The reductions in gastrointestinal (GI) blood flow, gastric emptying rate, intestinal absorption, and GI barrier function, accompanying increases in GI symptoms, can occur, and dehydration likely exacerbates these problems. Intestinal perfusion studies in humans have found that exercise at intensities below -70%-80% maximal oxygen consumption (VO2max) appear to affect intestinal absorption of infused solutions. Very little research has studied the direct effect of dehydration during exercise on intestinal absorption. The overall effect during exercise would likely be a greater degree of hyper-thermia, increased cardiovascular strain, altered metabolic function, and central nervous system dysfunction. Increased GI temperature and reductions in GI blood flow will likely be exacerbated by dehydration further decreasing gastric emptying and, thus, intestinal absorption rates. GI symptoms can result from reduced gastric emptying, intestinal absorption, and GI barrier dysfunction that will likely inhibit fluid intake, also promoting higher core body temperatures and modified metabolism.

Previous studies have shown that acute aspirin use causes increased intestinal permeability to ingested permeability probes. The purpose of the present studies was to determine whether acute aspirin use also increases concentrations of urinary physiological markers of intestinal barrier dysfunction. The urinary markers were: 1) D‐lactate (produced by intestinal bacteria; a marker of intestinal barrier dysfunction if increased in the plasma or urine), 2) intestinal fatty acid binding protein (I‐FABP; a marker of small intestinal enterocyte damage), and 3) claudin‐3 (an intestinal tight junction protein). Two studies were conducted and involved ingestion of aspirin (975 mg) or placebo the night before and the morning of an experiment. Eight healthy subjects participated in each study. Six hours after the morning dose of aspirin or placebo, subjects provided a urine sample. In the first study, the urine was assayed for D‐lactate. In the second study, the urine was assayed for I‐FABP and claudin‐3. No significant differences were found between aspirin and placebo experiments for D‐lactate in study 1, or for I‐FABP or claudin‐3 in study 2. These results indicate that urinary concentrations of D‐lactate, I‐FABP, and claudin‐3 do not increase with acute aspirin use.

The primary purpose of this study was to determine the aspirin dose that increases gastrointestinal (GI) permeability. A pilot study was also conducted to determine whether the menstrual cycle affects GI permeability. Both portions of the study involved 4 experimental conditions. For the aspirin portion, 8 subjects ingested 0 mg, 325 mg, 650 mg, or 975 mg of aspirin the night before and the morning of an experiment. For the menstrual cycle pilot study, 5 female subjects with regular menstrual cycles were tested for GI permeability on the same day each week for 4 weeks. GI permeability was assessed by the urinary excretion of ingested probes. Sucrose (5 g) was used to determine gastroduodenal permeability. Lactulose (5 g) and rhamnose (2 g) were used to assess small intestinal permeability via the lactulose-to-rhamnose urinary excretion ratio (L/R). The data indicated that the menstrual cycle had no effect on GI permeability. In contrast, gastroduodenal permeability was significantly (P < 0.008) increased following a dose of 650 mg aspirin and small intestinal permeability (L/R) was significantly (P < 0.008) increased following a dose of 975 mg aspirin. These results suggest healthy individuals should be cautious even with acute aspirin use as it may result in GI barrier dysfunction.

Editor-in-Chief Tommy Boone, PhD, MBA Review Board Todd Astorino, PhD Julien Baker, PhD Steve Brock, PhD Lance Dalleck, PhD Eric Goulet, PhD Robert Gotshall, PhD Alexander Hutchison, PhD M. Knight-Maloney, PhD Len Kravitz, PhD James Laskin, PhD Yit Aun Lim, PhD Lonnie Lowery, PhD Derek Marks, PhD Cristine Mermier, PhD Robert Robergs, PhD Chantal Vella, PhD Dale Wagner, PhD Frank Wyatt, PhD Ben Zhou, PhD

