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Studies based on single cells have revealed vast cellular heterogeneity in stem cell and progenitor compartments, suggesting continuous differentiation trajectories with intermixing of cells at various states of lineage commitment and notable degrees of plasticity during organogenesis 1-5 . The hepato-pancreato-biliary organ system relies on a small endoderm progenitor compartment that gives rise to a variety of different adult tissues, including the liver, pancreas, gall bladder and extra-hepatic bile ducts 6,7 . Experimental manipulation of various developmental signals in the mouse embryo has underscored important cellular plasticity in this embryonic territory 6 . This is reflected in the existence of human genetic syndromes as well as congenital malformations featuring multi-organ phenotypes in liver, pancreas and gall bladder 6 . Nevertheless, the precise lineage hierarchy and succession of events leading to the segregation of an endoderm progenitor compartment into hepatic, biliary and pancreatic structures have not yet been established. Here we combine computational modelling approaches with genetic lineage tracing to accurately reconstruct the hepato-pancreato-biliary lineage tree. We show that a multipotent progenitor subpopulation persists in the pancreato-biliary organ rudiment, contributing cells not only to the pancreas and gall bladder but also to the liver. Moreover, using single-cell RNA sequencing and functional experiments we define a specialized niche that supports this subpopulation in a multipotent state for an extended time during development. Together these findings indicate sustained plasticity underlying hepato-pancreato-biliary development that might also explain the rapid expansion of the liver while attenuating pancreato-biliary growth., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The gut microbiota is part of the human body that is involved in body metabolism and the occurrence of various diseases. Detecting and analyzing their genetic information (microbiome) is as important as analyzing human genes. The core microbiome, the key functional genes shared by all humans, helps better understand the physiology of the human body. Information on the gut microbiome of a diseased person can help diagnose and treat disease. The pancreatobiliary system releases functional antimicrobial substances, such as bile acids and antimicrobial peptides, which affect the gut microbiota directly. In response, the gut microbiota influences pancreatobiliary secretion by controlling the generation and emission of substances through indirect signaling. This crosstalk maintains homeostasis of the pancreatobiliary system secretion and microbiota. Dysbiosis and disease can occur if this fails to work properly. Bile acid therapy has been used widely and may affect the microbial environment in the intestine. An association of the gut microbiota has been reported in many cases of pancreatobiliary diseases, including malignant tumors. Traditionally, most pancreatobiliary diseases are accompanied by infections from the gut microbiota, which is an important target for treatment. The pancreatobiliary system can control its function through physical and drug therapy. This may be a new pioneering field in the study or treatment of the gut microbiota.

Despite considerable recent insight into the molecular phenotypes and type 2 innate immune functions of tuft cells in rodents, there is sparse knowledge about the region-specific presence and molecular phenotypes of tuft cells in the human digestive tract. Here, we traced cholinergic tuft cells throughout the human alimentary tract with immunohistochemistry and deciphered their region-specific distribution and biomolecule coexistence patterns. While absent from the human stomach, cholinergic tuft cells localized to villi and crypts in the small and large intestines. In the biliary tract, they were present in the epithelium of extra-hepatic peribiliary glands, but not observed in the epithelia of the gall bladder and the common duct of the biliary tract. In the pancreas, solitary cholinergic tuft cells were frequently observed in the epithelia of small and medium-size intra- and inter-lobular ducts, while they were absent from acinar cells and from the main pancreatic duct. Double immunofluorescence revealed co-expression of choline acetyltransferase with structural (cytokeratin 18, villin, advillin) tuft cell markers and eicosanoid signaling (cyclooxygenase 1, hematopoietic prostaglandin D synthase, 5-lipoxygenase activating protein) biomolecules. Our results indicate that region-specific cholinergic signaling of tuft cells plays a role in mucosal immunity in health and disease, especially in infection and cancer.

