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BACKGROUND AND AIMS: The gastrointestinal (GI) tract extracts nutrients from ingested meals while protecting the organism from infectious agents frequently present in meals. Consequently, most animals conduct the entire digestive process within the GI tract while keeping the luminal contents entirely outside the body, separated by the tightly sealed GI epithelium. Therefore, like the skin and oral cavity, the GI tract must sense the chemical and physical properties of the luminal contents to optimize digestion. Specialized sensory enteroendocrine cells (EECs) in GI epithelium interact intimately with luminal contents. A subpopulation of EECs express the mechanically gated ion channel Piezo2 and are developmentally and functionally like the skin’s touch sensor, that is, the Merkel cell. We hypothesized that Piezo2+ EECs endow the gut with intrinsic tactile sensitivity. METHODS: We generated transgenic mouse models with optogenetic sensors in EECs and Piezo2 conditional knockouts. We used a range of reference standard and novel techniques from single cells to living animals, including single-cell RNA sequencing and opto-electrophysiology, opto-organ baths with luminal shear forces, and in vivo studies that assayed GI transit while manipulating the physical properties of luminal contents. RESULTS: Piezo2+ EECs have transcriptomic features of synaptically connected mechanosensory epithelial cells. EEC activation by optogenetics and forces led to Piezo2-dependent alterations in colonic propagating contractions driven by intrinsic circuitry, with Piezo2+ EECs detecting the small luminal forces and physical properties of the luminal contents to regulate transit times in the small and large bowel. CONCLUSIONS: The GI tract has intrinsic tactile sensitivity that depends on Piezo2+ EECs and allows it to detect the luminal forces and physical properties of luminal contents to modulate physiology.

G-protein–coupled receptors (GPCRs) are the largest family of transmembrane signaling proteins. In the gastrointestinal tract, GPCRs expressed by epithelial cells sense contents of the lumen, and GPCRs expressed by epithelial cells, myocytes, neurons, and immune cells participate in communication among cells. GPCRs control digestion, mediate digestive diseases, and coordinate repair and growth. GPCRs are the target of more than one third of therapeutic drugs, including many drugs used to treat digestive diseases. Recent advances in structural, chemical, and cell biology research have shown that GPCRs are not static binary switches that operate from the plasma membrane to control a defined set of intracellular signals. Rather, GPCRs are dynamic signaling proteins that adopt distinct conformations and subcellular distributions when associated with different ligands and intracellular effectors. An understanding of the dynamic nature of GPCRs has provided insights into the mechanism of activation and signaling of GPCRs and has shown opportunities for drug discovery. We review the allosteric modulation, biased agonism, oligomerization, and compartmentalized signaling of GPCRs that control digestion and digestive diseases. We highlight the implications of these concepts for the development of selective and effective drugs to treat diseases of the gastrointestinal tract.

The effects of fat on gastric emptying (GE), gut hormones, and energy intake are dependent on digestion to free fatty acids (FFAs). In animals, small intestinal oleic acid inhibits energy intake more potently than the triacylglyceride (TG) triolein, but there is limited information about the comparative effects of FFA and TG in human beings. We compared the effects of FFA and TG on GE, gut hormone secretion, appetite, and energy intake in healthy males.Nine men (age, 23 +/- 2 y; body mass index, 22 +/- 1 kg/m(2)) were studied on 3 occasions to evaluate the effects of (1) 40 g oleic acid (FFA, 1830 kJ), (2) 40 g macadamia oil (TG, 1856 kJ; both 600-mL oil-in-water emulsions stabilized with 4% milk protein and labeled with 15 MBq (123)I), or (3) 600 mL 4% milk protein (control, 352 kJ), administered intragastrically, on GE, plasma cholecystokinin (CCK) and peptide-YY (PYY) levels, appetite perceptions, and subsequent energy intake.GE of FFA was much slower than that of TG (P.05), with greater retention of FFA, than TG, in the proximal stomach (P.001). Hunger was less (P.05), and fullness was greater (P.05), after FFA when compared with control and TG. Increases in plasma CCK and PYY levels were greater after FFA than TG or control (P.05). Energy intake tended to be less after FFA compared with TG (control, 4754 +/- 610 kJ; TG, 5463 +/- 662 kJ; FFA, 4199 +/- 410 kJ).FFAs empty from the stomach more slowly, but stimulate CCK and PYY and suppress appetite more potently than TG in healthy human beings.