The purpose of this study was to determine the effect of Lactobacillus acidophilus (L. acidophilus; LA) on aspirin‐induced gastrointestinal (GI) permeability. Fourteen subjects (8 male; 6 female; age = 21 ± 0.4 yrs) completed three trials: 1) LA placebo/aspirin, 2) LA placebo/aspirin placebo, and 3) LA/aspirin. Subjects ingested either LA (10 billion colony forming units per day) or placebo for seven days. On the evening of the sixth day and morning of the seventh day they ingested aspirin (1300 mg) or aspirin placebo. Subjects then drank a solution (150 ml) containing 5 g sucrose, 5 g lactulose, and 2 g rhamnose and urine was collected for 5 hours. Gastroduodenal permeability was determined from urinary sucrose excretion and small intestinal permeability was determined from the lactulose‐to‐rhamnose urinary excretion ratio. Gastroduodenal permeability was significantly (p < 0.017) greater in the LA placebo/aspirin and LA/aspirin trials compared to the LA placebo/aspirin placebo trial. Small intestinal permeability was also significantly (p < 0.017) greater in the LA placebo/aspirin and LA/aspirin trials compared to the LA placebo/aspirin placebo trial. These results indicate that aspirin ingestion increases GI permeability and 7 days of LA does not reduce this effect. Supported by the Gatorade Sports Science Institute. Danisco USA, Inc. provided the L. acidophilus.

The intestinal barrier is formed by enterocyte membranes, tight junctions, secreted mucus, and immunologic factors, such as tissue macrophages. Dysfunction of this barrier can be caused by different types of stress (e.g., physiological, pathological, psychological, pharmacological) and can lead to increased intestinal permeability. Increased permeability to endotoxin, a component of the walls of gram-negative bacteria, causes local or systemic inflammatory reactions, or both. The immune response(s) can then promote more serious conditions. Exertional heat stroke is an example of such a condition. During severe exercise-heat stress, possibly combined with other stresses, reductions in intestinal blood flow, direct thermal damage to the intestinal mucosa, or both, can cause intestinal barrier disruption and endotoxemia. The resulting inflammatory response is believed to be involved in altered thermoregulation and multiple-organ dysfunction. Possible means for preventing or attenuating, or both, many stress-induced intestinal barrier problems include environmental, pharmaceutical, or nutritional approaches, or a combination of these.

Lambert, GP, Lanspa, SJ, Welch R, Shi, X. Combined Effects of Glucose and Fructose on Fluid Absorption from Hypertonic Carbohydrate-Electrolyte Solutions. JEPonline 2008;11(2):46-55. This study examined the effect of glucose and fructose, compared to glucose alone on water absorption from hypertonic carbohydrateelectrolyte solutions (CES) in the small intestine. Six solutions were perfused into the duodenojejunum and water flux was determined using the segmental perfusion technique. The solutions were: 1) 6% glucose, 2) 3% glucose + 3% fructose, 3) 8% glucose, 4) 4% glucose + 4% fructose, 5) 10% glucose, or 6) 5% glucose + 5% fructose. All solutions also contained 20 mEq sodium, 3 mEq potassium and flavoring/coloring to simulate commonly ingested CES. Water flux was related to osmolality (r = 0.79) and the 6% glucose, 3% glucose + 3% fructose, and 4% glucose + 4% fructose solutions promoted a greater (P < 0.05) water absorption rate than the 8% glucose, 10% glucose and 5% glucose + 5% fructose solutions. These results indicate increasing osmolality negatively affects fluid absorption, and this is attenuated in a moderately hypertonic 8% CES by using both fructose and glucose compared to glucose alone.

The purpose of this study was to determine gastrointestinal (GI) permeability during prolonged treadmill running (60 min at 70 % V.O2max) with and without fluid intake (3 ml/kg body mass/10 min). Twenty runners (11 males, 9 females; age = 22 +/- 3 (SD) yrs; mean V.O2max = 55.7 +/- 5.0 ml/kg/min) completed four experiments: 1) rest, 2) running with no fluid (NF), 3) running with ingestion of a 4 % glucose solution (GLU), and 4) running with ingestion of a water placebo (PLA). To determine GI permeability, subjects also drank a solution containing 5 g sucrose (S), 5 g lactulose (L), and 2 g rhamnose (R) immediately prior to each trial. Gastroduodenal permeability was determined by urinary S excretion, while small intestinal permeability was determined by the L/R excretion ratio. Percent body mass loss (i.e., dehydration) was negligible during rest, GLU and PLA, while NF resulted in a 1.5 % loss of body mass (p < 0.05). Gastroduodenal and intestinal permeability were significantly (p < 0.008) increased in NF compared to rest. There were no other differences in GI permeability. These results indicate that fluid restriction during 1 h of steady-state running increases GI permeability above resting levels.