Background and Aims: Duodenal-jejunal bypass (DJB) shows great effects on weight loss and diabetes improvement. Previously, we reported that the bilio-pancreatic (BP) limb plays an important role in glycemic improvement and in serum bile acid (BA) level increase as reported by Miyachi et al. (Surgery 159(5):1360-71, 2016). This study aimed to investigate the mechanism of BA elevation after DJB and the relationship between these effects and BP-limb length., Methods: Otsuka Long-Evans Tokushima Fatty rats with diabetes were randomly assigned into four groups: one sham group and three DJB groups. Three DJB groups were defined according to the BP-limb length: 0 cm, 15 cm, and 30 cm. The lengths of the alimentary limb and common channel were set equally in each DJB groups. Body weight, glucose tolerance, and BA levels in the liver, bile juice, portal vein, and intestinal contents were assessed postoperatively. Changes in enterohepatic circulation of BAs were assessed using labeled BA., Results: BA elevation after DJB was higher with longer BP-limb. In the 30-cm group, the serum total BA level and BA levels in the portal vein, liver, and bile juice were greater than those in other groups. The enterohepatic circulation was shortened in the 15-cm and 30-cm groups., Conclusions: Shortening of the "enterohepatic circulation" by early reabsorption of BAs in the BP-limb, not by the early influx of bile juice into the ileum, was the main cause of BA elevation after DJB. Thus, glycemic improvement and elevation of BA concentration after DJB depend on the BP-limb length.

Background and Aims: Roux-en-Y gastric bypass improves glucose metabolism in clinical practice, and duodenal-jejunal bypass (DJB), an experimental bypass procedure, also improves metabolism in animals. However, the mechanism remains controversial; especially, the role of the biliopancreatic limb (BP-limb) remains unclear. Our aim was to examine the importance of the function of the BP-limb after DJB using a novel operative model., Methods: Otsuka Long-Evans Tokushima Fatty rats with diabetes were divided into the following groups: DJB with a short alimentary limb (A-limb) and long BP-limb (B-DJB group), DJB with jejunectomy (J-DJB group) in which the entire length of the jejunum used for the BP-limb of the B-DJB group was excised; and a sham operation group. Glucose tolerance, plasma bile acid levels, and the gut microbiota were assessed postoperatively., Results: Glucose tolerance was improved and weight gain was suppressed after surgery in the B-DJB group. In contrast, these effects were cancelled in the J-DJB group. The plasma levels of bile acids in the B-DJB group were greater than those in other groups. The analysis of gut microbiota showed distinct differences between the B-DJB and other groups; especially, the relative abundance of genus Bifidobacterium was much higher in the B-DJB group., Conclusion: The BP-limb played an important role in the control of weight gain, glucose tolerance, and increased plasma bile acid levels after DJB in this rat model of type 2 diabetes mellitus. Plasma bile acids and gut microbiota may be involved in these processes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Timely and accurate diagnosis of pancreatic ductal adenocarcinoma (PDAC) is critical in order to provide adequate treatment to patients. However, the clinical signs and symptoms of PDAC are shared by several types of malignant or benign tumors which may be difficult to differentiate from PDAC with conventional diagnostic procedures. Among others, these include ampullary cancers, solid pseudopapillary tumors, and adenocarcinomas of the distant bile duct, as well as inflammatory masses developing in chronic pancreatitis. Here, we report an approach to accurately differentiate between these different types of pancreatic masses based on molecular analysis of biopsy material. A total of 156 bulk tissue and fine needle aspiration biopsy samples were analyzed using a dedicated diagnostic cDNA array and a composite classification algorithm developed based on linear support vector machines. All five histological subtypes of pancreatic masses were clearly separable with 100% accuracy when using all 156 individual samples for classification. Generalized performance of the classification system was tested by 10 × 10-fold cross validation (100 test runs). Correct classification into the five diagnostic groups was demonstrated for 81.5% of 1,560 test set predictions. Performance increased to 85.3% accuracy when PDAC and distant bile duct carcinomas were combined in a single diagnostic class. Importantly, overall sensitivity of detection of malignant disease was 92.2%. The molecular diagnostic approach presented here is suitable to significantly aid in the differential diagnosis of undetermined pancreatic masses. To our knowledge, this is the first study reporting accurate differentiation between several types of pancreatico-biliary tumors in a single molecular analytical procedure.