Background & Aims: The aim of the present study was to determine the effect of intraileal administration of capsaicin on gastrointestinal motility. Methods: Mongrel dogs equipped with strain gauge force transducers on the stomach, small intestine, and colon were used. We studied the effects of intraileal capsaicin on gastrointestinal contractions with or without pharmacologic antagonists. The effects of capsaicin administration into the lumen of innervated and extrinsically denervated ileal Thiry loops were also studied. Results: Intraileal capsaicin dose dependently inhibited postprandial contractions at all sites and interdigestive contractions in the upper gastrointestinal tract. Intraileal capsaicin-induced inhibition of gastrointestinal contractions was partially reversed by a nitric oxide (NO) synthase inhibitor, a 5 hydroxytryptamine-3 receptor antagonist (5-HT 3 ), and an opiate antagonist. Administration of capsaicin into the innervated ileal Thiry loop had inhibitory effects on gastrointestinal contractions, but gastrointesinal motor activity was not affected by capsaicin administered into the extrinsically denervated Thiry loop. Conclusions: Stimulation of ileal afferent fibers by capsaicin inhibits gastrointestinal contractions via an extrinsic neural reflex. GASTROENTEROLOGY 2002;123:1904:1911

Background & Aims: Gastric blood flow exhibits cyclical increases in phase with the interdigestive contractions and secretion of the stomach in dogs. The aim of this study is to clarify the regulatory role of motilin in interdigestive gastric blood flow in dogs. Methods: Blood flow of the left gastric (LGA) and superior mesenteric (SMA) arteries were measured by ultrasound transit-time blood-flow meters in 5 conscious dogs. Motilin was infused intravenously with or without Phe-cyclo[Lys-Tyr(3-tBu)-βAla-] · trifluoroacetate (GM-109; motilin antagonist), granisetron (5-HT 3 antagonist), atropine, hexamethonium (C6), phenoxybenzamine, propranolol, or cimetidine. Results: Motilin (12.5, 25, 50, and 100 pmol · kg −1 · h −1 ) induced LGA blood-flow responses, consisting of a sustained increase and a rapid phasic change coupled with a contraction, without affecting the blood pressure, heart rate, and SMA blood flow. GM-109 completely abolished the LGA, motility, and secretory responses to motilin (100 pmol · kg −1 · h −1 ). Atropine abolished motilin-induced gastric contractions, secretion, and phasic changes of LGA blood flow but failed to affect the sustained flow increase. However, atropine partially inhibited the LGA responses to lower doses of motilin. The LGA flow responses to motilin were not inhibited by granisetron, C6, α-adrenergic, β-adrenergic, or H 2 blockers. Motilin induced significantly larger gastric vasodilatation than the equivalent doses of VIP. Conclusions: Motilin has a potent and selective gastric vasodilator effect, which appears to be mediated by both cholinergic and noncholinergic mechanisms. Motilin plays an important role in the regulation of interdigestive gastric blood flow in dogs. GASTROENTEROLOGY 2002;123:1578-1581

Background & Aims: Irreversible amino acid losses at the human ileum are not taken into account when tracer-derived amino acid requirements are calculated because the data available are scarce. We have investigated amino acid losses at the ileal level in humans after ingestion of a protein meal. Methods: Thirteen volunteers ingested a single meal of 15 N milk or soy proteins. The appearance of 15 N and 15 N amino acids in the ileal effluents collected using an ileal tube was monitored for 8 hours. Results: In the soy group, higher losses of endogenous nitrogen, especially originating from amino acids, were observed, as well as a higher flow rate of dietary non–amino acid nitrogen. With soy protein, the digestibilities of valine, threonine, histidine, tyrosine, alanine, and proline were significantly lower than with milk. Ileal losses of leucine, valine, and isoleucine amounted to 12, 10, and 7 mg · kg −1 · day −1 , respectively. Threonine ileal loss (9–12 mg · kg −1 · day −1 ) was particularly high compared with the current amino acid requirement. Conclusions: Amino acid losses at the human terminal ileum are substantial and depend on the type of dietary protein ingested. Although it remains unclear whether intact amino acids are absorbed in the colon, we suggest that ileal losses should be considered an important component of amino acid requirements. GASTROENTEROLOGY 2002;123:50-59