This study assessed tolerance to fluid ingestion with repeated sessions of drinking while running. Seven trained distance runners (age 22 ± 2 yr; VO2max = 54.4 ± 7.1 ml/kg/min) performed six 90 min treadmill runs (~1/week) at 65% VO2max while ingesting a glucose‐electrolyte solution. During run 1, subjects drank ad libitum every 10 min and sweat rate was determined. On runs 2‐6, subjects drank every 10 min at a rate to match the sweat rate determined in run 1. Stomach comfort (1–4 scale) and other gastrointestinal symptoms were also assessed every 10 min. Gastric emptying rate was determined in runs 2 and 6. Subjects consumed significantly (P < 0.05) more fluid during runs 2–6 (mean ± SD; 1247 ± 162 ml), than during run 1 (508 ± 476 ml). Stomach comfort improved (P < 0.05) on runs 5 and 6 (1.7 ± 0.5 units) compared to run 2 (2.3 ± 0.5 units). Gastric emptying rate was not different between runs 2 and 6 (12.0 ± 1.9 ml/min vs. 12.3 ± 2.3 ml/min, respectively). These results indicate repeated sessions of drinking at a rate that matches sweat rate improves stomach comfort, however, gastric emptying rate does not change under such conditions. Supported by the Gatorade Sports Science Institute

Reduced intestinal blood flow and high intestinal temperatures during exercise-heat stress can lead to intestinal barrier dysfunction. Such dysfunction may increase intestinal permeability to endotoxin. During exercise-heat stress, intestinal barrier dysfunction and endotoxemia can produce gastrointestinal symptoms and increased production of pro-inflammatory cytokines. Such problems may be a warning sign ('canary in the coal mine') for the onset of exertional heat stroke. Failure to heed such a warning may culminate in problems indicative of exertional heat stroke such as circulatory collapse and multiple organ failure. Prior exposure to exercise-heat stress may, however, be a protective mechanism.

This study was conducted to determine the effects of aspirin or ibuprofen on gastrointestinal permeability when combined with exercise. Eight runners completed three 60 min treadmill runs at 70 % VO(2max). For 24 hours prior to each run, subjects ingested aspirin (2 x 325 mg), ibuprofen (2 x 200 mg), or placebo capsules every 6 hours. Immediately before each run, a solution containing 5 g sucrose, 5 g lactulose, and 2 g rhamnose was ingested. Urine produced during each run, and for 4 h afterwards was collected. Urinary excretion of sucrose is an indicator of gastroduodenal permeability. The excretion ratio of lactulose-to-rhamnose assesses small intestinal permeability. Sucrose excretion (%) was greater (p < 0.017) for aspirin (0.37 [0.2 - 0.97]) compared to placebo (0.09 [0.05 - 0.30]) or ibuprofen (0.22 [0.1 - 0.39]) and sucrose excretion for ibuprofen was greater than placebo. The lactulose-to-rhamnose ratio was greater for aspirin (0.09 [0.08 - 0.30]) than placebo (0.065 [0.04 - 0.08]) however ibuprofen (0.08 [0.06 - 0.19]) was not different from aspirin or placebo. These results indicate that with prolonged running, gastroduodenal permeability is increased if aspirin or ibuprofen is used prior to such exercise. Furthermore, aspirin promotes greater gastroduodenal permeability and also increases small intestinal permeability.

Intestinal absorption of fluids is influenced by the osmolality and substrate composition of the solutions. This study examined the effect of glucose (G) and fructose (F), compared to G alone, on intestinal absorption of hypertonic carbohydrate-electrolyte solutions (CES). Solutions were perfused into the duodenjejunum at 15 ml/min using the segmental perfusion technique. The solutions were: 6% G (n = 5), 3% G + 3% F (n = 6), 8% G (n = 6), 4% G + 4% F (n = 6), 10% G (n = 4) and 5% G + 5% F (n = 4). Water flux was strongly related (r = 0.79) to test segment osmolality in the study. The 6% G, 3% G + 3% F, and 4% G + 4% F solutions promoted significantly (P < 0.05) more fluid absorption than the 8% G, 10% G and 5% G + 5% F solutions. Mean fluid absorption for all solutions containing G + F tended (p = 0.06) to be greater than for solutions only containing G (−2.1 ± 1.1 vs. 0.8 ± 1.0 ml/h/cm, respectively; negative value indicates absorption). These data indicate that osmolality plays a major role in fluid absorption of hypertonic CES, the presence of both G and F in hypertonic CES can attenuate the effect of higher osmolality under certain conditions, and G + F tends to promote greater fluid absorption overall from hypertonic solutions than when only G is present. Supported by the Quaker Oats Company.

