Main findings and proposed mechanism

The present meta-analysis finds a significant association between childhood trauma and the inflammatory markers, with effect sizes being greatest for TNF-α (z=0.20, 95% CI=0.10–0.29), followed by IL-6 (z=0.09, 95% CI=0.04–0.15) and then CRP (z=0.08, 95% CI=0.04–0.11). As such, this provides strong evidence that childhood traumatic events significantly impact on the inflammatory immune system, with trajectories reaching into adulthood, thus offering a potential molecular pathway by which early trauma confers vulnerability to developing psychiatric and physical disorders later in life.

The molecular mechanisms that account for these long-term changes in immune function need to be further explored. Putatively, changes in epigenetic regulation of gene expression may be responsible for this increased immune activation; this appears plausible in view of the considerable evidence that childhood trauma induces modifications of HPA- and neuroplasticity-related methylation patterns.47, 48, 49 In particular, early trauma leads to greater methylation of the glucocorticoid receptor (GR) and greater demethylation of FKBP5.48, 50, 51, 52 The increased methylation of the GR correlates with reduced GR function as shown by impaired negative feedback of the HPA axis,52 while FKBP5 is a heat-shock protein that binds and thereby inhibits the cytosolic GR. As the GR itself is a crucial regulator of inflammatory activity, lower expression and function of the GR due to epigenetic suppression may allow for this exacerbated inflammatory activity. Notably, increased inflammation itself can then maintain and exacerbate the impaired GR function,14, 15, 16 thus leading to sustained GR resistance into adulthood. Notably, based on differences in effects sizes found in the present analysis, the association between childhood trauma and adulthood inflammation is stronger for inflammatory pathways related to TNF-α; and, indeed, the GR is crucial in regulating TNF-α signalling and TNF-induced cytokine production, as well as conveying protection against TNF-related tissue damage.53

The present paper also found evidence that individual types of trauma exposure impact differentially on the inflammatory markers: most interestingly, physical and sexual abuse is associated with significant increased TNF-α and IL-6, but not CRP. Conversely, CRP seemed to be primarily related to parental absence during early development. Interestingly, rodent models have demonstrated that maternal separation is associated with elevated TNF-α levels in the periphery and cerebrospinal fluid54 as well as in prefrontal and hippocampal brain regions.55 These results stress the need for assessing the potential different effects of each type of trauma in future research. Moreover, this finding raises the question as to why different types of childhood trauma are associated with different aspects of inflammatory dysregulation.

While there is currently no clear answer to this question, several variables associated with individual trauma types, including chronicity and context of the stressor, age of exposure, duration of exposure or relationship to the perpetrator, may offer some insight. For example, it has been shown in adolescent women that episodic stress in the context of high chronic stress leads to reduced GR expression, while GR expression is increased in the absence of chronic stress.56 Moreover, there is evidence that different types of trauma impact differentially on mental health: specific subtypes of anxiety disorders appear to develop depending on whether one is exposed to physical or sexual childhood abuse,4 and childhood sexual abuse is particularly associated with the development of auditory verbal hallucinations in psychosis.5 The effect of early trauma on behaviour in adulthood may be further modulated by other developmental insults: Giovanoli et al.57 showed that prenatal immune viral challenge in mice synergistically interacts with peripubertal stress exposure thus increasing the vulnerability to develop neuropathological behaviours later on in life. Interestingly, these mice show transient neuroimmunological changes, evident during adolescence but not in adulthood, suggesting the presence of sensitive periods of peripubertal brain maturation which might differentially influence behavioural outcomes. Further supporting the role of immune-related molecular pathways in the long-term consequences of early-life trauma, previous preclinical studies have shown that early-life stress tends to have a programming effect on neuroimmune functions, leading to a pro-inflammatory state in adulthood, which in turn can trigger an exaggerated cytokine secretion and increase in microglia activity following an immune challenge. In particular, maternal deprivation early in life has been shown to enhance IL-1β responsiveness in adulthood, due to elevated IL-1 receptor levels at the post-synapse of adult hippocampal neurons.58 Moreover, prenatal stress in mice increases expression of IL-1β and TNF-α in the hippocampus during adulthood, and this pro-inflammatory state results in an enhanced activation of microglia and astrocytes in response to an immune challenge.59

