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J Proteome Res. 2015 Nov 6;14(11):4734-42. doi: 10.1021/acs.jproteome.5b00603. Epub 2015 Oct 27.

Gastrointestinal Symptoms and Altered Intestinal Permeability Induced by Combat Training Are Associated with Distinct Metabotypic Changes.

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Department of Pharmacy, Faculty of Science, National University of Singapore , 18 Science Drive 4, Singapore 117543, Singapore.
Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore , 1E Kent Ridge Road, Singapore 119228, Singapore.
Brain-Gut Research Group , Bubenbergplatz 11, CH-3011 Bern, Switzerland.
Combat Care Laboratory, DSO National Laboratories , 20 Science Park Drive, Singapore 118230, Singapore.
Department of Medicine, Division of Digestive Diseases and Nutrition, Rush University Medical Center , 1653 West Congress Parkway, Chicago, Illinois 60612, United States.


Physical and psychological stress have been shown to modulate multiple aspects of gastrointestinal (GI) physiology, but its molecular basis remains elusive. We therefore characterized the stress-induced metabolic phenotype (metabotype) in soldiers during high-intensity combat training and correlated the metabotype with changes in GI symptoms and permeability. In a prospective, longitudinal study, urinary metabotyping was conducted on 38 male healthy soldiers during combat training and a rest period using gas chromatography-mass spectrometry. The urinary metabotype during combat training was clearly distinct from the rest period (partial least-squares discriminant analysis (PLSDA) Q(2) = 0.581), confirming the presence of a unique stress-induced metabotype. Differential metabolites related to combat stress were further uncovered, including elevated pyroglutamate and fructose, and reduced gut microbial metabolites, namely, hippurate and m-hydroxyphenylacetate (p < 0.05). The extent of pyroglutamate upregulation exhibited a positive correlation with an increase in IBS-SSS in soldiers during combat training (r = 0.5, p < 0.05). Additionally, the rise in fructose levels was positively correlated with an increase in intestinal permeability (r = 0.6, p < 0.005). In summary, protracted and mixed psychological and physical combat-training stress yielded unique metabolic changes that corresponded with the incidence and severity of GI symptoms and alteration in intestinal permeability. Our study provided novel molecular insights into stress-induced GI perturbations, which could be exploited for future biomarker research or development of therapeutic strategies.


combat stress in soldiers; intestinal permeability; irritable bowel syndrome; metabolomics; metabonomics

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