The purpose of this study was to determine the effects of exercise intensity on active and passive intestinal glucose absorption. Eight trained runners (age = 23 +/- 2 y; VO2max = 62.1 +/- 5.8 mL x kg(-1) x min(-1)) performed a 1 h resting experiment and three 1 h treadmill experiments at 30, 50, or 70% VO2max in a thermoneutral environment. Immediately prior to each experiment, euhydrated subjects ingested a solution containing two non-metabolizable glucose analogs, 3-O-methyl-D-glucose (3MG; actively absorbed; 5 g) and D-xylose (passively absorbed; 5 g). During the following 5 h, all urine was collected and the amount of 3MG and D-xylose in the urine was determined. Using repeated measures ANOVA, a significant (P < 0.05) reduction in urinary excretion of each carbohydrate was observed at 70% VO2max compared to the other intensities suggesting that both active and passive intestinal absorption of glucose may be reduced during prolonged running at this intensity.

Abstract Many farmers experience chronic bronchitis, airflow obstruction, and asthma. It is thought that these respiratory problems may be related to workplace inhalation of organic dust containing endotoxin. The purpose of this study was to determine whether whole blood cytokine responsiveness to endotoxin is associated with airflow disorders (i.e., airflow obstruction, chronic bronchitis, and doctor-diagnosed asthma). Farmers (N = 95) were recruited from a rural cohort study and completed a respiratory symptom and history questionnaire, spirometry, and blood sampling. Blood was incubated 24 hours in the presence and absence of endotoxin and supernatants were analyzed for TNF-á, IL-1â, IL-6, and IL-8. Hypoor hyper-responsiveness to endotoxin was based on whether cytokine values were in the lower or upper 10% of the group range, respectively. A significant association existed between TNF-á hyper-responsiveness and chronic bronchitis. These results indicate that the whole blood cytokine assay may be useful to identify individual responsiveness to endotoxin, and may provide an additional diagnostic tool to evaluate persons potentially at risk for developing chronic bronchitis following exposure to organic dust in the workplace.

Arizona Respiratory Center and Departments of Internal Medicine (TDL, MMV) and Pediatrics (FDM), College of Medicine, University of Arizona, Tucson; Department of Exercise Science and Athletic Training (PL), Creighton University, Omaha, NE, Department of Internal Medicine, Pulmonary and Critical Care Medicine Section (SVE, DJR), University of Nebraska Medical Center, Omaha, NE and Department of Occupational and Environmental Health (JM), College of Public Health, University of Iowa, Iowa City, IA

Reduced splanchnic blood flow and hyperthermia during exercise-heat stress can produce gastrointestinal barrier dysfunction and increased gastrointestinal permeability. This may allow endotoxin to enter the internal environment, causing local and systemic immune responses. These responses may be involved in the cause and outcome of exertional heatstroke. Countermeasures may reduce gastrointestinal permeability and possibly exertional heatstroke occurrence and outcome.

Rationale and Objectives: Farmers experience airway obstruction, which may be attributable in part to endotoxin inhalation. CD14 is a receptor for endotoxin. Materials and Methods: Based on our findings of increased circulating CD14 associated with the CD14/ -159 T allele, we hypothesized that carriers of this allele would have decreased lung function among endotoxin-exposed individuals. CD14/-159TT farmers (n = 19) had significantly lower lung function as measured by FEV1 (p = 0.028) and mean forced expiratory flow during the middle half of the FVC (FEF25-75) (P = 0.05) compared with farmers with the C allele (n = 78). Also, farmers with the CD14/-1619GG genotype (n =11) were associated with lower lung function (FEV1, p = 0.008; FEF25-75, p = 0.009) compared with farmers with the A allele (n = 86). Results: No association between CD14/-550 and lung function was observed (FEV1, p = 0.32; FEF25-75, P = 0-11). Increased prevalence of wheezing was reported in farmers homozygous for CD14/-159T (p = 0.013) or CD14/-1619G (p = 0.019) compared with farmers with the CC or AA genotype, respectively. No association was found between TLR4/Asp299GIy and lung function or wheeze. Conclusion: We conclude that the CD14/-159 or CD14/-1619 loci may play a role in modulating lung function and wheeze among agricultural workers.