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

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


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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anxiety / diagnosis
  • Anxiety / physiopathology
  • Anxiety / urine*
  • Biomarkers / urine
  • Depression / diagnosis
  • Depression / physiopathology
  • Depression / urine*
  • Fructose / urine*
  • Gas Chromatography-Mass Spectrometry
  • Hippurates / metabolism
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestines / physiopathology
  • Irritable Bowel Syndrome / diagnosis
  • Irritable Bowel Syndrome / physiopathology
  • Irritable Bowel Syndrome / urine*
  • Least-Squares Analysis
  • Longitudinal Studies
  • Male
  • Metabolome*
  • Military Personnel
  • Permeability
  • Phenylacetates / metabolism
  • Prospective Studies
  • Pyrrolidonecarboxylic Acid / urine*
  • Stress, Physiological
  • Stress, Psychological / diagnosis
  • Stress, Psychological / physiopathology
  • Stress, Psychological / urine*
  • Young Adult


  • Biomarkers
  • Hippurates
  • Phenylacetates
  • Fructose
  • 3-hydroxybenzeneacetic acid
  • Pyrrolidonecarboxylic Acid
  • hippuric acid