Glenn R. Davis

An evaluation of the importance of gastric acid secretion in the absorption of dietary calcium.

Since calcium solubility is a prerequisite to calcium absorption, and since solubility of calcium is highly pH-dependent, it has been generally assumed that gastric acid secretion and gastric acidity play an important role in the intestinal absorption of calcium from ingested food or calcium salts such as CaCO3. To evaluate this hypothesis, we developed a method wherein net gastrointestinal absorption of calcium can be measured after ingestion of a single meal. A large dose of cimetidine, which markedly reduced gastric acid secretion, had no effect on calcium absorption in normal subjects, and an achlorhydric patient with pernicious anemia absorbed calcium normally. This was true regardless of the major source of dietary calcium (i.e., milk, insoluble calcium carbonate, or soluble calcium citrate). Moreover, calcium absorption after CaCO3 ingestion was the same when intragastric contents were maintained at pH 7.4 (by in vivo titration) as when intragastric pH was 3.0. On the basis of these results, we conclude that gastric acid secretion and gastric acidity do not normally play a role in the absorption of dietary calcium. Other possible mechanisms by which the gastrointestinal tract might solubilize ingested calcium complexes and salts are discussed.

Permeability Characteristics of Human Jejunum, Ileum, Proximal Colon and Distal Colon: Results of Potential Difference Measurements and Unidirectional Fluxes

In order to assess the passive permeability characteristics of the human intestine in vivo, we measured potential difference in the jejunum, ileum, proximal colon, and distal colon during perfusion of various test solutions that were designed to establish chemical gradients for sodium or chloride, or both or neither. In addition, unidirectional fluxes of sodium and chloride were measured in 30-cm segments of the jejunum and ileum and entire colon during perfusion of balanced electrolyte solution. These studies indicate that there are marked differences in the pathways for passive ion movement in the areas of the intestine studied. In the jejunum, this pathway appears to be highly permeable to both sodium and chloride with modest cation selectivity. In the ileum this pathway is much more cation selective, predominantly because of a relative impermeability to chloride. In the colon, on the other hand, these passive pathways appear to be more anion than cation selective. The implication of these results for normal transport physiology are discussed.

Studies of the Mechanism of the Antidiarrheal Effect of Codeine

To determine whether the antidiarrheal action of opiate drugs in humans is due to enhanced intestinal absorption rates, as suggested by recent experiments in animals, or is due to altered intestinal motility, as traditionally thought, we studied the effect of therapeutic doses of codeine on experimental diarrhea and on the rate of intestinal absorption of water and electrolytes in normal human subjects. Our results show that codeine (30-60 mg i.m.) markedly reduced stool volume during experimental diarrhea induced by rapid intragastric infusion of a balanced electrolyte solution. There was, however, no evidence that codeine stimulated the rate of intestinal absorption in the gut as a whole or in any segment of the gastrointestinal tract, either in the basal state or when absorption rates were reduced by intravenous infusion of vasoactive intestinal polypeptide. We also measured segmental transit times to determine whether and where codeine delayed the passage of fluid through the intestine. Codeine caused a marked slowing of fluid movement through the jejunum, but had no effect on the movement of fluid through the ileum or colon. In other studies, we found that the opiate antagonist naloxone did not significantly affect water or electrolyte absorption rates in the jejunum or ileum. We conclude (a) that therapeutic doses of codeine increase net intestinal absorption (and thereby reduce stool volume) by increasing the contact time of luminal fluid with mucosal cells, not by increasing the rate of absorption by the mucosal cells; and (b) that endogenous opiates do not regulate intestinal absorption in humans.

Evaluation of chloride/bicarbonate. Exchange in the human colon in vivo.

During perfusion of a plasma-like solution, colonic absorption rate of chloride was much higher than the secretion rate of bicarbonate (34 vs. 3.5 meq/h, respectively). This might suggest that anion exchange (Cl/HCO3) accounts for only a small fraction of total chloride absorption. However, if the colon absorbs as well as secretes bicarbonate, this reasoning would underestimate the magnitude of the anion exchange. To see if the colon absorbs bicarbonate, we perfused a chloride-free solution (which would eliminate bicarbonate secretion via (Cl/HCO3 exchange) and found that the colon absorbed bicarbonate at a rate of 5.1 meq/h. Calculation of electrochemical gradients and measurement of luminal fluid PCO2 indicated that this bicarbonate absorption was mediated passively in response to electrical gradients, rather than via reversed Cl/HCO3 exchange or acid secretion. The combined results of the plasma-like and chloride-free perfusion experiments suggest Cl/HCO3 exchange at a rate of 8.6 meq/h (the sum of bicarbonate movements, 3.5 and 5.1 meq/h, observed in the two experiments). To obtain a second estimate under different experimental conditions, a choline chloride-choline bicarbonate (sodium-free) solution was perfused; with this solution, chloride and bicarbonate absorption dependent on active sodium transport should be eliminated or markedly reduced, and the magnitude of Cl/HCO3 exchange should be revealed. This experiment suggested a Cl/HCO3 exchange rate of 9.3 meq/h, similar to the first estimate. As chloride was absorbed at a rate of 34 meq/h during perfusion of the plasma-like solution, the Cl/HCO3 exchange provides for approximately one-fourth of total chloride absorption.