Peripheral mechanisms in appetite regulation include the motor functions of the stomach, such as the rate of emptying and accommodation, which convey symptoms of satiation to the brain. The rich repertoire of peripherally released peptides and hormones provides feedback from the arrival of nutrients in different regions of the gut from where they are released to exert effects on satiation, or regulate metabolism through their incretin effects. Ultimately, these peripheral factors provide input to the highly organized hypothalamic circuitry and vagal complex of nuclei to determine cessation of energy intake during meal ingestion, and the return of appetite and hunger after fasting. Understanding these mechanisms is key to the physiological control of feeding and the derangements that occur in obesity and their restoration with treatment (as demonstrated by the effects of bariatric surgery).

Background & Aims: Numerous studies have suggested phospholipid inhibition of dietary cholesterol absorption through the gastrointestinal tract. This study addressed the importance of luminal phospholipid hydrolysis in this process. Methods: The effect of phospholipase inhibition on cholesterol transport from intestinal lumen to the lymphatics was evaluated in lymph fistula rats. Cholesterol and phospholipid absorption efficiency in intact animals was evaluated in control and phospholipase A 2 (PLA 2 ) gene–targeted mice. Results: The PLA 2 inhibitor FPL 67047XX retarded cholesterol absorption in a lymph fistula rat model. Under basal chow-fed dietary conditions, cholesterol absorption efficiency from a single bolus meal, and plasma lipid levels, were similar among PLA 2 (+/+), PLA 2 (+/−), and PLA 2 (−/−) mice. Interestingly, the nonhydrolyzable phospholipid dioleoyl ether phosphatidylcholine suppressed cholesterol absorption by 10% to 18% in mice without regard to their PLA 2 genotype. When 1-palmitoyl-2-[ 14 C]oleoyl-phosphatidylcholine was used as the substrate, the radiolabeled phospholipid was found to be hydrolyzed and absorbed with equal efficiency in PLA 2 (+/+), PLA 2 (+/−), and PLA 2 (−/−) mice. Conclusions: These results suggested that although phospholipid digestion in the intestinal lumen is a prerequisite for efficient cholesterol absorption, additional enzyme(s) can compensate for pancreatic PLA 2 in catalyzing phospholipid digestion and facilitating cholesterol absorption in PLA 2 knockout mice. GASTROENTEROLOGY 2001;120:1193-1202

Background & Aims: We tested the hypothesis that short-chain organic acids in the colon derived from dietary pectin, wheat bran, and oat bran are protective against the development of colon cancer because they induce transforming growth factor (TGF)-β1, which in turn inhibits cell growth by inducing cyclin-directed kinase (cdk) inhibitors. Methods: U4 human colon carcinoma cells differentiate into water- and salt-transporting columnar enterocytes and therefore model normal colonocytes. The composition and kinase activity of cdk/cyclin complexes were determined by immunoprecipitation and Western blotting studies in U4 cells treated in vitro with short-chain fatty acid (SCFA) mixtures that mimic the digestion products of wheat bran, oat bran, pectin, and cellulose (as control), which is largely unfermentable. Results: Induction of the cdk inhibitors p21cip1 and p27kip1 by fiber-mimicking SCFA mixtures occurs much more rapidly and is many-fold greater than their induction by TGF-β1. The SCFA mixtures most effective in causing growth inhibition and cdk inhibitor production mimicked those from wheat bran > oat bran > pectin. Conclusions: cdk inhibitor induction by SCFA mixtures is not mediated by TGF-β1. The SCFA mixture mimicking digested wheat bran fiber was the most effective of all mixtures tested in inhibiting cell growth through induction of cdk inhibitors. GASTROENTEROLOGY 1998;114:940-946

BACKGROUND & AIMS: Most studies of intestinal amino acid absorption use methods in which intestinal function is studied immediately after surgical manipulation. The unphysiological experimental conditions present in these studies limit the ability to extrapolate their results to normal physiological conditions. The aim of this study was to determine the rates of proline and leucine absorption under normal physiological conditions. METHODS: Absorption of proline and leucine was measured in long-term catheterized rats using a method of dual infusion of radiolabeled isotopes. RESULTS: The maximum transport velocity and apparent membrane permeability for proline were 16.1 mumol/ min and 0.07 mumol.min-1.mmol/L-1. For leucine, the maximum transport velocity and apparent membrane permeability were 14.9 mumol/min and 0.08 mumol.min-1.mmol/L-1. Surgical bowel manipulation decreased the maximum transport velocities for proline and leucine by > 80%. The adverse effects of surgery were present for 24 hours. CONCLUSIONS: Under normal physiological conditions, most proline and leucine is absorbed by active transport. Measurements of amino acid absorption using methods in which the intestine has been surgically manipulated within the previous 24 hours significantly underestimate proline and leucine absorption and do not reflect absorption under normal physiological conditions. (Gastroenterology 1997 Sep;113(3):865-74)

