Lifetime Adversity – Inflammation – CRP Levels
A recent study published in Brain, Behavior and Immunity suggests that adversity during childhood and trauma during adulthood are associated with elevated high sensitivity C-reactive protein (hsCRP).
This is perhaps the first large population-based study to assess the connection between adulthood trauma exposure and inflammation.
Strong evidence links childhood stress exposure with adverse health outcomes. Adversity in childhood increases risk for adult-onset mood and anxiety disorders in the general population, and depression and post-traumatic stress disorder (PTSD) in military personnel.
Childhood adversities also increase risk for physical illnesses including cardiovascular disease, diabetes, and metabolic disorders. Among adults, those with combat or non-combat trauma exposure had an increased rate of psychiatric disorders and physical illnesses including heart failure, stroke, and autoimmune disorders.
The biological mechanisms underlying the link between trauma and poor health are not well understood, but there is evidence that inflammation may play a key role. Emerging evidence indicates that elevated inflammation is associated with psychopathology. Large bodies of research now link depressive and anxiety disorders with elevated levels of inflammation.
PTSD has also been linked with elevated levels of inflammatory markers, including C-reactive protein (CRP) and higher levels of CRP predicted risk for PTSD symptoms in a prospective study of 2610 war zone–deployed marines.
Both childhood adversity and specific types of adulthood trauma exposure have been associated with elevated levels of systemic inflammation. Childhood maltreatment has been linked with elevated levels of high sensitivity C-reactive protein (hsCRP) in participants 20 years later.
Similarly, childhood adversity, defined as having experienced one or more unusually stressful events in childhood, has been associated with elevated adulthood levels of systemic inflammation.
Of note, childhood adversity appears to increase vulnerability to the effects of later stressful events. For example, stress sensitization models hypothesize that childhood adversity may sensitize individuals to psychiatric psychopathology by lowering their tolerance to later stressors.
In the Brain, Behavior and Immunity study over 11,000 adults ranging from age 59 to 79 years participated in the Health and Retirement Study. Subjects were screened for childhood adversity by reporting whether they had experienced repeating a year of school, having parents with drug or alcohol problems, or being physically abused before the age of 18 years.
Subjects then reported if, after age 18, they had experienced any of seven traumatic life events: death of a child, natural disaster, combat, having a family member addicted to drugs or alcohol, being assaulted, having a life-threatening illness or accident or having a spouse or child with such. Data were adjusted for age, gender, race, education, year of collection, and other possible confounders.
Joy E. Lin et al. from the School of Medicine, University of California, San Francisco, USA report that childhood adversity and adulthood trauma were independently associated with elevated levels of hsCRP, while subjects who had experienced both had higher hsCRP levels as compared to subjects with a history of adulthood trauma only. Of note, subjects who had experienced childhood adversity also had increased prevalence of adulthood trauma.
It is known that childhood and adulthood stress is associated with higher risk for physical illness such as cardiovascular disease, diabetes, and even autoimmunity.
The mechanisms are not well-understood, however, although chronic low-grade inflammation is thought to play a role based on studies of patients with depression, anxiety and post-traumatic stress disorder. While hsCRP is a nonspecific marker in and of itself, it is an easy way to detect low levels of inflammation.
The association of both childhood adversity and adulthood trauma with elevated inflammation, reported in this study, could be linked to mechanisms underlying the increased morbidity and/or mortality in subgroups of stress-exposed individuals.
Large population-based studies such as the present study help establish associations which in turn can direct further investigation into molecular mechanisms and risk modifiers, eventually contributing to individual patient care.
Source: Brain Behav Immun. 2016 Mar; 53:105-12. doi: 10.1016/j.bbi.2015.11.015. Epub 2015 Nov 23
Updates
2020
A 2020 study by Eleonora Iob, Rebecca Lacey and Andrew Steptoe utilized data from the English Longitudinal Study of Ageing.
Adverse childhood experiences (ACEs) were assessed through retrospective reports at wave 3 (2006/07). CRP was measured at waves 4 (2008/09) and 6 (2012/13), and hair cortisol at wave 6. The aim of this study was to investigate the association of multiple types of ACEs with hair cortisol and repeated measures of CRP in a large sample of older adults, distinguishing between cumulative risk and dimensions of ACEs.
