitative contribution of each of the segments to net water movement.

Several important aspects are revealed in Figure 5 which would not be evident from an examination of PEG concentrations alone. This is especially true for the large intestine. For example, the upper portion of Figure 5 shows that in the 3-day-old control pigs, the actual quantitative contribution of the large intestine to net water absorption is minimal. However, the actual percentage of fluid intake entering the large intestine is only ~10%-12%. Similarly, the percentage of fluid intake in the 3-wk-old control pigs, shown in the lower portion of Figure 5 , has been reduced to ~15%-20% by the time the ingesta enter the large intestine. Thus, these figures would indicate that in normal pigs at both of these ages, the small intestine accounts for the majority of net water absorption.

The most striking differences in the infected pigs were observed in the large intestine. The colons of e ...... the 3-day-old group were unable to absorb a significant volume even when presented with six times the load seen in the controls. This is clearly not the case in the older infected pigs. These data are shown for both the entire group of 8 older pigs (shaded bars) and for only the 5 older pigs with villous atrophy (open bars). This separation is justified on the basis of the histologic results given above; the correlation between villous height and PEG concentration in the jejunum of these infected 3-wk-old pigs was 0.96. These results indicate that actual net luminal accumulation of water was present in the upper one-half of the small intestine in the 5 pigs with villous atrophy. They also show that the lower small intestine and large intestine were capable of compensating for this large increase in flow.

The pH and osmotic pressure of the gastrointestinal contents for all groups of pigs are shown in Figure 6 . The pH was lower in the large intestinal contents of infected animals and this was especially true in the 3-day-old group. The cecal pH of both GASTROENTEROLOGY Vol. 86, l\:o. 6 control and infected 3-wk-old pigs was markedly lower than that seen in the 3-day-old pigs.

The osmolality of gastrointestinal contents for 3day-old pigs varied little throughout the tract and was similar to the milk osmolality. Considerably higher values were present in gastric contents of 3wk-old pigs. These values decreased markedly in the small intestine of infected pigs, whereas in the controls, a marked decrease occurred in the colon.

The concentrations of Na, K, and CI are shown in Figure 7 . The concentration of Na increased along the small intestine to a greater degree in the 3-dayold control group than in the infected pigs, and similarly decreased in the colon to a greater degree in the control pigs. This apparently reflects a decrease in surface area for diffusion in infected pigs; however, no apparent differences in Na concentration were noted in the older pigs. The reasons for these differences in age are unclear, but it should also be noted that the substantial net secretion present in the jejunum of the older infected pigs may have contributed to their luminal Na concentration. Small differences in the concentration of CI between control and infected pigs were noted; however, gastric contents of older pigs had CI concentrations that were about twice the values shown in the younger 7. ~ SI $1, S1 2 Ce C SI SIt S1 2 Ce C Figure 7 . Concentrations of Na, Cl, and K in gut segments from 3day-old and 3-wk-old control and infected pigs. St, stpmach; SI" proximal one-half small intestine; SI 2 , distal one-half small intestine; Ce, cecum and proximal loop of spiral colon; C, distal colon. Mean ± SE, n = 8.

pigs. These concentrations were reduced substantially in the lower small bowel. Potassium concentrations displayed a reciprocal relationship with Na, but no marked differences were seen among the different groups. The composite results of SCF A and total carbohydrate concentrations in the cecum and colon contents of these pigs are shown in Table 1 . Concentrations of SCF A were much lower in the 3-day-old infected group than in the control group, whereas in COLONIC FUNCTION IN TGE 1507 the older pigs, similar and higher total SCF A concentrations were present in both groups. An increase in lactate concentration was noted in the older infected group of pigs .

In contrast, total carbohydrate concentrations were much higher in the 3-day-old infected group than in the controls. In fact, the concentrations of carbohydrate in the colon of the infected pigs would account for >40% of the total osmolality of the contents (d. Figure 6 and Table 1 ) if all of the contents were in the form of lactose. However, in the older pigs, similar low concentrations of total carbohydrate were seen in both groups, and the carbohydrate concentration in the colons of the 3-wk-old infected pigs was only about one-sixth that of the young infected group .

Although the much lower SCF A concentrations in 3-day-old pigs suggested undev.eloped microbial populations in the large bowel, it was questioned whether this observation would also apply to conventionally reared pigs. For example, the hysterectomy-derived animals maintained in a laboratory environment may not obtain a lush microbial population as quickly as pigs reared on the sow. Therefore, 3 conventional pigs were removed from the sow on day 5 of their life and contents from the cecum and colon were collected and analyzed for SCF A, as described above. These results showed that SCF A concentrations ranged from 51.8 to 132 mM in the proximal colon and from 31.8 to 60.6 mM in the distal colon. Thus, these concentrations ranged from those observed in the same age group of hysterectomy-derived control pigs to nearly as high as those in the 3-wk-old cQntrol group. Therefore, it is probable that the artificial experimental conditions uniformly delayed the development of a microbial population to some degree. 