Relationships between the NO synthase inhibitor and gastric and pancreaticobiliary functions measured simultaneously in the digestive state have been little studied. The aim of this study was to estimate the effect of NO synthase inhibitor on integrated digestive function in conscious dogs. A strain gauge force transducer was implanted on the gastric antrum of 6 mongrel dogs to measure gastric contractile activity and two duodenal cannulas were inserted into the proximal and distal sites to measure the gastric emptying rate and the pancreaticobiliary output into the duodenum using our novel method. Postprandial pancreatic and biliary secretion were presented as amylase and bile acid activity, respectively. Furthermore, a cervical cannula was placed into the superior vena cava as a route for the administration of NO synthase inhibitor, N omega-nitro-L-arginine (L-NNA), at a dose of 2.5 mg/kg-h. In a group given L-NNA, gastric contractile activity after ingestion was significantly enhanced, but the emptying rates of gastric solids and liquids were significantly suppressed in comparison with the control. The mean 0-1 h amylase integrated output was significantly (P < 0.05) decreased in comparison with the control, and the mean bile acid integration of 0-1 h output was also significantly (P < 0.01) decreased. A possible explanation for this observation is that smaller volumes of nutrient are delivered into the duodenum; however, it could also be that postprandial pancreaticobiliary secretion is inhibited by an alteration of blood flow or by a change in contractions of the sphincter of Oddi after the administration of L-NNA.

Background: Oxygen-free radicalscan play a role in the development of chronic pancreatitis, altering the redox state with damage of cell constituents and decrease in antioxidant defences., Aims: To measure levels of lipoperoxidation products, conjugated dienes and lipid hydroperoxides, in pure pancreatic juice and serum of chronic pancreatitis patients and compare them to that in controls. To investigate a possible correlation with serum indexes of pancreatic inflammation (amylase and lipase)., Patients: Pancreatic juice was collected during ERCP, after secretin stimulation, in 20 patients with chronic pancreatitis and 11 controls with biliary diseases., Methods: Lipid hydroperoxide levels were determined with FOX2 method and measured as absorbance at 560 nm. Conjugated diene levels were measured using second-derivative spectroscopy., Results: No substantial difference was present in serum levels of lipid hydroperoxides, conjugated dienes (in both isomeric forms) and isomer-ratio values between those of patients with chronic pancreatitis and controls. In pancreatic juice, there was a significant increase in lipid hydroperoxides and conjugated dienes levels (especially trans-trans isomers) in chronic pancreatitis patients compared with controls, with a decrease in cis-trans isomers and a significant difference in isomer-ratio values., Conclusions: Increased levels of lipid hydroperoxides and conjugated dienes in the pancreatic juice of chronic pancreatitis patients is indicative of an enhanced lipoperoxidation and antioxidants consumption in pancreatic tissue, confirmed by the decreased isomer-ratio values as an indirect index of decreased antioxidant capacity. The lack of significant difference in conjugated diene and lipid hydroperoxide levels in the serum of chronic pancreatitis patients versus that of controls suggests an oxidative stress limited to pancreatic tissue and indicative of an organ-specific pathology, confirmed by the parallel behaviour of oxidative parameters (lipid hydroperoxides and conjugated dienes) and indexes of pancreatic inflammation (amylase and lipase).