Effect of vasoactive intestinal polypeptide on active and passive transport in the human jejunum.

The effect of intravenous vasoactive intestinal polypeptide (VIP) on normal transport mechanisms in the human jejunum in vivo was examined with the triple-lumen, steady-state perfusion technique. By using special test solutions that revealed different aspects of jejunal transport, we were able to evaluate the effect of VIP on specific transport processes, such as active bicarbonate absorption, active chloride secretion, and passive absorption or secretion of sodium chloride. At an infusion rate of 200 pmol/kg per h, VIP inhibited active bicarbonate absorption by approximately 42%, stimulated active chloride secretion to a slight extent, and slightly reduced passive sodium chloride absorption. A larger dose of VIP, 400 pmol/kg per h, had essentially the same effect on active bicarbonate absorption and active chloride secretion, but it markedly depressed passive sodium chloride absorption and also inhibited passive secretion induced by mannitol. VIP reduced the lumen-to-plasma unidirectional sodium and chloride flux rates, while the plasma-to-lumen flux rates were decreased to a lesser extent or remained unchanged. The potential difference became more lumen-negative with VIP, but the sodium diffusion and glucose-stimulated potential were not affected. We conclude that the major effect of VIP in the human jejunum is to decrease the normal absorption of water and electrolytes--not only active bicarbonate-mediated absorption, but also the passive absorption in response to osmotic forces generated by active or facilitated absorptive processes. Although an increase in chloride secretion does occur, this does not appear to be of major importance.

Active chloride secretion in the normal human jejunum.

To determine whether the small intestine normally secretes fluid, it would be necessary to reduce or inhibit the greater absorptive processes that would otherwise mask such secretion if present. To do this, we perfused bicarbonate-free solutions in the jejunum of normal subjects, because it has been shown that active absorption from this part of the human small intestine is dependent on luminal bicarbonate. We found that the jejunum did secrete sodium chloride and water when isotonic bicarbonate-free solutions were perfused. Further studies revealed that the sodium secretion was passive, but that chloride was secreted against an electrochemical gradient and that observed chloride flux ratios did not agree with the flux ratios calculated for passive chloride movement. We conclude, therefore, that the normal jejunum actively secretes chloride, but that this is masked by greater absorptive processes when balanced electrolyte solutions are perfused. The rate of this active chloride secretion may be one of the factors that regulate the rate of fluid absorption in the normal human intestine.

Ox Bile Treatment of Severe Steatorrhea in an Ileectomy—Ileostomy Patient

Bile salt therapy is not used in patients with steatorrhea due to bile salt deficiency because of fear that severe diarrhea would be caused or exacerbated. We report a patient who previously had had colectomy, partial ileectomy, and ileostomy for Crohns disease. She had severe steatorrhea due to bile salt deficiency and severe diarrhea (the latter apparently due to fatty acid inhibition of electrolyte and water absorption). The diarrhea was improved by loperamide, but severe steatorrhea and malnutrition persisted. The steatorrhea and malnutrition were corrected by ox bile, without an increase in diarrhea. Presumably, the deleterious effect of bile salts per se on small bowel absorption of water and electrolytes was mitigated by correction of fat malabsorption. At least in this patient, bile salt therapy was highly beneficial.

Dose-response, meal-stimulated gastric antisecretory study of prostaglandin E1 analog, misoprostol, in man

In a randomized, double-blind, crossover trial, the effects of 50-, 100-, and 200- Μg doses of misoprostol on meal-stimulated gastric acid secretion were compared with placebo in 16 healthy male subjects. Compared with placebo, the 100- and 200- Μg doses produced significant reductions in acid output for 2 and 3 hr, respectively, following the test meal (P=0.05). Misoprostol did not influence either the fasting or postprandial serum gastrin levels as compared with placebo. No adverse experiences were reported by any of the subjects. One subject experienced a transient rise in SGPT as compared with baseline, which may have been due to ethanol intake. This study provides a scientific rationale on which to base additional trials of misoprostol in patients with disease related to gastric acid production.

Ileal Chloride Secretion as a Cause of Secretory Diarrhea in a Patient with Primary Intestinal Tuberculosis

Severe secretory diarrhea resulting in dehydration and hypokalemia was observed in a patient in whom primary cecal tuberculosis was diagnosed by colonoscopy. Although the ileum appeared normal at colonoscopy and by biopsy, intestinal perfusion studies showed that the ileum was secreting water and electrolytes. Chloride secretion against a high electrical gradient suggested active anion secretion. Absorption in the colon was unimpaired. The diarrhea resolved after 4 wk of antituberculous therapy. Repeat perfusion studies after 3 mo showed normal absorption in the ileum. This case report suggests that intestinal tuberculosis can cause secretory diarrhea. The mechanism by which secretion occurs is not clear, but probably involves active anion secretion.