BACKGROUND & AIMS: Intraileal nutrients modulate gastrointestinal motility, but effects of maldigestion on postprandial motility are unknown. The aim of this study was to compare motor responses with ileal nutrient exposure in health and pancreatic insufficiency after a meal or intraluminal perfusion. METHODS: After oroileal multilumen intubation for duodeno-jejuno-ileal sampling, marker perfusion, and motility recording, 14 normal subjects and 12 patients with severe pancreatic insufficiency received a labeled liquid meal twice, either with placebo or pancreatin. Effects of intraileal nutrient perfusion on fed motility induced by duodenal amino acid perfusion were also investigated. RESULTS: Compared with normals, untreated patients had greater cumulative ileal nutrient delivery (69 +/- 21 vs. 487 +/- 232 kJ), shorter fed pattern (196 +/- 22 vs. 131 +/- 14 minutes), greater 90% gastric emptying (163 +/- 12 vs. 128 +/- 10 minutes), and faster small intestinal transit (86 +/- 9 vs. 44 +/- 6 minutes). Pancreatin reversed these changes. Ileal nutrient perfusion converted fed into interdigestive-like motility in normals (7 of 8) and patients (4 of 5). CONCLUSIONS: In subjects with pancreatic insufficiency, a low-energy liquid meal induces shorter fed motor pattern associated with accelerated gastric emptying and intestinal transit compared with healthy subjects. Because changes responded to enzyme treatment and could be reproduced by ileal nutrient perfusion, ileal delivery of malabsorbed chyme may be involved as a mechanism. (Gastroenterology 1997 May;112(5):1624-34)

BACKGROUND & AIMS: Amylase inhibition induces carbohydrate tolerance, satiety, and weight loss and prolongs gastric emptying, effects that may be useful in the treatment of obesity and non-insulin-dependent diabetes mellitus. The aim of this study was to determine (1) purity of a wheat amylase inhibitor preparation, (2) intraduodenal concentration of the wheat amylase inhibitor preparation that inhibits > 90% amylase activity (which causes carbohydrate malabsorption), and (3) if the inhibitor alters pancreaticobiliary secretions or intraluminal pH. METHODS: High-performance liquid chromatography followed by electrophoresis and sodium dodecyl sulfate-polyacrylamide gel electrophoresis were used for characterization. Groups of 3 subjects received intraduodenal infusions of 3.0, 4.5, or 6.0 mg/mL of the inhibitor for 90 minutes during the middle of a 270-minute essential amino acid solution infusion (which stimulates 50% maximal pancreatic enzyme secretion). Pancreatic enzyme and bile acid delivery to the duodenum were measured for a 270-minute period. RESULTS: The inhibitor is 96% protein, 59% containing 0.19, 0.28, 0.38, and 0.53 inhibitors. The 0.38 inhibitor has the most antipancreatic alpha-amylase activity. The inhibitor reduced amylase activity in the duodenum dose dependently (r = 0.7; P=0.04); > 4 mg/mL inhibited > 90% amylase activity but did not affect delivery of other enzymes or bile acids to the duodenum or gastric or duodenal pH. CONCLUSIONS: The preparation has a high protein purity and a high specific activity against alpha-amylase activity and effectively inhibits human pancreatic amylase activity secreted into the duodenum. (Gastroenterology 1996 Nov;111(5):1313-20)

