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Published in final edited form as: Physiol Behav. 2023 Aug 8;271:114319. doi: 10.1016/j.physbeh.2023.114319

Adverse Childhood Experiences and Obesity Linked to Indicators of Gut Permeability and Inflammation in Adult Women

Bryant H Keirns 1, Natalie G Keirns 2, Cindy E Tsotsoros 3, Harley M Layman 2, Madison E Stout 2, Austin R Medlin 7, Christina M Sciarrillo 1, T Kent Teague 4,5,6, Sam R Emerson 1, Misty AW Hawkins 7
PMCID: PMC10592146  NIHMSID: NIHMS1925547  PMID: 37562704

Abstract

Gut permeability may increase cardiovascular disease risk by allowing bacterial components (e.g., lipopolysaccharide or LPS) to enter the bloodstream, leading to low-grade inflammation. People with adverse childhood experiences (ACEs) consistently display evidence of chronic inflammation, but the source of this inflammation, and whether gut permeability may contribute, is unknown. Moreover, whether ACE status may further perturb obesity-associated gut permeability and inflammation is unknown. Women (N=79, aged 18–84y) free of cardiometabolic diseases and inflammatory conditions and not regularly taking anti-inflammatory medications were included in a 2×2 factorial design with low or high ACE status (either 0 ACEs or 3+ ACEs) and body mass index (BMI) (either normal-weight [18.5–24.9 kg/m2; NW] or obesity [>30 kg/m2; OB]) as factors (n=15–27/group). Serum LPS binding protein (LBP), soluble CD14 (sCD14), fatty-acid binding protein-2 (FABP2), LPS core IgM, and the ratio of LBP:sCD14 were used as indicators of gut permeability. Inflammatory markers C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 were also measured. Data were analyzed using 2-way ANCOVA (age-adjusted). LBP, LBP:sCD14 and FABP2 were higher in OB versus NW, regardless of ACE status (PBMI < 0.05). Higher ACE status was associated with increased circulating LBP:sCD14 and LPS core IgM (PACE < 0.05). sCD14 was unrelated to BMI or ACEs. CRP was elevated in OB versus NW (PBMI <0.001) and tended to be higher with 3+ ACEs compared to 0 ACEs (PACE = 0.06). Moreover, TNF-α was greater in 3+ ACEs relative to 0 ACEs (PACE = 0.03). IL-6 was unrelated to BMI or ACE status. No interaction effects were observed for any marker of gut permeability or inflammation. In sum, ACE status and obesity were independently associated with evidence of gut permeability and systemic inflammation but did not interact in relation to indicators of gut permeability.

Keywords: Adverse childhood experiences, gut permeability, inflammation, obesity, cardiovascular disease

1. Introduction

Adverse childhood experiences (ACEs) are pervasive psychosocial stressors that can include physical, verbal, and/or sexual abuse; physical and/or emotional neglect; or several types of household dysfunction (i.e., divorce, substance use, mental health diagnoses, incarceration) [1, 2]. ACEs are robustly linked with unfavorable health outcomes such as cardiovascular disease (CVD), with 92% of studies reporting increased risk of CVD in adults who experienced ACEs [3, 4]. Chronic, low-grade inflammation is implicated in CVD pathogenesis, and the inflammatory markers C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and interleukin (IL)-6 are consistently higher in those with ACEs [5]. However, despite this link between ACEs, inflammation, and CVD risk, mechanisms driving inflammation – and associated CVD risk – in those who have experienced ACEs remain unclear.

One increasingly appreciated source of low-grade inflammation is a phenomenon known as “gut or intestinal permeability,” which describes a state where the gut fails to serve as an effective physical barrier and pro-inflammatory bacterial components (e.g., lipopolysaccharide or LPS) translocate into the systemic circulation [6]. Upon LPS translocation, an immune response is initiated where LPS binding protein (LBP) and CD14 facilitate LPS binding to toll-like receptor (TLR)-4 on immune cells, which ultimately leads to transcription of many inflammatory cytokines (e.g., IL-6, TNF-α) [6]. Still other serum markers are indicative of an immune response to LPS (e.g., LPS core IgM) or gut mucosal injury (i.e., fatty-acid binding protein-2 [FABP2], and therefore are considered markers of gut permeability [7, 8]. Importantly, evidence of gut permeability-induced inflammation has been linked to several chronic diseases such as obesity, CVD, and type 2 diabetes [9].