Studies were undertaken to provide information regarding cell-specific expression of mucin genes and their relation to developmental and neoplastic patterns of epithelial cytodifferentiation. In situ hybridization was used to study mRNA expression of mucin genes in duodenum and accessory digestive glands (liver, gallbladder, pancreas) of 13 human embryos and fetuses (6. 5-27 weeks' gestation), comparing these with normal and neoplastic adult tissues. These investigations demonstrated that the pattern of mucin gene expression in fetal duodenum reiterated the patterns we observed during gastric and intestinal ontogenesis, with MUC2 and MUC3 expression in the surface epithelium and MUC6 expression associated with the development of Brünner's glands. In embryonic liver, MUC3 was already expressed at 6.5 weeks of gestation in hepatoblasts. As in adults, MUC1, MUC2, MUC3, MUC5AC, MUC5B, and MUC6 were expressed in fetal gallbladder, whereas MUC4 was not. In contrast, MUC4 was strongly expressed in gallbladder adenocarcinomas. MUC5B and MUC6 were expressed in fetal pancreas, from 12 weeks and 26 weeks of gestation, respectively. Surprisingly, MUC3 which is strongly expressed in adult pancreas, was not detected in developmental pancreas. Taken together, these data show complex spatio-temporal regulation of the mucin genes and suggest a possible regulatory role for mucin gene products in gastroduodenal epithelial cell differentiation.

Background: The upper small bowel is of pivotal importance for the stimulation of exocrine pancreatic secretion in response to a meal. We hypothesize that more distal delivery of nutrients into the small intestine will result in less activation of pancreatic secretion., Materials and Methods: Eight healthy subjects (3 male, 5 female; age 23 +/- 1 years) participated in two experiments, performed in random order. Subjects were intubated with a 4-lumen tube. Duodenal outputs of pancreatic enzymes and bilirubin were measured by aspiration using a recovery marker. The distal opening was used for continuous administration of a mixed liquid meal and located at either the ligament of Treitz or 60 cm further distally. Gallbladder volume was measured and blood samples were drawn for determination of gastrointestinal hormones. The duration of each experiment was 4 h; with 1 h fasting and 3 h continuous administration of nutrients., Results: During proximal jejunal feeding, pancreatic enzyme output increased significantly over basal levels. No significant increase over basal levels was observed during distal jejunal feeding. Bilirubin output and gallbladder contraction were significantly (P < 0.05) reduced during distal compared to proximal jejunal feeding. No significant differences were found in plasma levels of CCK, PYY and neurotensin between proximal and distal jejunal feeding., Conclusion: Continuous feeding in the distal jejunum does not stimulate exocrine pancreatic secretion but maintains gallbladder contraction, although to a lesser extent. These effects are not related to hormonal changes but probably reduced activation of the enteropancreatic reflexes.

EM574, an erythromycin derivative and a potent motilin receptor agonist, is now under clinical trial as a gastroprokinetic drug. The aim of this study was to estimate the effect of EM574 on postprandial pancreaticobiliary secretion, gastric motor activity, and emptying in conscious dogs. Five mongrel dogs were prepared. Indwelling cannulas for both infusion of phenolsulfonphthalein and aspiration of luminal samples were inserted into the proximal and distal duodenum, respectively. EM574 (3-30 microg/kg) was given intraduodenally through the indwelling distal duodenal cannula at the start of feeding. Postprandial pancreatic and biliary secretions were assessed by measuring the outputs of amylase and bile acid into the duodenum, respectively. Gastric motor and emptying activity were measured by means of a force transducer method and our own freeze-drying method, respectively. One hundred grams of a freeze-dried standard meal was given as a solid marker after being mixed with 100 ml of normal saline containing 15 g of polyethylene glycol as a liquid marker. EM574 at doses of 10 and 30 microg/kg significantly increased the mean integrated postprandial amylase output into the duodenum, but the mean integrated postprandial bile acid output was not significantly increased. EM574 increased postprandial gastric antral motor activity dose-dependently. EM574 at doses of 10 and 30 microg/kg significantly accelerated gastric emptying of liquids and solids, respectively. EM574 enhances gastric antral motor activity and accelerates gastric emptying of solids and liquids with a concomitant increase in postprandial pancreatic amylase, but not bile acid, output in normal dogs.

