The intestinal barrier is an essential component in maintaining human health, and several diseases and disorders have been associated with a disrupted intestinal barrier function. To evaluate the efficacy of different interventions intended to strengthen intestinal barrier function, there is a need for both appropriate challenge models as well as easily accessible biomarkers. The overall aim of this thesis was to explore new challenge models of human gut barrier as well as to investigate potential biomarkers to assess its function. Paper I shows that a sauna-induced dehydration protocol increased intestinal permeability without causing major damage to the intestinal barrier, suggesting it as a potential challenge model of the gut barrier. Paper II shows that the acute intense psychological stress generated by skydiving did not affect intestinal permeability, indicating that gut barrier disruption likely requires sustained psychological stress. Paper III describes the systemic effect of an established strenuous exercise challenge on various biomarkers of gut barrier and immune function, as well as their correlations. Paper IV used a cohort of patients with diarrhoea-predominant irritable bowel syndrome (IBS-D) to show how several biomarkers linked to increased permeability correlated with other markers associated with IBS-D. All papers also explored potential surrogate permeability markers for the urinary excretion ratio of lactulose and rhamnose which is a common in vivo method for measuring small intestinal permeability. In conclusion, this thesis provides insights into different challenge models of the human intestinal barrier function and addresses important considerations about the application of currently used biomarkers for its assessment.
The intestinal barrier plays a crucial role in maintaining gut health, and an increased permeability has been linked to several intestinal and extra-intestinal disorders. There is an increasing demand for interventions aimed at strengthening this barrier and for in vivo challenge models to assess their efficiency. This study investigated the effect of sauna-induced dehydration on intestinal barrier function (clinicaltrials.gov: NCT03620825). Twenty healthy subjects underwent three conditions in random order: (1) Sauna dehydration (loss of 3% body weight), (2) non-steroidal anti-inflammatory drug (NSAID) intake, (3) negative control. Intestinal permeability was assessed by a multi-sugar urinary recovery test, while intestinal damage, bacterial translocation and cytokines were assessed by plasma markers. The sauna dehydration protocol resulted in an increase in gastroduodenal and small intestinal permeability. Presumably, this increase occurred without substantial damage to the enterocytes as plasma intestinal fatty acid-binding protein (I-FABP) and liver fatty acid-binding protein (L-FABP) were not affected. In addition, we observed significant increases in levels of lipopolysaccharide-binding protein (LBP), IL-6 and IL-8, while sCD14, IL-10, IFN-ɣ and TNF-α were not affected. These results suggest that sauna dehydration increased intestinal permeability and could be applied as a new physiological in vivo challenge model for intestinal barrier function.
Funding agency:
Örebro University
Background and aim: Psychological stress has been shown to increase intestinal permeability and is associated with the development of gastrointestinal disorders. This study aimed to investigate skydiving as an alternative model to analyse the effect of acute psychological stress on intestinal barrier function.
Materials and methods: Twenty healthy subjects participated in a tandem skydive followed by a negative control visit, of which 19 (9 females and 10 males, 25.9 ± 3.7 years) were included in the study. Intestinal permeability was assessed by a multi-sugar urinary recovery test. Sucrose recovery and lactulose/rhamnose ratio in 0-5h urine indicated gastroduodenal and small intestinal permeability, respectively, and sucralose/erythritol ratio in 5-24h urine indicated colonic permeability. Blood samples were taken to assess markers associated with barrier function. This study has been registered at ClinicalTrials.gov (NCT03644979) on August 23, 2018.
Results: Skydiving resulted in a significant increase in salivary cortisol levels directly after skydiving compared to the control visit. Cortisol levels were still increased two hours after landing, while cortisol levels before skydiving were not significantly different from the baseline at the control visit. Skydiving did not induce a significant increase in gastroduodenal, small intestinal or colonic permeability. There was also no significant increase in plasma intestinal and liver fatty acid-binding proteins, suggesting no damage to the enterocytes.
Discussion: These results show that the acute intense psychological stress induced by skydiving does not affect intestinal permeability in healthy subjects. Future models aiming to investigate the effect of stress on human intestinal barrier function should consider a more sustained exposure to the psychological stressor.
Faculty of Medicine and Health, Örebro University ORU2016/01178