Although much research has demonstrated that lifestyle factors often associated with poor health outcomes (e.g., high-fat diets, alcohol intake) promote intestinal permeability, a growing body of research has implicated psychological stress as a regulator of the gut barrier [10, 11]. For example, acute stress induced by a public speaking task increased 2-hour urinary lactulose-mannitol ratio – a functional test of gut permeability – in healthy participants with elevated cortisol [12]. Similarly, serum zonulin, which is considered an indirect marker and regulator of gut permeability, increased 10 minutes after a stress task in a population of generally healthy men [13]. Although clinical evidence is limited to acute stressors, preclinical work has demonstrated that chronic stress can also negatively influence gut integrity. Specifically, water restriction, social disruptions, and crowded housing conditions are associated with evidence of gut permeability (e.g., increased ion and macromolecule gut permeability, decreased abundance of colonic tight junction proteins), and in some cases, gut inflammation (i.e., mononuclear cell infiltration and myeloperoxidase activity) in animals [14–17]. Moreover, rats subjected to early life adversity in the form of maternal separation and limited maternal access to nesting materials also displayed increased intestinal permeability; however, whether a similar relationship exists between ACEs and gut permeability in humans remains unknown [18, 19]. Therefore, the purpose of this study was to investigate the relationship between ACEs and serum indicators of gut permeability and inflammation in humans. We also aimed to examine the potential for high ACE status to exacerbate obesity-associated gut permeability.

2. Materials and Methods

2.1. Participants

The present study was a secondary analysis of two ongoing studies at a large southern university and surrounding metros examining: 1) the relationship between ACEs, serum indicators of brain health (i.e., brain-derived neurotropic factor [BDNF], glial cell line-derived neurotrophic factor [GDNF]), and stress reactivity, and 2) the impact of ACEs on neurocognitive performance and BDNF/GDNF status in younger versus older populations (both associated with Clinical.Trials.gov Identifier: NCT04076722). All participants in these studies were female and recruited using mass email, flyers, word of mouth, and the snowball method. Interested participants were screened for eligibility by phone or email to ensure inclusion/exclusion criteria were met. Primary exclusion criteria included currently using weight loss medications or participating in a weight loss program, pregnant or breastfeeding, previous bariatric surgery, no significant medical or psychiatric comorbidities, including uncontrolled metabolic disorders (e.g., thyroid, renal, liver), diabetes, heart disease, stroke, cancer, eating disorder, psychosis, mania, dementia, etc. To be included in the present analyses, participants also had to be free of cardiometabolic diseases (other than obesity) and inflammatory conditions (e.g., inflammatory bowel disease, rheumatoid arthritis, etc.), not chronically taking anti-inflammatory medications, and no history of using tobacco products or illicit drugs. This research was carried out in accordance with the declaration of Helsinki and approved by the Oklahoma State University Institutional Review Board (AS-19–65).

2.2. Study Design

Participants included in this study (N=79; aged 18–84 years) were grouped in a 2×2 factorial design with BMI and ACE status as factors (n=15–27/group). BMI was separated as either normal-weight (18.5–24.9 kg/m2) or obesity (> 30.0 kg/m2). ACE status was divided as low or high ACEs: 0 ACEs or 3+ ACEs, respectively, as measured by the Adverse Childhood Experiences Scale [4]. This approach yielded four groups: normal weight and low ACEs, normal weight and high ACEs, obesity and low ACEs, and obesity and high ACEs.

2.3. Anthropometric Measures

Trained research assistants measured body mass (Tanita), waist and hip circumference, and blood pressure (Omron).