Background/aims: We have investigated the effect of acute hyperglycemia on pancreaticobiliary secretion and pancreatic polypeptide (PP) release., Methods: Duodenal outputs of bilirubin, trypsin, lipase, amylase and bicarbonate were measured using a recovery marker under basal conditions and in response to modified sham feeding (MSF) in 6 healthy subjects on two separate occasions: during normoglycemia and during acute hyperglycemia (15 mmol/l)., Results: During hyperglycemia the basal pancreaticobiliary output was significantly (p < 0.05) reduced. During normoglycemia MSF significantly (p < 0.05) increased the output of bilirubin and pancreatic enzymes; during hyperglycemia only the output of pancreatic enzymes increased significantly (p < 0.05) over basal. During MSF the outputs of bilirubin (16 +/- 4 vs. 4 +/- 2 micromol/30 min), trypsin (26 +/- 7 vs. 7 +/- 4 U/30 min), lipase (36 +/- 11 vs. 15 +/- 6 kU/30 min), amylase (3.4 +/- 0.7 vs. 1.4 +/- 0.7 kU/30 min) and bicarbonate (0.8 +/- 0.1 vs. 0.5 +/- 0.1 mmol/30 min) were significantly (p < 0.05) reduced during hyperglycemia compared to normoglycemia. During hyperglycemia basal and MSF-stimulated PP levels were significantly (p < 0.05) reduced compared to normoglycemia. MSF did not significantly influence plasma cholecystokinin levels in both experiments., Conclusions: This study indicates (1) that the blood glucose levels affect basal and cephalic stimulated pancreaticobiliary secretion and (2) that the PP secretion during hyperglycemia is reduced, suggesting impaired vagal cholinergic activity during hyperglycemia.

Pancreatico-biliary secretion is reduced during acute hyperglycemia. We investigated whether alterations in pancreatico-biliary flow or volume output are responsible for the observed reduction in duodenal output of pancreatic enzymes and bilirubin during hyperglycemia. Eight healthy subjects were studied on two occasions during normoglycemia and hyperglycemia (15 mmol/l). Pancreatico-biliary output was measured by aspiration using a recovery marker under basal conditions (60 min), during secretin infusion (0.1 CU/kg.h) for 60 min and during secretin + CCK (0.5 IDU/kg.h) infusion for 60 min. Secretin was infused to stimulate pancreatico-biliary flow and volume output. Secretin significantly (P<0.005-P<0.05) increased volume and bicarbonate output and CCK significantly (P<0.01) increased the output of bilirubin, pancreatic enzymes, bicarbonate and volume, both during normoglycemia and hyperglycemia. During hyperglycemia basal, secretin stimulated and secretin + CCK stimulated total pancreatico-biliary output were significantly (P<0.005-P<0.05) reduced compared to normoglycemia. The incremental outputs, however, were not significantly different between hyper- and normoglycemia. Pancreatic volume output was significantly (P<0.05) reduced during hyperglycemia compared to normoglycemia under basal conditions (31+/-16 m/h versus 132+/-33 m/h) during secretin infusion (130+/-17 ml/h versus 200+/-34 m/h) and during secretin + CCK infusion (370+/-39 ml/h versus 573+/-82 ml/h). Plasma PP levels were significantly (P<0.05) reduced during hyperglycemia. It is concluded that 1) hyperglycemia significantly reduces basal pancreatico-biliary output 2) the incremental pancreaticobiliary output in response to secretin or secretin + CCK infusion is not significantly affected during hyperglycemia, 3) a reduction in volume output contributes to the inhibitory effect of hyperglycemia on pancreatico-biliary secretion, 4) hyperglycemia reduces PP secretion suggesting vagal-cholinergic inhibition of pancreatico-biliary secretion and volume during hyperglycemia.

