Combat-training stress pro-inflammatory markers intestinal permeability

Combat-training stress: pro-inflammatory markers linked to increased intestinal permeability and gastrointestinal symptoms

Combat-training stress – pro-inflammatory markers – increased intestinal permeability

A study published in the February 2013 issue of Alimentary Pharmacology and Therapeutics reports that soldiers participating in as little as 6 weeks of combat training had high stress; anxiety and depression levels combined with gastrointestinal (GI) symptoms, pro-inflammatory immune activation and increased intestinal permeability.

The most frequently reported symptoms unrelated to trauma in soldiers in high-pressure operational situations are gastrointestinal (GI), including abdominal pain, diarrhoea, constipation and nausea besides a range of cognitive changes. Many cases of diarrhoea in the battlefield may be infectious, but often an infectious cause is not documented and stress-related functional GI disorders (FGID), either postinfectious or not, are a legitimate differential diagnosis. 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.

Data from the Gulf, Iraq and Afghanistan conflicts have highlighted the significance of GI symptoms on military efficiency and manpower loss on the front lines. However, underlying mechanisms, apart from infectious diarrhea, have not been extensively investigated. Although considerable evidence exists on the late consequences of combat stress and anxiety in veterans, much less is known about the effects of ongoing and protracted stress in the battlefield. Also, the stress responses related to the GI-tract have been mainly characterized using animal models, and little is known about the long-term effects of stress in the battlefield.

The hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system are the two major stress systems in humans and provide bidirectional neuroendocrine links between the brain and gut. Activation of the HPA axis during acute stress results in increased secretion of corticotropin-releasing hormone (CRH), which can modulate gut neuroimmune responses directly as well as via mucosal immune cells and inflammatory mediators, such as tumour necrosis factor (TNF)-α and interleukin-1 and -6 (IL-1, IL-6). This can lead to disruption of intestinal barrier integrity and further release of inflammatory mediators.

In this prospective, longitudinal study, Li and colleagues from the Neurogastroenterology Research Unit, Department of Medicine, National University of Singapore, Singapore, investigated 37 male army medical rapid response troops, and monitored their GI symptoms, stress markers, segmental intestinal permeability using the 4-sugar test (sucrose, lactulose, mannitol and sucralose) and immune activation were assessed during the 4th week of an intense combat-training and a rest period.

The authors demonstrate that protracted combat-training stress induced GI symptoms associated with increased upper and lower intestinal barrier permeability and elevated systemic levels of interleukin (IL)-6, and tumor necrosis factor (TNF)-α. Notably, the subgroup that had suffered the most GI symptoms also scored higher in anxiety, depression and stress.

IBS-like symptoms, such as abdominal pain and discomfort, diarrhoea and/or constipation developed de novo in 70% of previously asymptomatic soldiers during combat-training and persisted in 30% into the posttraining rest period 12 days later.

Previous research indicates a multidirectional link between stress, immune activation, increased IP, visceral hypersensitivity and GI symptoms. In this study, increased permeability was shown in all segments of the GI tract using commonly used, non-invasive sugar markers. Thus, combat-training increased sucrose excretion approximately 160% above resting levels, indicating substantially elevated proximal GI permeability.

The study also confirmed the co-incidence of increased stress-related cognitive and systemic factors and elevated pro-inflammatory cytokines, and demonstrated the novel link to abnormal intestinal permeability in ongoing mixed physical and psychological stress in humans.

This human study indicates that protracted and intense physical and psychological stress in soldiers may alter GI permeability and thus, may elicit clinical GI symptoms. The authors suggest that the responsiveness of an individual’s stress–neuroimmune axis at rest, and during stress, influences downstream GI permeability changes and related GI symptoms and vice versa.

One possible mechanism is that the increased intestinal permeability is most likely due to stress-driven neuroimmune activation, with subsequent increases of systemic or local production of   TNF-α and IL-6. This, in turn, leads to disruption of intestinal barrier integrity and further release of inflammatory mediators.

In conclusion, this study suggests that combat-training stress induces GI symptoms associated with increased upper and lower intestinal barrier permeability and elevated systemic pro-inflammatory cytokine concentrations. According to the authors, the identification of a subgroup of individuals with greater propensity for GI adverse events, may allow selection of those at-risk of long-term effects of stress, such as functional GI disorders, as well as the development of protective measures.

Source: Aliment Pharmacol Ther. 2013, 37:799. doi: 10.1111/apt.12269. Epub 2013 Feb 24.

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