2.4. Serum Analyses

All participants reported for a blood draw following overnight fast (≥ 8 hours). Participants were instructed to avoid vigorous exercise and anti-inflammatory medications for 24 hours leading up to the blood draw. Fasting venous blood was collected using BD Vacutainer tubes and allowed to clot for 60 minutes and then serum acquired by centrifugation per standard tube manufacturer’s protocol. Commercially available immunoassay kits were then used to measure several serum indicators of inflammation and gut permeability. CRP, TNF-α, IL-6, and interferon [IFN]-γ were measured using Meso Scale Discovery (MSD) V-PLEX kits and a MESO QuickPlex SQ 120 instrument. Gut permeability was assessed using serum indicators of LPS exposure using ELISA assay kits for LBP (ThermoFisher), sCD14 (R&D systems), and LPS core IgM (Hycult Biotech). ELISA plates were read on a Bio-Rad iMark plate reader. The ratio of LBP: sCD14 was also calculated, as this ratio may better reflect LPS exposure and related inflammation than the individual proteins alone and higher LBP:sCD14 has previously been linked to obesity[20–22]. Fatty acid-binding protein (FABP)-2 (R&D systems ELISA kit) was measured as a marker of intestinal mucosal injury [7].

2.5. Data Analyses

All data were analyzed using SPSS 27. Before applying additional exclusion criteria for the present analyses, missing data for indicators of gut permeability and inflammation were imputed (average of 5 imputations were utilized) for the entire dataset on n = 13 participants using the SPSS missing data add-on. After filtering for additional exclusion criteria (i.e., no cardiometabolic or inflammatory conditions, not consistently using anti-inflammatory medications) relevant to the present study, imputed data was only used for n = 2 participants.

All data were then checked for normality using the Shapiro-Wilk test. To correct non-normally distributed data, extreme outliers impairing normality were first removed using the ROUT test [23] and, if necessary, data were transformed. Data still not fitting the normal distribution were analyzed using a nonparametric test. General participant characteristics and anthropometrics were analyzed using an unadjusted two-way ANOVA (or Friedman’s test for non-normal data). Distribution of race and education status across groups were assessed with χ2. Primary outcomes (i.e., markers of gut permeability and inflammation) were analyzed using a 2-way ANCOVA adjusted for age. Main effects of BMI and ACEs are denoted by PBMI and PACE, respectively. Superscripts were only utilized when an interaction between BMI and ACEs was observed.

3. Results

3.1. Participant Characteristics

Participant characteristics are presented in Table 1. Groups with obesity displayed greater body mass, BMI, waist circumference, hip circumference, and waist-to-hip ratio (PBMI’s < 0.001) versus normal-weight groups. Women with 3+ ACEs exhibited higher waist-to-hip ratio relative to the 0 ACE groups (PACE < 0.001). No differences were observed with respect to participant age, race, education status, and blood pressure when considering BMI class, ACEs status, or study groups.

Table 1.

Participant Characteristics

NW & 0 ACEs (n=18) NW & 3+ ACEs (n=19) OB & 0 ACEs (n=15) OB & 3+ ACEs (n=27) BMI p-value ACE p-value BMI* ACE p-value
General Characteristics/Anthropometrics
Age (years) 35 ± 27 38 ± 26 43 ± 24 43 ± 20 0.071 0.553 0.861
Body weight (lbs.) 134.8 ± 13.9 129.5 ± 15.13 208.5 ± 36.8 219.2 ± 47.7 <0.001 0.976 0.250
BMI (kg/m2) 21.9 ± 2.3 22.1 ± 1.7 35.8 ± 7.0 37.3 ± 7.8 <0.001 0.523 0.602
Waist Circumference (cm) 71.6 ± 10.0 73.3 ± 9.0 100.0 ± 16.1 105.1 ± 13.4 <0.001 0.129 0.593
Hip Circumference (cm) 96.5 ± 6.2 93.9 ± 6.5 122.8 ± 13.6 123.1 ± 11.1 <0.001 0.553 0.440
Waist: Hip Ratio 0.7 ± 0.1 0.8 ± 0.2 0.8 ± 0.1 0.9 ± 0.1 <0.001 <0.001 0.616
Systolic BP (mmHg) 113 ± 9 115 ± 13 114 ± 20 120 ± 18 0.514 0.294 0.300
Diastolic BP (mmHg) 75 ± 9 73 ± 10 75 ± 13 76 ± 9 0.635 0.830 0.346
Race
Non-Hispanic white 72.2 % (n=13) 57.9% (n=11) 86.7% (n=13) 63.0% (n=17) 0.287#
Marginalized groupa 27.8% (n=5) 42.1% (n=8) 13.3% (n=2) 37% (n=10)
Education
High school graduate 33.3% (n=6) 47.4% (n=9) 26.7% (n=4) 14.8% (n=4) 0.330#
Some college, no degree 38.9% (n=7) 26.3% (n=5) 33.3% (n=5) 33.3% (n=9)
Bachelor’s degree 16.7% (n=3) 5.3% (n=1) 26.7% (n=4) 18.5% (n=5)
Graduate or Professional degree 11.1% (n=2) 21.1% (n=4) 13.3% (n=2) 33.3% (n=9)
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General characteristics and anthropometrics were analyzed by 2-way ANOVA. Race and education distribution were assessed with χ2 (χ2 p-value denoted by #). A significant BMI p-value indicates a difference between individuals with obesity versus normal-weight, regardless of ACE status. A significant PACE indicates a difference between with 3+ ACEs versus 0 ACEs, regardless of BMI. A significant BMI