In the case of CRP, the impact of childhood trauma on adulthood inflammation may be characterised by synergistic effects with the presence of ‘state‘ (current) ill health, as the effect sizes were significantly greater in clinical samples, including patients with cancer. However, this effect was not observed when focussing exclusively on psychiatric disorders, suggesting that in these individuals the ‘trait‘ effects (the history of childhood trauma) may be the main driver of the immune activation. It should be noted that, although the increase in inflammatory activity is not comparable to that of acute systemic inflammatory disorders, it still has clinical relevance. We know that 95% of CRP values in healthy individuals range between 0.07 and 5.25 mg l−1,60 which translates into a mean of 2.66 mg l−1 and a standard deviation of 4.18 mg l−1; this is in line with epidemiological findings, showing mean CRP values in the general population ranging between 1.4 and 2.9 mg l−1.61 Considering the standardised mean difference of 0.2 (equivalent to a Fisher's z of 0.1), individuals with a history of childhood trauma would show an average CRP increase of 0.84 mg l−1, or a mean CRP value of 3.5 mg l−1, which is above the threshold of 3 mg l−1 acknowledged as risk factor for future heart attack, stroke and development of diabetes.62 Thus, inflammatory activation as a consequence of childhood trauma is best conceptualised as a subtle effect that is likely to have a significant impact on physical and mental health.

Limitations

The present meta-analysis found significant yet small effect sizes in the context of particularly high levels of heterogeneity, which remained after subsequent meta-regressions and subgroup analyses. However, this may reflect the fact that the papers reviewed here show great variations in both theoretical and methodological approaches, and that there is considerable variation in the assessment of inflammatory markers (see Table 1). Such variations in measurement instruments may be associated with differences in sensitivity, which, especially in the context of the apparently small changes associated with childhood trauma, may create type II errors. Sensitivity analysis looking at the different instruments to assess trauma shows larger effect sizes for validated instruments when compared with non-standardised assessments (see Supplementary material). Notably, sensitivity analysis also shows that prospective studies show greater effect sizes and lower heterogeneity than studies using retrospective trauma assessment (see Supplementary material). In light of these various potential sources of heterogeneity, the choice of random-effect models, albeit more conservative, was indeed the most appropriate for the present purpose. While the lack of evidence for publication bias suggests that the present findings are not an artefact of a distorted literature, the potential impact of selection biases cannot be ruled out given its effect in the results for IL-6 and CRP. Finally, not all the studies included in the meta-analysis explicitly reported acute infection as exclusion criteria for their analyses, and this could have partially affected the findings of those individual studies.

Implications

The present meta-analysis demonstrates a significant association between childhood trauma and increased immune activation in adulthood, and highlights possible differential effects of different types of trauma as well as heterogeneity in the findings. Future research should further investigate the molecular mechanisms behind this association, and particularly whether inflammatory and neuroendocrine changes actually occur in parallel in the same individuals, and how these changes are embedded from a molecular point of view. Contextualising these data within a wider array of biological systems may be crucial in identifying why some individuals go on to develop physical or psychiatric disorders, whereas other remain resilient in the face of exposure to trauma.

These findings are also clinically relevant. Besides the potential impact of the increased inflammation on metabolic outcomes and physical illness, as discussed above, the assessment of inflammatory markers may also aid the development of prevention and treatment strategies. For example, a recent meta-analysis has demonstrated that elevations in CRP and IL-6 appear to precede the development of depressive disorders,63 and that patients with increased inflammation are less likely to respond to conventional antidepressants,64 and more likely to respond to adjunctive anti-inflammatory treatment.65 Thus, assessment of childhood trauma in conjunction with that of inflammatory markers may prove crucial in developing more effective prevention strategies and treatments, affecting long-term mental health outcomes.