BACKGROUND & AIMS: Starch that escapes digestion in the small intestine (resistant starch [RS]) may act similarly to nonstarch polysaccharides in the colon. The aim of this study was to examine the effect of raw potato starch alone and in combination with wheat bran on tumor development and precancer events in a rat model of colorectal cancer. METHODS: Three groups of rats received either a low-RS/low-fiber ("basic") diet, the basic diet containing raw potato starch as 20% of carbohydrate content, or the potato starch diet plus 10% of "wheat bran" fiber. Epithelial proliferation, aberrant crypt foci (ACF), and tumors were measured 6 and 20 weeks after a 10-week course of dimethylhydrazine. RESULTS: Rats on the potato starch diet had tumors more frequently and had larger tumors than rats consuming the wheat bran or basic diets. Parallel effects on the density of ACF were found 6 weeks after the carcinogen. Although epithelial proliferation was significantly enhanced by potato starch compared with the basic diet, the addition of wheat bran did not suppress this enhancement. CONCLUSIONS: This type-2 RS enhances epithelial proliferation, ACF density, and tumor formation. The addition of wheat bran to an RS- containing diet suppresses tumorigenesis, acting on events responsible for the formation of ACF but not the events controlling the hyperproliferative phase. (Gastroenterology 1996 Feb;110(2):508-14)

Epidemiological and experimental studies have shown that dietary fiber may prevent colon cancer. Resistant starch, like dietary fiber, is not subject to digestion in the small intestine. However, it is unknown whether resistant starch inhibits colonic carcinogenesis. In vitro studies have shown that butyrate slows the growth of cultured colon cancer cells. The effect of resistant starch diet on 1,2-dimethylhydrazine-induced colonic carcinogenesis in rats was evaluated, and the colonic butyrate concentration was measured.Sprague-Dawley rats were randomly divided into five groups that were fed diets containing no fiber, 3% cellulose, 10% cellulose, 3% resistant starch, or 10% resistant starch. Colonic carcinogenesis and butyrate concentration of colonic contents and feces in each diet group were compared.Total cancer volume per rat in the 10% cellulose group was significantly lower than that in the basal group (109 +/- 54 mm3 and 247 +/- 83 mm3; P0.05), but the other groups showed no significant differences. The butyrate concentration in colonic content and in feces were higher in the resistant starch groups than in the cellulose groups.The resistant starch diet increased butyrate concentration but did not inhibit colonic carcinogenesis. It remains doubtful whether butyrate inhibits the proliferation of colon cancer cells.

Background & Aims: Secretions from the exocrine and endocrine pancreas may modulate interdigestive motility. To test this hypothesis in humans, we investigated interdigestive cycling in patients with chronic pancreatitis (CP) as a model of impaired pancreatic function. Methods: Antroduodenal motility, pancreatic enzyme output, and pancreatic polypeptide release were monitored for two consecutive interdigestive cycles in 13 controls and 9 patients with CP. Results: Interdigestive enzyme output was severely impaired in patients with CP (>80% decrease); however, secretory cycling was still evident in most patients. All parameters describing interdigestive motility were similar in controls and patients with CP (duration of the migrating motor complex [MMC] was 107 ± 19 minutes in patients with CP vs. 114 ± 15 minutes in controls). The time between cyclic peaks of enzyme secretion (76 ± 4 minutes vs. 101 ± 4 minutes in controls) and pancreatic polypeptide (63 ± 4 minutes vs. 106 ± 7 minutes in controls) was shortened in patients with CP, and peaks were no longer temporally related to the MMC. Only 56% of phase III activity fronts were associated with a concomitant secretory peak in patients with CP compared with 92% in healthy subjects. Conclusions: CP not only decreases pancreatic secretion but interrupts the coordination among interdigestive cyclic phenomena. Our findings in several animal and human models refute the concept that pancreatic mechanisms exert a major regulatory influence on interdigestive motor activity.