*

ACE p-value indicates an interaction between some combination of BMI and ACE status. Data are presented as mean ± SD and α = 0.05.

a

Historically marginalized groups include American Indian/Alaska Natives, Asians, African Americans, Hispanic whites, and multi-racial individuals.

Abbreviations: NW normal-weight; OB obesity; ACEs adverse childhood experiences; BMI body mass index; BP blood pressure.

3.2. Serum Markers of Intestinal Permeability

LBP, LBP:sCD14 ratio, and FABP2 were greater in those with obesity relative to normal-weight participants, consistent with increased gut permeability and damage (Figure 1A/C/D; Table 2; PBMI’s ≤ 0.05). Similarly, individuals with 3+ ACEs displayed ~20% higher LBP:sCD14 ratio (Figure 1C; PACE < 0.05), as well as higher circulating LPS core IgM (Figure 1E; PACE < 0.05) compared to those with 0 ACEs. No main effects or group differences were noted for sCD14 and no BMI*ACE interactions were observed for these indicators of gut permeability.

Figure 1. Serum Biomarkers of Gut Permeability.

Figure 1.

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(A) LBP (B) sCD14 (C) LBP:sCD14 ratio (D) FABP2 and (E) LPS Core IgM. Data points represent individual participants. A significant BMI p-value indicates a difference between individuals with obesity versus normal-weight, regardless of ACE status. A significant PACE indicates a difference between with 3+ ACEs versus 0 ACEs, regardless of BMI. A significant BMI*ACE p-value indicates an interaction between some combination of BMI and ACE status. Main effects of BMI can be visualized by comparing solid versus striped bars. Main effects of ACEs can be visualized by comparing orange versus grey bars. Data are presented as mean ± SD. Abbreviations: NW normal-weight; OB obesity; ACEs adverse childhood experiences; LBP lipopolysaccharide binding protein; sCD14 soluble cluster of differentiation 14; FABP2 fatty acid-binding protein-2; LPS lipopolysaccharide.

Table 2.

