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. 2023 Nov 10;34:100702. doi: 10.1016/j.bbih.2023.100702

A cross-sectional study of correlations among blood-based biomarkers for intestinal permeability: A pilot study of United States veterans with posttraumatic stress disorder symptoms

Andrew J Hoisington a,b,c,d, Christopher E Stamper a,b,c, Kelly A Stearns-Yoder a,b,c, Fatemeh Haghighi e,f, Christopher A Lowry a,b,c,g, Lisa A Brenner a,b,c,h,∗
PMCID: PMC10709025  PMID: 38073767

Abstract

While many studies of intestinal permeability (IP) are focused on those with gastrointestinal (GI) disorders, there is a rising trend to analyze IP among individuals with mental health conditions including posttraumatic stress disorder (PTSD) with and without diagnosed GI conditions. This interest stems from the association between gut dysbiosis and chronic inflammation, which are mechanisms linked to stress-related somatic and mental health conditions. Efforts to date have resulted in the exploration of non-invasive and feasible measures to identify an IP biomarker that could also serve as a treatment target. Additionally, those conducting studies regarding IP often recruit individuals without health problems and compare levels of biomarkers of IP to those obtained from participants with conditions of interest. This study aimed to assess correlations between blood-based biomarkers of IP, as well as examine the association between blood-based biomarkers of IP and PTSD symptoms. Blood was sampled from seventeen United States military Veterans with variable severity of PTSD symptoms per the posttraumatic checklist for DSM-5 (PCL-5) (n = 6 with scores over 31 indicating clinically meaningful symptoms of PTSD; overall range 0–49, mean 20.8, standard deviation 15.7) and analyzed blood biomarkers of IP including citrulline, diamine oxidase, glucagon-like peptide-2, intestinal fatty-acid binding protein, lipopolysaccharide binding protein, lipopolysaccharide, and zonulin. Correlations between the IP blood-based biomarkers ranged from ρ of −0.31 to 0.35. None of the measured biomarkers were significantly correlated to PTSD symptom severity scores (ρ of −0.34 to 0.05). Although based on limited sample size, our results call into question the specificity of blood-based biomarkers of IP when: (1) studying persons with and without PTSD symptoms in whom clinical GI disorders are not necessarily the focus of the study; and (2) comparing IP results among individuals with well-defined disease states to those without the disease (e.g., controls). Further studies are needed to explore the role of external factors (e.g., nutrition, obesity, alcohol use) on IP and to determine if the biomarkers studied are appropriate for measuring IP in people with a range of symptoms related to PTSD.

Keywords: Intestinal permeability, Blood-based biomarker, PCL-5, Posttraumatic stress, PTSD

Highlights

  • •

    Accurate blood-based biomarkers of intestinal permeability are used in more recent mental health research studies.

  • •

    Mental health conditions, including PTSD, is associated with chronic inflammation and gut dysbiosis.

  • •

    Paired measures of blood-based biomarkers in Veterans with PTSD were not correlated with each other nor PTSD severity.

  • •

    Caution is urged in using blood-based biomarkers of intestinal permeability without presence of gastrointestinal disorder.

1. Introduction

Inflammation is associated with mental health conditions including posttraumatic stress disorder (PTSD) (Brenner et al., 2022). Chronic inflammation is increasing in developed countries (Rook et al., 2014) and may attribute to the rising prevalence of allergic asthma (Mutius, 2022), cardiovascular diseases (Alfaddagh et al., 2020), type 1 and type 2 diabetes (Tsalamandris et al., 2019), autoimmune disorders (Dinse et al., 2020), and stress-related psychiatric disorders (Flux and Lowry, 2023). Recent studies suggest that the gut microbiome plays a predominant role in modulating or promoting systemic inflammation among those with mental health disorders (Ouabbou et al., 2020). Advancements in understanding the mechanistic role of the gut microbiome, particularly its influence on inflammation, neuroinflammation, and hypothalamic-pituitary-adrenal axis activity, has led to a focus on the role of intestinal permeability (IP) in disease progression (Ratsika et al., 2023). Gut dysbiosis and the associated loss of intestinal integrity could facilitate translocation of bacteria and bacterial products across the gut mucosa and increase systemic inflammation (Schoultz and Keita, 2020). Overall, the impacts of gut dysbiosis, increased IP, and systemic inflammation are believed to represent a cascade of effects leading to negative physical and mental health outcomes.

Theoretically, IP and inflammation are both biological responses to conditions that can be quantified. To measure IP, research using blood-based biomarkers are increasingly being employed due to their ease of collection (one-time blood draw) and relative simplicity to measure concentrations with commercially available enzyme-linked immunosorbent assay (ELISA) kits (Schoultz and Keita, 2020). Moreover, IP biomarkers in the blood are reported to be stable when frozen (Kuzma et al., 2019). As such, measuring alterations of IP associated with wide range of disorders (e.g., mental health conditions) could provide a therapeutic target for clinical interventions.