In relation to the ACEs cumulative score, the authors found elevated CRP values at wave 4 and higher CRP levels across waves 4 and 6 in participants reporting three or more ACEs compared with those who did not experience any ACEs, independently of demographic, socioeconomic, lifestyle, and medication confounders. The results also suggested that the predicted increase in hair cortisol with age was greater amongst participants with three or more ACEs compared to those without.
Authors’ Highlights
- Older adults exposed to ACEs had higher CRP levels than those without ACEs.
- Different dimensions of ACEs had similar associations with CRP.
- Exposure to 3+ ACEs was related to a steeper increase in hair cortisol with age.
The investigators concluded that their study suggests that the relationship between ACEs and pro-inflammatory responses is likely to persist into later life.
Older adults with three or more ACEs had an elevated risk of high CRP levels both cross-sectionally and across a 4-year period. All ACEs dimensions (i.e. Threat, Dysfunctional Household, Low Parental Bonding, and Loss of an Attachment Figure) were associated with increased CRP levels and had similar effect sizes.
2022
A 2022 study by Eleonora Iob et al. investigated the associations of adverse childhood experiences (ACEs) with longitudinal patterns of early-life inflammation and depressive symptoms in young adulthood, considering both the patterning and timing of ACEs from the prenatal period through to adolescence.
The authors found that the associations of the cumulative ACEs scores and the FA-derived dimensions with the CRP trajectories were weak in all early-life periods. Bullying victimisation between 7 and 18 years was the only individual adversity associated with elevated CRP levels, and exposure to sexual abuse in adolescence was related to elevated CRP levels in boys but not in girls, independently of previous ACEs and other covariates.
The cumulative ACEs scores, FA-derived ACEs dimensions, and most individual adversities across all early-life periods were related to moderate and severe levels of depressive symptoms in young adulthood. The associations of ACEs during late childhood/adolescence with depressive symptoms were larger than those of earlier ACEs, also when accounting for previous ACEs exposure. The largest associations were found for sexual abuse and adversities involving physical/emotional threat in adolescence.
The investigators concluded that ACEs from the prenatal period until adolescence are robustly associated with moderate and severe levels of depressive symptoms in young adulthood. They suggested that early interventions to prevent ACEs and ACE-related trauma might help to reduce the risk of depression across the life course. CRP levels are not consistently associated with ACEs and depression in children and young people.
2023
A 2023 study by Danielle Dalechek et al. examined the relationships between reported ACEs, anxiety, and chronic pain and to assess the associations between ACEs, anxiety, and CRP levels, as well as the link between CRP and chronic pain.
The authors found that the frequency of sexual abuse and informing a professional about anxiety significantly interacted to predict elevated CRP. Moreover, ACEs (physical abuse, sexual abuse, and whether taken to a doctor) significantly interacted with CRP to predict pain.
The authors reported that CRP is significantly associated not only with certain ACEs and adult chronic pain outcomes but also with anxiety symptoms. Of note, childhood abuse significantly interacted with CRP to predict pain, and there were important results on the combined effect of specific ACEs.
The investigators concluded that their study suggests that mechanisms of the impact of ACEs on chronic pain may include inflammation and anxiety.
According to the authors the implications of this connection warrant further study to validate these relationships and potential mediations but are an important consideration in the underlying inflammatory components of systemic dysfunction after childhood adversity in adults with chronic pain, anxiety, and higher levels of CRP.
Cover Image Credit: (Left panel). Proposed mechanistic pathway linking chronic inflammation, IL-6/CRP signaling, the stress response, and pain perception with neuropsychiatric and prognostic outcomes. Legend: This flowchart illustrates the signaling associations and hierarchies among chronic inflammation, immune signaling intermediates, neuroendocrine stress responses, and pain sensitivity. Chronic peripheral inflammation, initiated by systemic disease, tissue injury, or immune dysregulation, leads to the upregulation of proinflammatory cytokines, specifically interleukin-6 (IL-6). IL-6 plays a central role in activating the hepatic acute-phase response, resulting in the synthesis and release of C-reactive protein (CRP) by hepatocytes.
From Monomeric [CRP] and CRP-Controlled Stress and Pain Hypersensitization as Novel Predictors of Cognitive Disturbance and AD in Chronic Inflammatory Disease by Mark Slevin and Amelia Tero-Vescan, Int J Mol Sci. 2025 Nov 21;26(23):11279. doi: 10.3390/ijms262311279
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