Biomarkers of Inflammation and Gut Permeability

NW & 0 ACEs (n=18) NW & 3+ ACEs (n=19) OB & 0 ACEs (n=15) OB & 3+ ACEs (n=27) BMI p-value ACE p-value BMI*ACE p-value
Biomarkers of Gut Permeability
LBP (ng/mL) 8190.0 ± 2286.0 8878.0 ± 2574 10899.0 ± 3015.0 12217.0 ± 3496.0 <0.001 0.145 0.652
sCD14 (ng/mL) 1455.7 ± 257.7 14102.6 ± 254.7 1536.2 ± 324.7 1409.3 ± 3234.5 0.700 0.183 0.571
LBP:sCD14 5.8 ± 2.1 6.4 ± 1.9 7.1 ± 1.4 8.9 ± 3.0 <0.001 0.026 0.270
FABP2 (pg/mL) 1461.0 ± 534.3 1728.0 ± 732.9 2006.0 ± 822.2 2028.0 ± 902.7 0.040 0.497 0.527
LPS Core IgM (MMU/mL) 56.2 ± 22.7 71.9 ± 42.7 43.7 ± 30.3 54.6 ± 27.9 0.081 0.045 0.628
Biomarkers of Inflammation
CRP (mg/L) 0.5 ± 0.4 0.7 ± 0.6 3.7 ± 3.0 5.7 ± 5.1 <0.001 0.065 0.986
IL-6 (pg/mL) 0.9 ± 1.4 0.6 ± 0.4 0.9 ± 0.5 0.8 ± 0.4 0.632 0.385 0.430
TNF-α (pg/mL) 2.2 ± 0.5 2.5 ± 0.6 2.1 ± 0.7 2.5 ± 0.6 0.458 0.028 0.556
IFN-γ (pg/mL) 4.3 ± 2.0 4.6 ± 3.1 3.6 ± 2.3 1.5 ± 0.3 0.016 0.882 0.424
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Indicators of gut permeability and inflammation were analyzed by 2-way ANCOVA adjusted for age. A significant BMI p-value indicates a difference between individuals with obesity versus normal-weight, regardless of ACE status. A significant PACE indicates a difference between with 3+ ACEs versus 0 ACEs, regardless of BMI. A significant BMI

*

ACE p-value indicates an interaction between some combination of BMI and ACE status. Data are presented as mean ± SD and α = 0.05.

Abbreviations: NW normal-weight; OB obesity; ACEs adverse childhood experiences; BMI body mass index; CRP C-reactive protein; IL interleukin; TNF tumor necrosis factor; IFN interferon; LBP lipopolysaccharide binding protein; sCD14 soluble cluster of differentiation 14; FABP2 fatty acid-binding protein-2; LPS lipopolysaccharide.

3.3. Serum Markers of Inflammation

Obesity was associated with nearly 10-fold greater CRP (Figure 2A; BMI estimated marginal means 4.8 mg/L versus 0.5 mg/L; PBMI <0.001), but interestingly, lower IFN-γ compared to normal-weight groups (Figure 2D; PBMI = 0.016). Groups with 3+ ACEs displayed higher TNF-α (Figure 2C; PACE = 0.028) and tended to have higher CRP compared to groups with 0 ACEs (PACE = 0.065). No differences were observed for IL-6 and no interaction effects were detected for any inflammatory marker.

Figure 2. Serum Biomarkers of Inflammation.

Figure 2.

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(A) CRP (B) IL-6 (C) TNF-α and (D) IFN-γ. Data points represent individual participants. A significant BMI p-value indicates a difference between individuals with obesity versus normal-weight, regardless of ACE status. A significant PACE indicates a difference between with 3+ ACEs versus 0 ACEs, regardless of BMI. A significant BMI*ACE p-value indicates an interaction between some combination of BMI and ACE status. Main effects of BMI can be visualized by comparing solid versus striped bars. Main effects of ACEs can be visualized by comparing orange versus grey bars. Data are presented as mean ± SD. Abbreviations: NW normal-weight; OB obesity; ACEs adverse childhood experiences; IL interleukin; TNF tumor necrosis factor; IFN interferon.

4. Discussion

The present study was the first to our knowledge to examine whether ACEs are associated with evidence of intestinal permeability in humans. This study was motivated by the observation that high ACE status is tightly linked to inflammation and CVD, but the mechanisms by which the chronic stress of ACEs may contribute to inflammation are unclear. We report that women previously experiencing 3+ ACEs displayed increased circulating LBP:sCD14 and TNF-α compared to those with 0 ACEs, consistent with some degree of gut permeability. Moreover, women in the high ACEs groups had higher LPS core IgM. We also observed evidence of gut permeability and damage (i.e., higher LBP, LBP:sCD14 ratio, FABP2) and inflammation (i.e., increased CRP) in those with obesity compared to normal-weight participants, but high ACEs was not associated with a greater increase in these measures in our sample.