This study was undertaken to investigate the effect of acute hyperglycemia on basal and bombesin-stimulated pancreaticobiliary secretion. Seven healthy subjects participated in two experiments performed in random order during normoglycemia and hyperglycemic clamping at 15 mM. Duodenal outputs of bilirubin, trypsin, amylase, and bicarbonate were measured by aspiration with a recovery marker under basal conditions for 60 min and during continuous infusion of bombesin (1 ng/kg x min) for 60 min. Plasma cholecystokinin (CCK) and pancreatic polypeptide (PP) levels were determined at regular intervals. Compared to normoglycemia, during hyperglycemia basal outputs of bilirubin (17 +/- 3 vs. 0.9 +/- 0.4 micromol/60 min), trypsin (24 +/- 4 vs. 4 +/- 1 U/60 min), amylase (12 +/- 1 vs. 3 +/- 1 kU/60 min), and bicarbonate (2.9 +/- 0.5 vs. 1.2 +/- 0.2 mmol/60 min) were significantly p < 0.05) reduced. Bombesin significantly (p < 0.05) increased pancreaticobiliary output during both normo- and hyperglycemia. During hyperglycemia bombesin-stimulated 60-min outputs of bilirubin, trypsin, amylase, and bicarbonate were not significantly different compared to those during normoglycemia. Basal and bombesin-stimulated plasma PP concentrations were significantly (p < 0.05) reduced during hyperglycemia, but plasma CCK levels were not significantly different. It is concluded that acute hyperglycemia reduces basal but does not affect bombesin-induced pancreaticobiliary secretion.

Purpose: Ranitidine plasma concentration vs. time profiles and the extent of ranitidine absorption were examined in the presence and absence of pancreatico-biliary secretions in order to elucidate factors which may contribute to secondary peaks after oral ranitidine administration., Methods: Ranitidine solution (300 mg) was administered to 4 fasting healthy subjects via an indwelling small-bore oroenteric tube located approximately 16 cm distal to the pylorus On 3 consecutive days, subjects randomly received ranitidine alone (control), ranitidine 10 min after 0.04 micrograms/kg IV cholecystokinin (CCK) sufficient to cause gall bladder emptying into the duodenum, and ranitidine 30 min after inflation of an occlusive duodenal balloon located approximately 10 cm distal to the pylorus to prevent pancreatico-biliary secretions from reaching the dosing port or beyond. Small bowel transit time (SBTT; min) was measured by breath H2. Serial blood samples, obtained over 12 hours in each treatment, were analyzed by HPLC to determine ranitidine AUC0-12 (ng*h/mL), as well as Cmax (ng/mL) and Tmax (min) of the first and subsequent peaks, if subsequent peaks were observed., Results: Ranitidine AUC0-12 and Cmax were not altered significantly by treatments; treatment effects on SBTT varied. Secondary peaks were observed in subjects #1 and #3 during the control treatment and subjects #2 and #4 during the CCk treatment. No secondary peaks were observed in any subject during the balloon treatment, and Tmax1 was delayed., Conclusions: Results support the hypothesis that pancreatico-biliary secretions (present in the intestinal lumen during control or CCK treatment) and gastrointestinal transit time may influence the occurrence of secondary peaks in ranitidine concentration vs. time profiles.

The effect of pancreaticobiliary secretion on the intestinal expression of the apo A-IV gene was examined in fasted rats. Pancreaticobiliary diversion, but not biliary diversion alone, into the ileum increased the ileal apo A-IV mRNA expression by 24 h post-operation. Jejunal apo A-IV mRNA was reduced by biliary exclusion. The data suggest that the biliary constituent plays an important role in the apo A-IV gene expression in the entire length of the small intestine, and that up-regulation of the apo A-IV gene requires exocrine pancreatic in addition to biliary secretion.