Villous atrophy, associated with decreased levels of mucosal disaccharidases, has been uniformly demonstrated in studies of TGE (1, 6) . These changes have suggested that unabsorbed carbohydrate may be responsible for osmotic retention of water in the small bowel lumen or even the induction of net secretion because of the increase in effective osmotic pressure of the luminal contents (17) .

The present results concerning the small intestine of infected pigs demonstrated zero net fluid movement, or even net fluid secretion into the jejunum in the case of the older pigs. This latter effect appeared to be the result of dilution of the hypertonic gastric contents with a hypotonic fluid, the osmolality of which can be calculated to be ~185 mosmoliL. Thus, these results in the small intestine are consistent with the hypothesis of small bowel malabsorption and fluid accumulation as a result of osmotic forces; however, an active secretory process by the small intestine cannot be entirely ruled out.

The response of the large intestine to TGE infection differed markedly in the two age groups of pigs. The colon of the 3-day-old pigs was incapable of net fluid absorption, whereas the 3-wk-old colon increased absorption some sevenfold over the control and this compensatory response prevented a significant increase in the fecal output of water.

Several possible reasons for this change in colonic function should be considered. First, it is possible that in the young pigs there may be a defect in colonic transport mechanisms caused directly by the virus. However, this seems unlikely because the virus does not invade epithelial cells or cause histologic changes in the large intestine. Furthermore, a significant fraction of the osmotic activity entering and leaving the colon of these young pigs was in the form of carbohydrate (presumably lactose) which, as such, cannot be absorbed by the colonic mucosa.

Second, pigs of this age group may have undeveloped colonic transport mechanisms or colonic absorptive capacity (e.g., surface area). There is now evidence that, in fact, active Na absorption by in vitro pig colonic mucosa reaches very high and near maximal rates by day 1 of life due to high aldosterone secretion rates at this time (18, 19) . Therefore, it is unlikely that the transport capacity of this tissue represents a limiting factor in colonic absorption. However, the colon of these younger pigs is proportionally much smaller in size than in older pigs and the possibility of total surface area or transit time as a limiting factor needs to be explored. Nevertheless, the same argument can be invoked as with the first alternative; namely, a major proportion of the con- GASTROENTEROLOGY Vol. 86. No. 6 tents was in the form of carbohydrate which cannot be absorbed by colonic mucosa regardless of the surface area involved.

Finally, a most likely explanation of the differences in function concerns carbohydrate metabolism by colonic bacteria. In fact, it is precisely an overactive bacterial fermentation of carbohydrate to shortchain organic acids that has been postulated as being responsible for luminal acidification and osmotic diarrhea involving the colon; i.e., fermentative diarrhea (9) . Fermentation of carbohydrate did produce a degree of acidification and high levels of organic acids in the older pigs, and in the case of the older infected pigs, a proportion of this was in the form of D-and L-lactic acid. If the feed intake had not been restricted, it is likely that large amounts of lactic acid and acidification of the contents would have resulted in an osmotic diarrhea. However, under these experimental conditions, colonic absorption in the older pigs was unimpaired. Thus, the evidence suggests the alternative hypothesis; namely, that the fermentation process itself is the rate-limiting factor in reducing the osmotic load in the younger pigs. A similar conclusion was reached in human studies involving carbohydrate infusions into the intact colon (20) . Figure 8 summarizes the flow of carbohydrate in grams per day into and out of the large intestine together with the amount of carbohydrate disappearing from the colon, presumably fermented to SCF A. Also shown in parentheses is the number of :milliosmoles per day entering and leaving the large intestine that were not accounted for by the product (Na + K) x 2. This osmotic fraction would presumably include carbohydrate and peptides. This fraction was calculated for individual pigs instead of the pooled result for carbohydrate and, thus, may be a more accurate description of unabsorbed carbohydrate. In addition, these values are shown for only the 5 pigs with villous atrophy in the 3-wk-old infected group, whereas the pooled carbohydrate sample includes all pigs.

Clearly, the colon of the older infected pigs was capable of effectively disposing of the unabsorbed carbohydrate, whereas in the younger infected pigs, nearly all of the dietary carbohydrate passed through the colon unchanged. It is now well established that SCF A are rapidly absorbed by colonic mucosa and utilized as a source of energy. Therefore, the microbial process converts unabsorbable and, therefore, osmotically active material to rapidly absorbed SCF A, thereby reducing the effective osmotic pressure of the colonic contents, and salvaging calories which would otherwise be unavailable. In addition, these SCF A, at concentrations observed in the 3-wkold pigs, have been shown to augment Na and water absorption from the colon of several animal species, including humans (21, 22) . The development of microbial digestion, therefore, appears to playa central role in the changes in colonic function observed. It is necessary to point out, however, that the artificial experimental conditions may have delayed the development of microbial digestion in the young pigs. The range of SCF A concentrations observed in the conventional pigs of this same age suggests a more rapid, but wide, variation in the rate of development of the process under those conditions. Thus" the environment and diet of the animal may be equally or even more critical a factor than age in the inoculation of the bowel or the ability of the resident bacteria to ferment carbohydrate. Further study will be necessary to quantitatively assess the individual contribution of these factors to the development of colonic function.

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