Downregulation of duodenal SLC transporters and activation of proinflammatory signaling constitute the early response to high altitude in humans.

Solute carrier (SLC) transporters mediate the uptake of biologically active compounds in the intestine. Reduced oxygenation (hypoxia) is an important factor influencing intestinal homeostasis. The aim of this study was to investigate the pathophysiological consequences of hypoxia on the expression and function of SLCs in human intestine. Hypoxia was induced in human intestinal epithelial cells (IECs) in vitro (0.2; 1% O2 or CoCl2). For human in vivo studies, duodenal biopsies and serum samples were obtained from individuals (n = 16) acutely exposed to 4,554 meters above sea levels. Expression of relevant targets was analyzed by quantitative PCR, Western blotting, or immunofluorescence. Serum levels of inflammatory mediators and nucleosides were determined by ELISA and LC/MS-MS, respectively. In the duodenum of volunteers exposed to high altitude we observed decreased mRNA levels of apical sodium-dependent bile acid transporter (ASBT), concentrative nucleoside transporters 1/2 (CNT1/2), organic anion transporting polypeptide 2B1 (OATP2B1), organic cation transporter 2 (OCTN2), peptide transporter 1 (PEPT1), serotonin transporter (SERT), and higher levels of IFN-γ, IL-6, and IL-17A. Serum levels of IL-10, IFN-γ, matrix metalloproteinase-2 (MMP-2), and serotonin were elevated, whereas the levels of uridine decreased upon exposure to hypoxia. Hypoxic IECs showed reduced levels of equilibrative nucleoside transporter 2 (ENT2), OCTN2, and SERT mRNAs in vitro, which was confirmed on the protein level and was accompanied by activation of ERK1/2, increase of hypoxia-inducible factor (HIF) proteins, and production of IL-8 mRNA. Costimulation with IFN-γ and IL-6 during hypoxia further decreased the expression of SERT, ENT2, and CNT2 in vitro. Reduced oxygen supply affects the expression pattern of duodenal SLCs that is accompanied by changes in serum levels of proinflammatory cytokines and biologically active compounds demonstrating that intestinal transport is affected during systemic exposure to hypoxia in humans.

Disturbed eating at high altitude: influence of food preferences, acute mountain sickness and satiation hormones.

PURPOSE: Hypoxia has been shown to reduce energy intake and lead to weight loss, but the underlying mechanisms are unclear. The aim was therefore to assess changes in eating after rapid ascent to 4,559 m and to investigate to what extent hypoxia, acute mountain sickness (AMS), food preferences and satiation hormones influence eating behavior. METHODS: Participants (n = 23) were studied at near sea level (Zurich (ZH), 446 m) and on two days after rapid ascent to Capanna Margherita (MG) at 4,559 m (MG2 and MG4). Changes in appetite, food preferences and energy intake in an ad libitum meal were assessed. Plasma concentrations of cholecystokinin, peptide tyrosine-tyrosine, gastrin, glucagon and amylin were measured. Peripheral oxygen saturation (SpO(2)) was monitored, and AMS assessed using the Lake Louis score. RESULTS: Energy intake from the ad libitum meal was reduced on MG2 compared to ZH (643 ± 308 vs. 952 ± 458 kcal, p = 0.001), but was similar to ZH on MG4 (890 ± 298 kcal). Energy intake on all test days was correlated with hunger/satiety scores prior to the meal and AMS scores on MG2 but not with SpO(2) on any of the 3 days. Liking for high-fat foods before a meal predicted subsequent energy intake on all days. None of the satiation hormones showed significant differences between the 3 days. CONCLUSION: Reduced energy intake after rapid ascent to high altitude is associated with AMS severity. This effect was not directly associated with hypoxia or changes in gastrointestinal hormones. Other peripheral and central factors appear to reduce food intake at high altitude.

Determinants of fecal continence in healthy, continent subjects: a comprehensive analysis by anal manometry, rectal barostat and a stool substitute retention test.

BACKGROUND/AIMS: This study aimed to identify anal sphincter and rectal factors that determine anorectal filling sensations and continence during rectal filling in health. METHODS: Measurements of anorectal physiology were collected from 42 continent healthy subjects participating in a prospective trial. Rectal function and capacity were assessed by barostat. Anal sphincter functions were assessed by manometry. A validated stool substitute retention test was performed in which a viscous suspension was infused into the rectum at 60 ml/min to 1,500 ml. Multivariate regression was applied to identify physiologic factors that determine anorectal sensation and continence during rectal filling. RESULTS: The volume at which first awareness of rectal filling occurred associated with age (p < 0.03), rectal capacity (p < 0.06) and anal resting pressure (p < 0.003); urgency associated with rectal capacity (p < 0.0007), anal resting (p < 0.04) and squeeze pressure (p < 0.02); volume at first incontinence with rectal capacity (p < 0.0001) and squeeze pressure (p < 0.04) and the maximum volume retained were closely correlated with rectal capacity only (p < 0.0001). CONCLUSION: Anorectal filling sensations and continence in health require a rectal reservoir of adequate capacity and effective voluntary anal sphincter function. Complementary associations between continence, motor and sensory function indicate the presence of an adaptive mechanism that enables timely, appropriate responses to events that threaten fecal continence.