Background & Aims Abnormal delivery of bile acids (BAs) to the colon as a result of disease or therapy causes constipation or diarrhea by unknown mechanisms. The G protein–coupled BA receptor TGR5 (or GPBAR1) is expressed by enteric neurons and endocrine cells, which regulate motility and secretion. Methods We analyzed gastrointestinal and colon transit, as well as defecation frequency and water content, in wild-type, knockout, and transgenic mice ( trg5-wt , tgr5-ko , and tgr5-tg , respectively). We analyzed colon tissues for contractility, peristalsis, and transmitter release. Results Deoxycholic acid inhibited contractility of colonic longitudinal muscle from tgr5-wt but not tgr5-ko mice. Application of deoxycholic acid, lithocholic acid, or oleanolic acid (a selective agonist of TGR5) to the mucosa of tgr5-wt mice caused oral contraction and caudal relaxation, indicating peristalsis. BAs stimulated release of the peristaltic transmitters 5-hydroxytryptamine and calcitonin gene-related peptide; antagonists of these transmitters suppressed BA-induced peristalsis, consistent with localization of TGR5 to enterochromaffin cells and intrinsic primary afferent neurons. tgr5-ko mice did not undergo peristalsis or transmitter release in response to BAs. Mechanically induced peristalsis and transmitter release were not affected by deletion of tgr5 . Whole-gut transit was 1.4-fold slower in tgr5-ko than tgr5-wt or tgr5-tg mice, whereas colonic transit was 2.2-fold faster in tgr5-tg mice. Defecation frequency was reduced 2.6-fold in tgr5-ko and increased 1.4-fold in tgr5-tg mice compared with tgr5-wt mice. Water content in stool was lower (37%) in tgr5-ko than tgr5-tg (58%) or tgr5-wt mice (62%). Conclusions The receptor TGR5 mediates the effects of BAs on colonic motility, and deficiency of TGR5 causes constipation in mice. These findings might mediate the long-known laxative properties of BAs, and TGR5 might be a therapeutic target for digestive diseases.

In awake dogs with chronic gastric, duodenal, and jejunal fistulas, F(ab)1 fragments of somatostatin monoclonal antibody (mAb S607) were administered intravenously (IV) to test the hypothesis that intraintestinal lipid inhibits peptone-stimulated gastric acid secretion and emptying by a hormonal somatostatin mechanism. Plasma somatostatin was increased significantly by duodenal and jejunal perfusion with 20% lipid. Somatostatin administered IV caused dose-dependent inhibition of meal-stimulated gastric acid secretion and gastric emptying similar to that seen after intestinal perfusion with lipid. Administration of mAb S607 F(ab)1 fragments significantly reversed somatostatin (400 pmol.kg-1.h-1, IV)-induced inhibition of peptone-stimulated acid output and gastric emptying. Acid output inhibited by intraduodenal lipid was reversed partially after F(ab)1 administration, but the inhibitory effect of intrajejunal lipid was not altered. Inhibition of acid secretion by IV somatostatin and by intraintestinal fat was not caused by a decrease in circulating gastrin concentrations. Gastric emptying delayed by intraintestinal lipid was unaffected by antibody administration. Somatostatin does not appear to be a major hormonal mediator of intestinal fat-induced inhibition of gastric acid secretion or delayed gastric emptying in dogs.

The capacity of the human esophagus to secrete bicarbonate was studied in vivo in 10 healthy subjects. A 10-cm segment of the lower esophagus was isolated between two balloons, and the segment was perfused with an unbuffered isotonic saline solution (pH 7) for 30 minutes. The perfusate was collected, pooled, and analyzed for bicarbonate using a sensitive back-titration method. Measurements of aspirate amylase and salivary amylase and bicarbonate permitted correction of perfusate bicarbonate values for contamination by swallowed saliva. The esophagus of all 10 subjects were found to secrete bicarbonate in amounts ranging from 10 to 274 microEq/30 min (average, 78 microEq/30 min); based on in vitro studies, these amounts of bicarbonate were shown to be capable of neutralizing enough residual acid from an episode of reflux to increase pH from 2.5 almost to neutrality (pH 6-7). These findings document the presence within the human esophagus of an additional mechanism for defense against (acid) reflux damage, namely, through enhanced luminal acid clearance by the secretion of bicarbonate ions.

Somatostatin 28 (S-28), originating in gastrointestinal cells, is secreted into the circulation and increases in humans after ingestion of a mixed meal. To evaluate the possibility that the increased levels of S-28 post cibum might modulate the release of enzymes and bicarbonate from the exocrine pancreas, S-28 was infused intravenously into healthy volunteers to levels seen after food intake. During S-28 infusion, the output of lipase, trypsin, amylase, and bicarbonate stimulated by either exogenous cholecystokinin octapeptide or endogenous signals from intraduodenal administration of tryptophan or a mixture of amino acids was significantly reduced. It is concluded that S-28 released from the gut during food intake modulates pancreatic exocrine function in humans.