Although blood-based biomarkers aimed at quantifying IP are often grouped, noting differences both in terms of source and function may assist in understanding previously published inconsistent findings (Bischoff et al., 2014). Increased IP is theorized to increase circulatory biomarkers including intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), lipopolysaccharide binding protein (LBP), glucagon-like peptide-2 (GLP-2) and zonulin. In contrast, citrulline (Fragkos and Forbes, 2018) and diamine oxidase (DAO) (Wang et al., 2015) concentrations in the blood are decreased with increased IP. The accuracy of existing commercial kits in detecting the zonulin protein in blood has been noted (Power et al., 2021). In this study, we analyzed the plasma from participants with a range of self-reported PTSD symptoms assessed using the PTSD Checklist for DSM-5 (PCL-5) (Blevins et al., 2015). The aim of the study was to assess correlations between different blood-based biomarkers of IP, as well as examine the associations between these biomarkers of IP and PTSD symptom severity.

2. Methods

Data from seventeen US military Veterans were analyzed in a cross-sectional design study. Participants were not recruited based on presence or absence of any gastrointestinal (GI) disorders (however, two participants had inflammatory bowel disease noted in their electronic medical records). This study was conducted according to the guidelines in the Declaration of Helsinki, and all procedures involving human participants were approved by the Colorado Multiple Institutional Review Board (COMIRB, Protocol #18–2820), as well as the local VA regulatory committee. Written informed consent was obtained before Veterans participated in any study procedures.

Participants had a range of scores on the PCL-5, a self-report measure that assesses the presence and severity of PTSD symptoms (Blevins et al., 2015). Based on the recommended cut-off value of 31 on the PCL-5, there were 6 participants that had clinically meaningful symptoms of PTSD (Weathers et al., 2013). Blood was collected in EDTA tubes and centrifuged at 1500 g for 10 min to separate plasma. Plasma was aliquoted prior to freezing at −80 °C, ensuring all samples had only one freeze-thaw cycle. Plasma was analyzed through commercially available enzyme-linked immunoassays using the manufacturer-recommended instructions. IP targets included citrulline (no dilution; Cat No. CEA505Ge, Cloud Clone Corp, Katy TX), DAO (10-fold dilution; Cat No. CSB-E10137h, CUSABIO, San Diego, CA), GLP-2 (no dilution; Cat No. E-EL-H2238, Elabscience, Frederick, MD), I-FABP (5-fold dilution; Cat No. DFBP20, R&D Systems, Minneapolis, MN), LBP (500-fold dilution; Cat No. SEB406Hu, Cloud Clone Corp), LPS (no dilution; Cat No. CEB526Ge, Cloud Clone Corp), and zonulin (20-fold dilution; Cat No. KR5601, Immundiagnostik, Bensheim Germany).

Concentrations were determined based on manufacturer-recommended standard curve analyses, typically four parameter logistic curve fits, with adjustments for dilution factors. All samples were run in triplicate and targets were run at the same time to eliminate variations across plates. The intra-assay coefficient of variation for the IP markers was highest for GLP-2 (mean 24.8%, range 9.4%–76.0%) followed by DAO (mean 13.1%, range 4.3%–22.7%), citrulline (mean 6.2%, range 1.1%–15.2%), LBP (mean 5.4%, range 1.3%–10.2%), I-FABP (mean 3.3%, range 1.1%–6.2%), and zonulin (mean 2.0%, range 0.5%–6.7%). Spearman test for correlation coefficient (R) and p value was performed and generalized linear models with cofounding variables of age, gender, and body mass index (BMI) were conducted in RStudio (v 2022.07.1).

3. Results

Among the seventeen participants, the mean (range, ±SD) age was 47.2 years (32–71, ±10.8), and the mean (range, ±SD) body mass index was 28.9 (20.4–37.8, ±4.65. Participants were primarily male (82.4%) and Caucasian (88.2%). Individuals had mean (range, ±SD) concentrations of 1.2 ng/ml (0.93–1.5, ±0.13) for citrulline, 428 milli-international units per milliliter (mIU/ml) (208–728, ±166) for DAO, 3.90 ng/ml (2.1–7.8, ±1.68) for GLP-2, 1596 pg/ml (705–2364, ±451) for I-FABP, 15,714 ng/ml (3325–20,976, ±4724) for LBP, and 0.22 ng/ml (0.16–0.30, ±0.04) for zonulin. All participant LPS concentrations were below the detection limit, as perhaps expected from participants without major GI disorders (Bischoff et al., 2014). PCL-5 total scores had a mean (range, ±SD) of 20.7 (0–49, ±15.7). Six of the seventeen participants had a PCL-5 total score of 31 or higher, indicating they had clinically meaningful symptoms of PTSD.