This study was undertaken to investigate the effect of acute hyperglycemia on pancreatico-biliary secretion in healthy subjects. Duodenal outputs of bilirubin, amylase, trypsin and bicarbonate were measured by aspiration using a recovery marker under basal condition for 75 min and during continuous infusion of CCK (0.5 IDU/kg.h for 60 min). Seven healthy subjects participated in two experiments performed in random order during normoglycemia and during acute hyperglycemic clamping at 15 mmol/l. At regular intervals plasma PP levels were determined as an indirect measure of vagal-cholinergic tone. Basal pancreatico-biliary secretion was significantly (p<0.05) reduced during acute hyperglycemia. CCK significantly (p<0.05) increased bilirubin, amylase and trypsin output both during normo- and hyperglycemia. During the initial 30 min of CCK infusion the bilirubin, amylase and trypsin outputs were significantly (p<0.05) inhibited in the hyperglycemic experiment compared to normoglycemia. In the following 30 min of CCK infusion the bilirubin, amylase and trypsin output were not different between hyper- and normoglycemia. Basal and CCK-stimulated plasma PP concentrations were significantly (p<0.05) reduced during hyperglycemia. In summary: 1) basal pancreatico-biliary secretion is significantly reduced during acute hyperglycemia 2) during hyperglycemia CCK-stimulated pancreatico-biliary secretion is also significantly reduced with the pattern of a delayed response 3) hyperglycemia inhibits basal and CCK-stimulated PP secretion suggesting impaired vagal-cholinergic activity during hyperglycemia.

Effects of viscous indigestible polysaccharides on the pancreas exocrine function were investigated in growing rats. Rats were fed a nonfiber diet or a diet containing approximately 5% of one of the following fibers: apple pectin, lambda-carrageenan, locust bean gum, gum xanthan, guar gum or sodium (Na) alginate. Pancreatic-bile secretion was found to be elevated in rats fed for 2 wk the highly viscous polysaccharides, sodium alginate, locust bean gum, gum xanthan and guar gum. The polysaccharides may have interfered with the digestion and absorption of nutrients, resulting in a decreased digestibility and an enlargement of digestive organs. When alginic acid and calcium alginate, insoluble polysaccharides that did not contribute to viscosity, were given to rats, they had no effect on pancreatic and biliary secretion compared with sodium alginate. The results demonstrate that consumption of viscous indigestible polysaccharides leads to changes in the exocrine pancreatic-biliary function and may depress the process of digestion and absorption. Rats may compensate for the inefficiency of digestion and absorption with a hyperplasia/hypertrophy of digestive organs and an increased secretion of digestive juice.

In eight normal persons the plasma levels of secretin and cholecystokinin (CCK) measured after intraduodenal oleate were reproduced by intravenous (i.v.) infusion of synthetic secretin (3.4 pmol.kg-1.h-1) and CCK-8 (17.5 pmol.kg-1.h-1), either alone or in combination. Using an indicator dilution technique, the combined infusions of the two hormones were found to account for all the pancreatico-biliary secretion of amylase, bicarbonate, bile salts and volume elicited in response to intraduodenal oleate, pH 6. Furthermore, the bicarbonate secretion and the flow rate elicited by secretin were augmented by CCK, whereas no augmentation was found with regard to the CCK-stimulated enzyme and bile salts output.

In 20 normal persons we investigated the effects of duodenal osmolality on the release of secretin and cholecystokinin (CCK), pancreaticobiliary secretion, and fat absorption after intestinal infusion of emulsified oleic acid (pH 6.0). The release of CCK was found to be unaffected by the changes in osmolality, whereas the plasma levels of secretin were affected in parallel with volume and bicarbonate secretion. An inverse relation was found between fatty acid absorption and release of secretin and bicarbonate secretion but not between fatty acid absorption and release of CCK. It is suggested that the secretin and CCK cells respond differently to emulsified oleic acid.