Gastric acid enters the proximal duodenum both as free and buffered H+. The procedures in this study were threefold: (a) to determine the pH threshold for duodenal mucosal bicarbonate secretion, iso-osmolar citric acid (pH 2.5-4.0; H+, 1.1 mmol) was infused; (b) to examine the effect of varying acid loads (H+, 0.4-5.1 mmol), citric acid (pH 3.0) was perfused; and (c) to quantitate duodenal diffusion of CO2, citric acid (pH 5.0) gassed with CO2 (PCO2, 0-210 mm Hg) was tested. Basal bicarbonate secretion was similar on each test day, 230 mumol/cm.h. Citric acid at pH 2.5 and 3.0 increased bicarbonate output equally to about 560 mumol/cm.h (similar to 2 mmol of 100 mmol/L HCl); citric acid at pH 3.5 and 4.0 had no effect. Varying the acid load increased bicarbonate output similarly. Duodenal loss of CO2 was minimal (4%) with infusion of 50 mm Hg PCO2 and increased to approximately 25% (15 mm Hg/min) at higher PCO2 values. It is concluded that (a) the pH threshold for human duodenal mucosal bicarbonate secretion is 3.0; (b) a pH-sensitive, rather than an acid load-sensitive, regulatory process exists; and (c) CO2 loss plateaus at 15 mm Hg/min at a PCO2 of 200 mm Hg. (Gastroenterology 1992 Apr;102(4 Pt 1):1252-8)

Hydrogen is produced during fermentation in the large intestine and may be excreted in breath and flatus or further metabolized by the flora. However, there is little information about total H2 excretion from different substrates or the extent to which it is metabolized in the colon. We have therefore measured total H2 and methane excretion in 10 healthy subjects using a whole body calorimeter. Breath gases were measured simultaneously with total excretion in response to lactulose, pectin, and banana starch. Metabolic activities of the predominant H2 consuming anaerobes (methanogenic, sulfate reducing, and acetogenic bacteria) were measured in fecal samples. Total H2 excretion on a starch and fiber-free diet was 35 +/- 6.1 mL/24 h +/- SEM. H2 from 7.5 g, 15 g, and 22.5 g lactulose was 88.1 +/- 22.4 mL, 227.0 +/- 60.7 mL, and 321.8 +/- 79.2 mL. Four of the subjects also excreted CH4, which was 51.3 +/- 5.5 mL, 97.3 +/- 18.4 mL, and 157.5 +/- 36.3 mL for the respective lactulose doses. H2 excretion was less in methanogenic subjects (7.9 mL/g lactulose) than in nonmethanogenic (17.3 mL/g), but total H2 excreted as, hydrogen + methane, was 34.9 mL/g. H2 from pectin (20 g) was 14.1% +/- 3.2% and from starch (22.2 g) 38.6% +/- 9.2% of an equivalent lactulose dose. Sixty-five percent of total H2 and CH4 was expired in breath at total excretion rates up to 200 mL/24 h. Over this the proportion decreased to 25% with an overall average of 58%. Only subjects with CH4 excretion in vivo showed methanogenesis in feces, whereas nonmethanogenic subjects showed high sulfate-reducing activity in feces (58.7 +/- 5.6 nmol 35SO4 reduced.h-1.g-1 wet wt vs. 7.9 +/- 2.0 nmol.h-1.g-1 in methanogens). Acetogenesis rates were very low in both groups. It was concluded that H2 excretion varies with different substrates. The proportion of H2 that is exhaled in breath is higher than currently accepted and varies with total excretion rate. Substantial amounts of H2 are consumed by methanogenic and sulfate-reducing bacteria. (Gastroenterology 1992 Apr;102(4 Pt 1):1269-77)

Although glucose sensors regulating the gastric emptying of liquid meals are uniformly distributed throughout the canine small intestine, some data suggest that the distal small bowel more potently inhibits gastric emptying of solid foods. The aims of this study were to compare (a) the inhibition of gastric emptying by glucose sensors in the proximal intestine with the feedback from the distal intestine, (b) these effects on the gastric emptying of solids vs. liquids, and (c) the inhibitory effect of unhydrolyzed starch with glucose. In 7 dogs with chronic duodenal fistulas, the second, third, and fourth quarters of small bowel were perfused via chronically implanted transmural catheters. Gastric emptying of either solids or liquids was tracked by gamma camera while gastric output was diverted out the duodenal fistula and the small bowel perfused with test solutions of glucose (0.06-2.0 mol/L), 0.15 mol/L NaCl, or 8.5% soluble starch. It was found that (a) gastric emptying of solids but not liquids was approximately 3 times more potently inhibited by glucose in the fourth quarter vs. the first or second quarter of small bowel, and (b) only hydrolyzed starch inhibited gastric emptying of solids.