A comparison of the IP biomarkers showed no consistent trends or statistically significant correlation between any two biomarkers based on direct Spearman tests (Fig. 1). The biomarkers citrulline and DAO are plotted as their negatives, for biological response to be in the same direction with other markers. Only six of the fifteen correlations between biomarkers are in the positively correlated direction (40%), and none are significantly positively or negatively correlated. The pair of biomarkers most correlated were I-FABP and GLP-2. The six participants that had probable PTSD with PCL-5 scores 31 or higher did not have statistically different levels of any of the IP markers compared to the other 11 participants. None of the IP markers were significantly correlated to PCL-5 scores in Spearman correlations (Fig. 2) or in generalized linear mixed models adjusted for age, BMI, and gender.

Fig. 1.

Fig. 1

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Correlations between blood-biomarkers of intestinal permeability. Spearman test for correlation coefficient ® and p value; DAO, diamine oxidase; GLP-2, glucagon-like peptide-2; I-FABP, intestinal fatty acid-binding protein; LBP, lipopolysaccharide binding protein.

Fig. 2.

Fig. 2

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Correlations between blood biomarkers of intestinal permeability and PCL-5 scores. Spearman test for correlation coefficient (R) and p value; DAO, diamine oxidase; GLP-2, glucagon-like peptide-2; I-FABP, intestinal fatty-acid binding protein; LBP, lipopolysaccharide binding protein.

4. Discussion

Intestinal permeability is an outcome and treatment target of increasing interest. As such, multiple commercially available ELISA kits for biomarkers of IP are available. Spearman's rank correlation coefficients for correlations between different IP blood-based biomarkers ranged from (ρ) −0.31 to 0.35. In comparing these findings to published data, one study reported differences across IP markers among those with cardiometabolic diseases (measuring claudin-3, I-FABP, LBP, and zonulin), and identified zonulin and LBP as the most promising targets (Arango-González et al., 2023). In another study of individuals characterized as being obese, based on BMI levels, LBP was strongly correlated to lactose-mannitol ratio and LBP levels were significantly higher among those who were obese, while blood-based biomarkers of I-FABP and zonulin were not correlated to obesity or the other biomarkers (Seethaler et al., 2021b). The authors remarked that some blood-based biomarkers of IP might only be viable measures among those with disease states associated with severe chronic inflammation (e.g., Crohn's disease, ulcerative colitis). For other conditions in which chronic inflammation is not ubiquitous (e.g., PTSD), IP measurements might be more influenced by external factors such as nutrition (Inczefi et al., 2022), obesity (Khoshbin and Camilleri, 2020), high intensity physical exertion for long periods of time (Varanoske et al., 2022), and alcohol use (Jung et al., 2021).

Implementation of blood-based biomarkers for identification of IP has been further confounded by the lack of an in vivo gold standard measurement, even among those with GI disorders (Schoultz and Keita Å, 2020). One approach for IP measurement is orally ingested solutes that are excreted in urine. Various solutes exist but a common target is the lactose to mannitol ratio (LMR) (Sequeira et al., 2014). Studies assessing correlations between LMR and blood-based IP biomarkers have been mixed based on disease and biomarker (Seethaler et al., 2021a). A lack of standard process for LMR was used to explain the high heterogeneity in a meta-analysis of coeliac and Crohn's disease (Gan et al., 2022). In vitro testing in Ussing chambers is an alternative for a gold standard but the process of collecting multiple mucosal biopsies is too time-consuming and invasive to be used in large scale research studies or clinical evaluations (Speer et al., 2018). In the absence of a clear gold standard to measure IP, it has been suggested IP markers in multiple biological fluids (e.g., feces, urine, blood) could lead to a more accurate assessment (Schoultz and Keita Å, 2020). Moreover, as protocol complexity increases, feasibility of implementation decreases. We expect an increasing number of permeability biomarkers to be used by researchers in the future that will create new challenges to interpret findings and compare results across studies.

