Linking stress and inflammation – is there a missing piece in the puzzle?

KEYWORDS:

• Stress
• stress sensitivity
• inflammation
• gut microbiome
• hypothalamic-pituitary-adrenal axis

The stress response to adverse stimuli is a useful and vital adaptation to challenges in the environment. This permits organisms to adjust their reaction to stressors, form more efficient responses, maintain homeostasis, and physiologically prepare themselves for future exposure to those and related physiological and psychosocial triggers. However, acute and chronic stress each may have adverse effects, some of which appear to produce long-lasting negative outcomes including immunosuppression, cancer, metabolic, and psychiatric disorders [1,2]. Stress produces a response pattern known as general adaptation syndrome (GAS), which was described by Selye as having three phases: alarm, resistance, and exhaustion [3]. GAS systems are activated briefly during acute stress in the alarm phase involving adrenal epinephrine release and its related system-wide changes in physiological state (increased vasoconstriction, tachycardia, gluconeogenesis, enhanced central nervous system [CNS] catecholamine release). Afterward, compensatory mechanisms reestablish a normal state unless intense stressors are experienced where more permanent physiological alterations can be established [1,4]. In contrast, the main response pattern from chronic/sub-chronic stress (resistance phase) is activation of the hypothalamic-pituitary-adrenal (HPA) axis and persistent elevated secretion of cortisol [5].

Elevated and maintained serum glucocorticoid levels result in a resistance effect to stressors (Selye’s second phase, which is adaptive and beneficial). However, over the long term, a reduction (Selye’s third phase) in cortisol results from negative feedback by acting on hypothalamic glucocorticoid receptors, reducing ACTH release [6]. Essentially, this is an attempt by the HPA system to reestablish homeostasis from a hypercortisolic state. Failure can result in long-term hypercortisolism, which is maladaptive, depresses immune response, and increases inflammation [7,8].

It should be noted that inflammation is a normal part of physiology, which assists the cellular immune system, destroys bacterial and necrotic cells, eliminates cellular debris, and activates tissue repair. A parallel system to cellular immunity and contributing to inflammation response is the complement fixation cascade, a set of self-regulating pathways that can be activated by and can also activate the immune response. However, the extreme activation of the inflammatory response can generate a cytokine storm, which can result in life-threatening events leading to multiple organ failure [9].

Any inflammatory response will typically resolve through homeostatic feedback and resume normal inflammatory states. In contrast, a chronic state of inflammation appears to be maintained through processes that thwart the mechanisms tasked with maintaining what we regard as normative human physiology [10]. As a result, long-term elevated serum cytokines and cortisol steadily lead to allostatic alterations throughout the body. If normative inflammation states are viewed as a set of functions within a Lorenz space, these functions follow a trajectory orbiting a Lorenz attractor, which is essentially the sum of normal homeostatic mechanisms. Maintenance of altered, chronic inflammation-induced allostatic states, however, suggests that a new Lorenz attractor emerges around which inflammation mechanisms orbit and are stabilized. What this new attractor is has been a matter of debate (for example, there are strong associations between chronic inflammation and low socioeconomic status or excessive body fat [11]) and much work has been directed toward trying to identify it [12] as a potential target for pharmacological intervention.

Early life stress has been found to permanently alter the HPA axis regulation [13,14], imposes developmental changes in enteric glia-mast cell communication [15], and is linked to the development of irritable bowel syndrome in adulthood [16]. Several studies have provided evidence that early life stress also imposes epigenetic alterations that drive sensitization to psychosocial stress and increased risk of psychiatric disorders (reviewed in [17]) and may well be the pavement from which later inflammation and immune dysregulation originates. Moreover, lipid signaling products of bacteria are surprisingly potent (EC50s mostly in the low μM range), receptor-specific, and secreted mixtures of these chemicals are bacterial species-specific [18]. Therefore, any reduction in intestinal microbial alpha diversity, alteration in community species profile, or modifications of bacterial metabolism would likely produce global changes across a wide range of targets (e.g. toll-like receptors, G-coupled protein receptors, forkhead box p3, etc.). We suggest that this stabilizing mechanism for chronic inflammatory states consists of three components: a set of epigenetic predisposing factors, loss of colonic tight junction fidelity, and an alteration in commensal organisms.