The distal small intestine is an especially potent site for carbohydrate-triggered intestinal inhibition of gastric emptying of solids. Poorly digestible carbohydrates, such as lentils, may escape proximal absorption, travel over time to reach these inhibitory mechanisms, and slow the gastric emptying of a later meal. A slowing effect on gastric emptying may be associated with a lowering effect on postprandial glucose. The aims of this study were to determine (a) whether lentils (a poorly digestible carbohydrate) vs. bread (an easily digestible carbohydrate) eaten as a premeal (with equal amounts of carbohydrates) slow the gastric emptying of a second solid meal taken 4.0-4.5 hours later and (b) whether a slowing effect on the gastric emptying of the second meal is associated with a lower postprandial glucose response. We found that in 7 dogs and 10 humans, gastric emptying of the second meal was delayed after a lentil premeal compared with a bread premeal. However, there was no difference in the glucose response to the second meal under the two conditions.

The absorption of water and electrolytes from the proximal jejunal lumen increases immediately after a meal. This meal-induced jejunal absorption occurs in jejunal segments out of normal gastrointestinal continuity. This study was designed to characterize the jejunal absorptive response to a series of isovolumetric gavage-delivered stimuli. Twenty-five-centimeter canine proximal jejunal Thiry-Vella fistulas were constructed, and jejunal absorption studies (n = 66) were performed by luminal perfusion of the jejunal segments with an isotonic buffer containing 14C-labeled polyethylene glycol. Each study consisted of a 1-hour basal period, followed by a 3-hour experimental period. Nine groups were studied, each receiving one of the following isovolumetric stimuli delivered via the gavage route: water, 0.9% saline, mixed meal, protein, lipid, carbohydrate, and mannitol (150 mmol/L, 300 mmol/L, and 600 mmol/L). The water and 0.9% saline gavage groups showed no significant changes in integrated postprandial water and electrolyte absorption above basal. The isocaloric mixed meal, protein, lipid, carbohydrate, and mannitol groups all had significantly increased integrated postprandial jejunal water and electrolyte absorption above basal (P less than 0.05). These results indicate that a proabsorptive signal for meal-induced jejunal absorption originates from or distal to the stomach. Meal-induced jejunal absorption occurs in response to nutrients of diverse composition and is also responsive to nonnutritive solutes such as mannitol. These findings support a new role for gastric or intestinal chemo- or osmo-receptors in stimulating the neurohumoral mechanisms that mediate meal-induced jejunal absorption.

The control mechanism of canine colonic motor activity measured by means of chronically implanted force transducers was studied by comparing diurnal changes and migrating patterns in control dogs and dogs with innervated and extrinsically denervated colonic loops. Five force transducers (C1-C5) were placed on the colon, and the middle colon was transected to construct a loop including C2 and C3 transducers. Colonic continuity was established by an end-to-end anastomosis. In the fasted state, colonic motor complexes of 8-13 minutes' duration were observed to occur at intervals of 22-32 minutes in all three groups, but response to feeding was clearly different; significant enhancement of the colonic motor indexes lasting for 8-16 hours after feeding, which was observed at all recording sites in control dogs, was identified only in the proximal and distal colon in dogs with innervated and extrinsically denervated loops. In the innervated loop, significant enhancement of the motor indexes was observed only in the first 2 hours after feeding. In the extrinsically denervated loop, feeding did not induce any response. In both groups with loops, greater than 40% of the motor complexes that occurred in the proximal colon migrated to the distal colon directly across the anastomosis and less than 20% propagated to the loop. In addition, the migration time between the proximal and the distal colon was greatly reduced in both groups with loops compared with that in the control group. Another change observed within the loop was an increase in numbers of retrograde migrating colonic motor complexes. It is concluded that colonic motor activity is under the predominant control of intraluminal contents in the digestive state but that extrinsic nerves may play an important role in the response observed in the innervated loop in the first 2 hours after feeding, which should be defined as the gastrocolonic response in dogs. In the interdigestive state, the intrinsic nervous system and/or humoral factors may control the occurrence of colonic motor complexes.