A growing body of literature has implicated stress as having a negative impact on the gut barrier, which may contribute to low-grade systemic inflammation and potentially CVD risk [12, 13, 24]. Clinical data thus far has focused on the effect of acute stressors on gut permeability including public speaking for 30–45 minutes [12], the Trier Social Stress Test (i.e., a combination of speaking and math tasks in front of confederates) [13], and skydiving (i.e., ~45 seconds of free falling and ~15 minutes additional minutes falling with parachute) [24], with the majority of these studies reporting some evidence of gut permeability. Collectively, these clinical studies suggest that alterations in hypothalamic-pituitary-adrenal (HPA) axis signaling underpin stress-induced gut permeability. Specifically, increased cortisol is observed following psychosocial stress and exogenous corticotrophin-releasing hormone – a hypothalamic hormone upstream of cortisol secretion in the HPA axis – reproduces gut permeability [12, 13, 24]. Further, Vanuytsel et al. [12] provided evidence that HPA axis signaling ultimately activates a subset of immune cells (i.e., mast cells) and that blocking their activation prevents intestinal permeability. From a chronic stress standpoint, work to our knowledge has only been preclinical but has consistently linked many forms of chronic stress (including early life adversity) to intestinal permeability and local gut inflammation in instances it was assessed [14–19]. Our finding that previously experiencing 3+ ACEs was linked to higher serum LBP:sCD14 ratio builds on this preclinical data demonstrating early life stress is associated with signs of gut permeability (e.g., increases in functional indicators of gut permeability) and provides evidence for a similar relationship that is sustained in adult women. The increased LPS core IgM we observed in those with high ACE status indicates alterations in gut responses to LPS exposure but these data are difficult to interpret with certainty. Hawkesworth et al. [8] expected to observe higher LPS core IgM in individuals with obesity and type 2 diabetes (i.e., groups that would be expected to display gut permeability), but rather observed less of these antibodies in circulation compared to normal-weight individuals. Interestingly, we did not observe this effect in our groups with obesity. Hawkesworth et al. hypothesized that their finding may reflect a protective mechanism, whereby these individuals with obesity and type 2 diabetes are experiencing gut permeability and more LPS is translocating into the bloodstream, anti-LPS IgM is then neutralizing LPS, the IgM-LPS complex is being degraded, and ultimately circulating LPS core IgM is decreased. In other words, in this paradigm, lower LPS IgM would indicate increased intestinal permeability. However, this hypothesis has yet to be tested and more work is clearly needed to further elucidate what a cross-sectional measurement of LPS core IgM may reflect.

While this work focused on the relationship between ACE status and markers of intestinal permeability, there are other related aspects of gut health that impact disease risk that were not examined in this study but are worth noting in relation to gastrointestinal health, including gut microbiota composition and short chain-fatty acids. First, several studies have examined the relationship between early life stress and microbiota composition, albeit in relatively small samples and differing populations [25–27]. Specifically, among pregnant adult women, those with ≥ 2 ACEs had higher relative abundance of the genus Prevotella versus those with < 2 ACEs [26]. However, in generally healthy adults with history of early life adversity (measured by the Early Traumatic Inventory-Self Report), no differences were observed for any microbiota parameter assessed (i.e., overall diversity metrics, phylum and genus relative abundances), including Prevotella [27]. At least one study by Callaghan and colleagues [25] examined microbiota composition in children exposed to early life stress. This group reported that indicators of overall microbiota composition were less favorable (i.e., lower alpha diversity, observed richness, beta diversity), and Lachnospiraceae and Clostridiales lower, in children exposed to more adversity. Although these data examining ACEs and the gut microbiota are somewhat preliminary and precise implications are unclear, a much larger body of literature including preclinical models and a variety of stressors in humans, suggests psychosocial stress impacts the gut microbiota, often unfavorably [28].