Morphologic and functional adaptations of the functioning intestine were evaluated in 41 patients before and after biliopancreatic bypass for morbid obesity. This surgical procedure diverts pancreatobiliary secretions via the duodenum and the jejunum into the colon, the remaining small intestine being anastomosed to the stomach after antrectomy. In the proximal ileum there was an 80% increase of the height of villi; the specific activities of maltase, sucrase, and aminopeptidase in brush border membranes remained unaffected, and that of lactase tended to decrease. In the distal ileum villi heights increased only by 58%, and disaccharidase activities (except for maltase) were slightly enhanced. In the colon the mucosa displayed, in some patients, focal appearance of true villi, and brush border enzyme activities increased concomitantly. We conclude that biliopancreatic bypass induces an adaptation of all intestinal segments of the functioning intestine; this adaptation tends to compensate for the shortening of the gut continuity.

The purpose of this study was to determine whether or not nutrients in the colon influence pancreatic and biliary secretion in humans. In six healthy subjects, similar caloric loads (117 cals) of oleic acid, essential amino acids, and glucose in isomolar (280 mosmol/L), similar pH (7.4) solutions were infused into the right colon at 10 ml/min through a colonic tube passed by mouth. A background of submaximal pancreatic and biliary secretion was maintained by continuous intravenous infusion of the octapeptide of cholecystokinin. Biliary and pancreatic secretions were quantitated using the gastroduodenal intubation perfusion technique. Among the three nutrients tested, only oleic acid in the colon decreased pancreatic enzymes and bicarbonate outputs. The mean trypsin output decreased from 26.3 +/- 2.6 kU/h to 12.3 +/- 1.9 kU/h (46% +/- 6% of control), while the lipase output decreased from 62 +/- 6.6 kU/h to 36 +/- 5.6 kU/h (58% +/- 6% of control). Similarly, the output of bicarbonate in the duodenal aspirate decreased from 31 +/- 7.2 mEq/h to 16.3 +/- 3.1 mEq/h (61% +/- 5% of control). Intracolonic perfusion of essential amino acids or glucose had no effect on pancreatic enzymes and bicarbonate secretion. In contrast, all three nutrients in the colon inhibited biliary secretion. The mean output of bilirubin decreased from 56 +/- 6 mg/h to 19 +/- 2 mg/h (35% +/- 5% of control) during intracolonic perfusion of oleic acid. Essential amino acids lowered the output of bilirubin from 54 +/- 12 mg/h to 31 +/- 8.6 mg/h (65% +/- 6% of control), whereas glucose lowered it from 53 +/- 12 mg/h to 22 +/- 4 mg/h (45% +/- 5% of control). This differing response of pancreatic and biliary output to intracolonic perfusion of nutrients suggests differential sensitivity of the pancreas and gallbladder to these inhibitory influences. In malabsorption states, unabsorbed nutrients in the colon may inhibit pancreatic and biliary secretion, further contributing to the loss of nutrients from the gastrointestinal tract.

Although abdominal complaints are frequent in both acute and chronic alcoholism, little is known of the effect of ingestion of ethanol with a meal on the function of the upper digestive tract. We have studied the effects of oral ethanol (1 g/kg body wt) taken with food on the gastric emptying rate of a solid-liquid meal as measured by a dual radioisotope technique in six normal subjects; and the gastric response (emptying and secretion), biliopancreatic secretions, and duodenal nutrient absorption after an homogenized meal, as evaluated by a gastroduodenal intubation-marker perfusion technique on seven healthy volunteers. In the latter experiments, radioimmunoassays of gastrin, secretin, cholecystokinin, pancreatic polypeptide, motilin, somatostatin, gastric inhibitory polypeptide, and vasoactive intestinal polypeptide were performed serially. As compared with the control experiment, alcohol induced the following effects: marked delay of gastric emptying of solids, smaller slowing effect on gastric emptying of the liquid phase of the solid-liquid meal and of the homogenized meal; no significant change in gastric acid secretion; no change in the overall postprandial pancreatic enzyme outputs, but a delay of lipase secretion; no change in the early bile salt postprandial output, but a reduced bile salt secretion from the second postprandial hour onwards; no significant change in carbohydrate and lipid duodenal absorption; and a significantly greater postcibal gastrin release. The mechanisms for these effects of alcohol on upper digestive tract function remain to be clarified.