Characteristics of the esophageal low-pressure zone in healthy volunteers and patients with esophageal symptoms: assessment by high-resolution manometry.

BACKGROUND: Esophageal motility studies in humans have documented a low-pressure zone (LPZ) in the area of transition from striated to smooth muscle. While preliminary studies indicate that a bolus might be retained in this area, the clinical relevance of the LPZ remains unclear. AIM: To investigate a possible relationship between esophageal symptoms and the size of the esophageal LPZ. METHODS: We reviewed high-resolution manometry (HRM) data from patients with esophageal symptoms (dysphagia, chest pain, and heartburn/regurgitation) and asymptomatic volunteers. The proximal border of the LPZ was defined as the point where the amplitude of the proximal contraction wave declined below 30 mmHg, and the distal border as the point where the distal contraction wave first increased above 30 mmHg. RESULTS: The average (+/- standard error of mean [SEM]) length of the LPZ in 44 asymptomatic individuals was 5.4 +/- 0.6 cm and did not differ (P= 0.222) from the LPZ in 64 patients with dysphagia (6.8 +/- 0.4 cm), 34 patients with chest pain (6.4 +/- 0.6 cm), and 42 patients with gastroesophageal reflux disease (GERD) symptoms (7.0 +/- 0.6 cm). These results did not change when the length of the LPZ was corrected for total esophageal length. The time width of the LPZ in asymptomatic individuals (1.6 +/- 0.2 s) was shorter than in patients with dysphagia and GERD symptoms (dysphagia 2.4 +/- 0.2 s, GERD symptoms 2.8 +/- 0.3 s). CONCLUSION: A time delay between the proximal and distal esophageal contraction waves might be a meaningful variable in GERD and dysphagia.

[Every mountain too high when Nausea strikes: gastrointestinal function at high altitude]. / Wenn der Berg auf den Magen schlägt: Magen-Darm-Funktion in der Höhe.

For people unaccustomed to high altitude, exposure to height often leads to Acute Mountain Sickness, with headaches, difficulty breathing and gastrointestinal symptoms. Nausea and loss of appetite may result in less calorie intake and weight loss. At altitudes greater than 4000 m about 50-80% of people are affected. After only short exposure, gastrointestinal mucosal lesions can occur, potentially leading to gastrointestinal bleeding and lessened hunger. Patients with inflammatory bowel disorders may develop an acute exacerbation. At high altitude, an induction of numerous metabolic processes can be observed, including increased iron absorption. While the pathophysiology of hypobaric hypoxia has been well documented for the respiratory and cardiovascular system, this Mini-Review summarizes the current literature concerning the gastrointestinal function in high altitude.

Pour les personnes non habituées à, l'exposition à de hautes altitudes provoque souvent le mal aigu des montagnes, avec des céphalées, de la dyspnée et des symptômes digestifs. Des nausées et une perte de l'appétit peuvent entrainer une diminution de l'apport calorique et une perte de poids. À des altitudes supérieures à 4000 m, approximativement 50­80% des gens sont en sont affectés. Même après une exposition de courte durée des lésions de la muqueuse gastrointestinale peuvent apparaître, provoquant potentiellement un saignement gastrointestinal et une perte de l'appétit. Les malades souffrant d'affections inflammatoires du tube digestif peuvent être sujets à une exacerbation aiguë de leur affection. A haute altitude l'induction de nombreux processus métaboliques peuvent être observés, y compris une augmentation de l'absorption du fer. Alors que la physiopathologie de l'hypoxie hypobare a été bien documentée pour le système respiratoire et le système cardiovasculaire, il n'en est pas de même pour le système digestif. La présente revue a pour but de résumé ce qui est connu en ce qui concerne l'altitude et la fonction gastrointestinale.

Lactose malabsorption and intolerance: pathogenesis, diagnosis and treatment.

Lactose malabsorption is a common condition caused by reduced expression or activity of lactase in the small intestine. In such patients, lactose intolerance is characterized by abdominal symptoms (e.g. nausea, bloating, and pain) after ingestion of dairy products. The genetic basis of lactose malabsorption is established and several tests for this condition are available, including genetic, endoscopic, and H2-breath tests. In contrast, lactose intolerance is less well understood. Recent studies show that the risk of symptoms after lactose ingestion depends on the dose of lactose, lactase expression, intestinal flora, and sensitivity of the gastrointestinal tract. Lactose intolerance has recently been defined as symptoms developing after ingestion of lactose which do not develop after placebo challenge in a person with lactose maldigestion. Such blinded testing might be especially important in those with functional gastrointestinal diseases in whom self-reported lactose intolerance is common. However, placebo-controlled testing is not part of current clinical practice. Updated protocols and high-quality outcome studies are needed. Treatment options of lactose intolerance include lactose-reduced diet and enzyme replacement. Documenting the response to multiple doses can guide rational dietary management; however, the clinical utility of this strategy has not been tested. This review summarizes the genetic basis, diagnosis, and treatment of lactose malabsorption and intolerance.