Another component of overall gut health is the abundance of short chain-fatty acids (SCFA), which are fermentation products of certain gut bacteria from dietary fiber. These SCFA appear to have a number of beneficial effects including promoting gut barrier integrity, reducing inflammation, and serving as a direct energy source for colonocytes [32]. One study has examined the associations between stressful life events and emotional problems with fecal SCFA abundance in children and found that emotional problems were associated with higher butyrate, isobutyrate, valerate, and isovalerate [33]. Another study has taken the opposite approach – supplementing SCFA as a strategy to reduce acute stress – and observed that a SCFA blend containing acetate, propionate, and butyrate reduced the cortisol response, but not subjective ratings of stress, after a stress task [34]. Given the beneficial role of SCFAs in overall gut health, it may be predicted that SCFA abundance would be inversely related to psychological stress across studies, but literature is currently mixed. Considering these other factors (i.e., microbiota, SCFAs) in addition to markers of intestinal permeability will be important avenues of future research when examining overall gut health in those who have experienced ACEs. Taken together, this growing body of literature is consistent with the notion that psychological stress affects multiple aspects of human gut health, but more work is needed to clarify the interplay between the gut barrier, resident gut microbes, and short-chain fatty acid production in responses to stress in general and those with ACEs.

The link between ACEs and inflammation is striking, with a recent scoping review identifying that 100% of studies report increased inflammatory markers (i.e., CRP, IL-6, TNF-α) with higher ACE status [5]. Similar to these findings, we detected an ACEs main effect for TNF-α, with 3+ ACE groups displaying higher TNF-α than 0 ACE groups. Although not reaching statistical significance in our modest sample, the trend we observed towards higher CRP with 3+ ACE groups would appear to be in-line with the overall body of literature. With respect to BMI, this study replicates many studies indicating that obesity is associated with higher CRP, reflecting low-grade, chronic inflammation [35]. Conversely, we observed lower IFN-γ when comparing groups with obesity versus normal-weight groups. This finding was unexpected, as the role of IFN-γ in CVD is well-documented and has been associated with obesity previously [36, 37]. Nearly all studies examining ACEs and inflammation have relied on measures of systemic inflammation (i.e., serum CRP and cytokines), but the aforementioned study on negative emotional experiences and SCFAs in children examined fecal calprotectin, which is considered a marker of local gut inflammation [33]. Although no associations between stressful life events and emotional problems and calprotectin were observed in that sample, future studies should continue to examine how chronic stressors (such as ACEs) may influence measures of gut inflammation specifically, rather than only systemic indicators.

The present work is not without its limitations. Due to the nature of a secondary analysis, certain data were not available that may have better described our participants (e.g., metabolic characteristics, diet and physical activity data), and we did not have sufficient statistical power to adjust for all potential covariates including psychiatric conditions that could confound (or mediate) the relationship between ACEs and indicators of gut permeability (e.g., depression, anxiety). Similarly, the post-hoc nature of these analyses prevented us from measuring a functional test of gut permeability (e.g., urinary lactulose-mannitol ratio), and determined our sample size. Moreover, our sample is all women and therefore cannot be generalized to men or other genders.

Despite these limitations, this study is an essential first step in examining how gastrointestinal health may be an important link between early life adversity and consequent negative health outcomes. Future research should continue to examine how poor gut health may be related to inflammation in those with ACEs, ideally in a longitudinal manner, while accounting for our limitations and considering additional factors associated with ACEs that can affect gut permeability (e.g., alcohol use). Another interesting observation warranting follow-up work is that high ACE status and obesity were related to somewhat different biomarkers of gut permeability and inflammation. That is, while LBP:sCD14 was linked to both higher ACEs and obesity, only high ACE status was associated with increased LPS core IgM and TNF-α. On the other hand, only obesity was related to higher LBP, FABP2, and CRP. This differential pattern should be confirmed and more mechanistic studies conducted in an attempt to explain these data.

5. Conclusions

Overall, we provide evidence that ACEs are linked to indicators of gut permeability in women, which may be one mechanism driving inflammation and CVD risk in this population and point to novel targets for intervention.

Highlights.

  • 3+ ACEs were associated with evidence of gut permeability and inflammation.

  • Obesity was linked to markers of gut permeability and inflammation.

  • No combination of ACEs & BMI affected measures of gut integrity and inflammation.

Acknowledgements:

The authors thank all research participants and wish to acknowledge the technical assistance of Brenda Davis, Chibing Tan, and Ashlee Taylor from the Oklahoma University Integrative Immunology Center performing serum assays.

Funding:

This work was supported by the National Institutes of Health [P20GM109097, R36AG072342, F31HL152629).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Data Statement:

The data that support the findings of this study are available from the authors upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study are available from the authors upon reasonable request.

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