Data on IP among individuals with PTSD is lacking. The present study observed a positive non-significant relationship between PCL-5 and LBP concentrations, with the lack of correlation possibly due to the fact that the majority of participants (64.7%) had scores that did not indicate clinically meaningful symptoms of PTSD, or due to other health conditions that were not documented. A previous pilot study from our group on Lactobacillus reuteri DSM 17938 administered to individuals with co-occurring current PTSD and mild traumatic brain injury analyzed the same I-FABP IP biomarker in Veterans (Brenner et al., 2020). The placebo group in that study had a mean of 494 pg/ml I-FABP which is three times lower than in this pilot study, a difference that again might be due to other health conditions. Voigt et al. (2022), observed higher levels of LPS, LBP and HMGB1, a damage associated molecular pattern (DAMP), in US military Veterans with PTSD in comparison to healthy non-Veteran controls. PTSD symptom severity of the Veterans was assessed using PCL-5 total score, with a median score of 55.5 (range 30–75) that was higher than our cohort (median 20.8, range 0–49). It may not be possible to directly compare these data sets, as Voigt et al., 2022, did not use an exclusively Veteran population as a healthy control group, and there are many confounders implemented by military service that were not captured while using a nonveteran control group. Future studies could compare results to well-validated tests of intestinal permeability (e.g., lactulose/mannitol ingestion and quantification in urine) and also quantitate lactic and butyric acid from the gut (fecal analyses) since these also alter and/or modulate intestinal inflammation (Iraporda et al., 2015) and IP (Ma et al., 2022). The data then could be correlated with the blood IP biomarkers, then to PCL-5 scores. A good approach to understanding the association of PTSD and IP would be to conduct a human study to include: 1) Veterans with PTSD with known IP issues; 2) Veterans with PTSD w/o any known IP issues; 3) Veterans without PTSD with IP issues; and 4) Veterans without PTSD without IP issues.

It remains unclear if PTSD increases IP, or, conversely, existing IP issues increase PTSD onset/outcome. Not all PTSD patients have IP issues, nor do all persons with IP issues have PTSD. Studies by Voigt and colleagues (2021) suggest that persons with PTSD do indeed have an abnormal gut barrier but, interestingly, successful treatment of PTSD does not change permeability. Other researchers have shown that increased biomarkers of inflammation prior to deployment predict development of PTSD symptoms following deployment (Eraly et al., 2014; Schultebraucks et al., 2021).

This study has both strengths and limitations. In comparing seven different measures of blood-based biomarkers for IP, this is the largest data set for individuals without known GI disorders. However, additional blood-based biomarkers are available that were not used in this study. The current study may be underpowered to achieve statistical significance. For example, a recent study included n = 50 with major depressive disorder and n = 40 healthy controls and found significant correlations in plasma concentrations of biomarkers of IP in all subjects (N = 90) (Wu et al., 2023). Additionally, some ELISAs had high intra-assay coefficients of variation (for example, GLP-2; mean 24.8%, range 9.4%–76.0%). In such cases, it may be preferable to use other quantitative approaches, such as liquid chromatography mass spectrometry (van de Merbel, 2019). In addition, the PTSD assessment was determined with the PCL-5, not the gold standard of the clinically administered PTSD scale for DSM-5 (CAPS-5). The PCL-5 is an easy to administer self-report survey that Lee et al. (2022) showed to produce similar, but not identical results to the CAPS-5. Finally, we did not analyze any potential differences between commercial kits of IP permeability. We selected a variety of manufacturers for the kits but recognize that different kits could provide different IP results.

5. Conclusion

Findings from this study suggest that caution is likely indicated when using blood-based biomarkers of IP among those with conditions in which variability in inflammation has been noted (e.g., PTSD) or when no inflammation might be present (e.g., controls). Care should also be taken to include the blood-based biomarker tested and not group all biomarkers of IP together (e.g., report LBP IP was elevated versus stating IP was elevated). Additional studies with more participants and improved characterization of external factors are warranted to determine if blood-based biomarkers of IP are suitable for use in persons with non-GI diseases. Improved biological mechanistic studies on blood biomarkers of IP is also warranted.

Funding

Support was provided, in part, by the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Mental Health award number 1R01AT010005-01A1.

Declaration of competing interest

Dr. Brenner reports grants from the VA, DOD, NIH, and the State of Colorado, editorial renumeration from Wolters Kluwer, and royalties from the American Psychological Association and Oxford University Press. Dr. Lowry reports grants from the NIH, NSF, and Institute for Cannabis Research and serves on the Scientific Advisory Board of Immodulon Therapeutics, Ltd., is Cofounder, Board Member, and Chief Scientific Officer of Mycobacteria Therapeutics Corporation, and is a member of the faculty of the Integrative Psychiatry Institute, Boulder, Colorado, and the Institute for Brain Potential, Los Banos, California.

Contributor Information

Andrew J. Hoisington, Email: Andrew.Hoisington@va.gov.

Christopher E. Stamper, Email: Christopher.Stamper@va.gov.

Kelly A. Stearns-Yoder, Email: Kelly.Stearns@va.gov.

Fatemeh Haghighi, Email: Fatemeh.Haghighi@va.gov.

Christopher A. Lowry, Email: christopher.lowry@colorado.edu.

Lisa A. Brenner, Email: lisa.brenner@va.gov.

Data availability

Data will be made available on request.

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