As stress acts as a promoting factor in the development of chronic inflammation [2,12], it therefore follows that having an exaggerated and/or low-threshold stress response (stress sensitivity), whether innate or resulting from traumatic experience (for a listing of known epigenetic markers associated with trauma, see [19]), would make an individual more prone to develop chronic inflammation. The genetic basis for an innate sensitivity to stress has been difficult to ascertain and likely (at least partially) resides in an epigenetic mechanism since a recent meta-analysis failed to discover any clear genotypic pattern between adverse life events and risk for depression [20]. However, a genetic basis may still be likely in that different alleles within a gene family have different potentials for methylation (allele-specific methylation; ASM [21]). A wealth of evidence has also been accumulated establishing a direct effect of corticotrophin-releasing hormone (CRH), the PVN hormone at the headwaters of the HPA axis, on mast cell degranulation and increased serum histamine [22,23]. A recent meta-analysis of irritable bowel syndrome patient studies found increased colonic mast cell counts and the presence of T-cells (CD3+) in intestinal epithelium were a common feature [24]. Furthermore, a wide range of environmental chemical stressors (detergents, organic solvents, microparticulates) are capable of not only altering the intestinal microbiota but can also decrease intestinal epithelial tight junction expression [25]. Loss of tight junctions increases gut permeability and access of bacterial and ingested products to the circulatory system, resulting in immune activation, inflammation, and endocrine disruption.

In our laboratory, we have evidence of inborn stress sensitivity through work with mouse models that represent opposite poles of the social behavioral spectrum (dominant [DOM] and submissive [SUB] behavior), derived from a parent line through selective breeding based on a food competition paradigm [26]. Mice that are socially submissive (SUB mouse line) have an increased response to stressors and tendency to develop depressive-like states and chronic inflammation resulting in age-dependent splenomegaly and shortened lifespan [27]. Despite an established association between stress and the development of chronic inflammation, a mechanistic link explaining this association has been lacking.

Previous attempts to resolve this gap in knowledge have invoked body-wide alterations in physiology set points as a result of acute or chronic stress without implicating a specific mechanism, however recent evidence suggests a governing factor may come from a previously unappreciated source: intestinal commensals [28]. Here, we posit that stress-induced alterations in the gut microbiome are the underlying basis for stabilization of adverse, chronic inflammatory states.

Evidence for the importance of the gut microbiome in maintaining physiological states has been slow in coming; however, a watershed of recent studies has demonstrated the central importance of this previously overlooked component of human physiology [29]. Strong associations between overall health and gut flora diversity have been demonstrated, even implicating specific bacterial genera or species (for example, intestinal dysbiosis in psoriasis [30]). Further work has demonstrated bidirectional communication between gut microbiota and ascending and descending nerve fibers through direct contact with bacterial products and by interaction and mediation through the intestinal epithelium, thus indicating that the intestinal ecosystem chemically communicates with the CNS (termed the microbiota-gut-brain axis [29]). The participating nerve fibers not only include components of the enteric nervous system but descending and ascending vagus nerve fibers as well. (Most anatomy texts state that the vagus nerve is a parasympathetic motor nerve only; however, that is an oversimplification since the vagus contains approximately 80% afferent sensory fibers). Neuroendocrine signaling in conjunction with the autonomic nervous system can drive changes in the CNS, imposing top-down effects on the intestinal tract. The vagus nerve communicates with the enteric nervous system and induces a pro-anti-inflammatory effect [31] in addition to prompting the release of a host of bioactive molecules to the gut lumen (many; for a known listing, see [32]). Gut bacteria in turn influence the activity of enteroendocrine cells (increasing secretion of CCK, PYY, and GLP-1), release short-chain fatty acids (increase microglia density), tryptophan precursors and metabolites, and even neurotransmitters (GABA, 5-HT, catecholamines) to influence the CNS and endocrine and immune systems [29]. This bidirectional communication has been found to influence a variety of body systems, including the inflammation response [31,33].

In our research with the SUB mouse line, we find that the inborn sensitivity to stress predisposes to elevated inflammatory states [27,34] and we have strong evidence that inflammation in some target tissues, for example, adipose tissue, is the direct result of gut bacterial signaling [34]. These features correlated with reduced alpha diversity (bacterial richness) compared with background strain and DOM line mice, which did not exhibit abnormal inflammatory profile. Furthermore, transplantation of SUB microbiota into germ-free Swiss Webster mice induced SUB-like changes in their default inflammation state [34]. Considered collectively, we feel that exposure to stressors in stress-sensitive individuals, representing a specifically vulnerable demographic in the human population, sets the conditions for alterations in gut microbiome profile and increased intestinal permeability resulting from HPA axis activation and CNS influence. These effects in turn generate an aberrant intestinal microbial ecosystem that drives conditions, which develop and stabilize chronic inflammatory states. Therefore, a logical target for intervention therapy for a variety of diseases where excessive inflammation plays a critical part should involve restoration of healthy gut tight junction fidelity and microbiome profiles.

Disclosure statement

No potential conflict of interest was reported by the author(s).