Markers of gut barrier function and its associations with cardiometabolic indices among metabolically healthy obese Arab women

1. Introduction

It has been recently acknowledged that the gut barrier function plays a crucial role in intestinal homeostasis, regulation of nutrient absorption, and protection against harmful pathogens, essential components that dictate overall health and disease (Assimakopoulos et al., 2018; Alodaini, 2023). Disruptions to the gut barrier, especially to the gut microbiota ecosystem, lead to gut dysbiosis, which has been directly and strongly linked to various metabolic and inflammatory disorders (Das and Nair, 2019; Chong et al., 2025), including obesity (Almalki et al., 2024; Shemtov et al., 2023), and aging (Xu et al., 2024), highlighting the complex interactions between the gut microbiota, intestinal permeability, and metabolic health (Koutoukidis et al., 2022; Hairul Hisham et al., 2025).

Recently, several endogenous markers of gut barrier function have been observed to be altered among individuals with low-grade chronic inflammation, a hallmark of abdominal obesity and insulin resistance-related diseases linked to mortality (Kajikawa and Higashi, 2022; Zhang et al., 2024). Some of these gut dysbiosis markers include lipopolysaccharides (LPS) or endotoxin, cluster of differentiation 14 (CD14), and fatty acid binding protein 2 (FABP2). Endotoxins are bacterial fragments/components found within the gut microbiota that are is harmful when released in the circulation, contributing to low-grade chronic inflammation among obese individuals (Wang et al., 2024). CD14 is a glycoprotein on myelomonocyte lineage cells, involved in cell differentiation, immune response, and binding endotoxins (Roberts et al., 2024). FABP2 is an intestinal damage biomarker, which is released into the circulation when intestinal epithelial cells die, serving as a biomarker of intestinal damage (Efremova et al., 2024).

In Saudi Arabia, altered gut microbiota composition has been observed to be linked with adiposity markers, particularly in obese women (Aljazairy et al., 2022). Consequently, a recent epidemiologic study identified that 3 out of 10 obese Saudi Arabian adults are considered metabolically healthy obese (MHO), a distinct phenotype of obesity that is more common in women, that has no inherent cardiometabolic abnormalities or cardiovascular risk factors commonly associated with obese individuals (Wani et al., 2024). Consequently, among MHO individuals, the relationship between adiposity indices and gut barrier function markers remains poorly understood. To fill this gap, the present study sought to examine the associations of cardiometabolic indices and gut barrier function markers among MHO Saudi women. Understanding these relationships could open new avenues for targeted therapeutic strategies in managing obesity-related disorders, particularly in under-investigated homogenous populations such as the Arab ethnic group with distinct genetic, dietary, and lifestyle factors.

2. Material and Methods

3. Results

More than half of the participants were single (52%), and 82% had at least a college or post-graduate degree. None of the participants were smokers, and none had existing comorbidities or any type of medications (not shown in Table 1). Table 1 shows the descriptive clinical and metabolic characteristics of all 100 participants. The participants had a mean age of 31.0 ± 7.1 years, with an average weight of 88.4 ± 12.5 kg and a BMI of 35.1 ± 4.7 kg/m². The mean BMR was 1545.0 ± 163.9 kcal/day. Anthropometric measures, such as WC (94.5 ± 9.9 cm) and hip circumference (122.4 ± 9.5 cm), along with a WHR of 0.8 ± 0.1, suggest central adiposity. Metabolic parameters included total cholesterol (5.2 ± 1.2 mmol/L), HDL-C (1.4 ± 0.4 mmol/L), LDL-C (3.2 ± 0.8 mmol/L), and glucose (5.2 ± 1.4 mmol/L), with a median triglyceride level of 1.2 mmol/L. Insulin resistance, assessed via HOMA-IR, had a median of 2.1. Markers of gut barrier function, which included CD14, FABP2, and endotoxin, showed wide variability, with medians of 1585.9 pg/mL, 349.1 pg/mL, and 173.6 EU/mL, respectively. The rest of the measured parameters have been shown in Table 1. It is worthy to note that if the definition of prediabetes used HbA1c (>5.7) instead of glucose (>5.6), then 17 of the participants would not be considered as having MHO.

Table 2 shows Pearson correlation coefficients (R) between the markers of gut barrier function and insulin resistance—CD14, FABP2, endotoxin, and C-peptide—with various cardiometabolic parameters. CD14 showed a significant positive correlation with FABP2 (R = 0.23, p = 0.02. CD14 also exhibited a significant inverse correlation with C-peptide (R = -0.37, p = 0.02). Additionally, CD14 showed a borderline-significant positive correlation with HOMA-IR (R = 0.32, p = 0.05. On the other hand, FABP2 was inversely associated with age (R = -0.21, p = 0.04) and glucose levels (R=-0.22, P=0.03). It also showed a significant positive correlation with HbA1c (R = 0.24, p = 0.02. Endotoxin was significantly inversely associated with BMI (R = -0.21, p = 0.04) and HC (R = -0.24, p = 0.02). Lastly, C-peptide showed a significant inverse correlation with height (R = -0.29, p = 0.05) and a borderline-significant inverse correlation with LDL-C (R = - 0.27, p = 0.08). A sub-analysis was done removing all participants with HbA1c >5.7 (n=17) and found no significant associations between variables of interest (not shown in Table 2).

Stepwise linear regression analyses were used to identify significant predictors of CD14, FABP2, and endotoxin levels with cardiometabolic variables measured as shown in Table 3. For CD14, the only significant predictor was Log HOMA-β, with a regression coefficient of 0.8 ± 0.3; p = 0.02 (Fig. 1). The model explains 15% of the variability in insulin sensitivity (adjusted R² = 0.15; p = 0.02). For FABP2, the only significant predictor was log triglycerides, with a regression coefficient of -2.7 ± 1.0 and a p-value of 0.016 (Fig. 2). The model explains 17% of the variance perceived in triglyceride levels (adjusted R² = 0.17; p = 0.02). Lastly, no significant predictors were identified for endotoxin (Table 3).

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Fig. 1.

Significant positive correlation between Log CD14 and Log HOMA-β.

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Fig. 2.

Significant inverse correlation between log triglycerides and log FABP2.

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4. Discussion

This cross-sectional study aimed to investigate the relationships between markers of gut barrier function and metabolic parameters in Arab women with MHO, an under-investigated population in the context of obesity and gut health. The study results showed that CD14 was significantly associated with FABP2 and inversely associated with C-peptide in women with MHO, suggesting that higher levels of CD14 may indicate gut barrier dysfunction, which in turn disrupts lipid metabolism and contributes to increased insulin resistance. The findings are in accordance with a recent observational study of randomly selected participants from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, ascertaining CD14 and diabetes risk among whites and blacks, where higher CD14 levels were associated with 10% increase in incident diabetes among whites in particular (Cruden et al., 2024). The significant association of CD14 with FABP2 reinforces the role of CD14 in adipose tissues and supports a recent animal study that showed CD14 deficiency in rats exhibited ideal body composition, resistance to high-fat diet, and may serve as a proangiogenic marker (Lv et al., 2025). It is worthy to note that CD14 in the present study predicts a substantial variance in insulin sensitivity, as seen in HOMA-β. In a recent systematic review by Sharigyn and colleagues (2023), CD14 with endotoxin activates toll-like receptors (TLR) of the immune system, which in turn influences glucose responsiveness, adipose gene expression, and metabolism, with CD14-deficient mice showing increased resistance to obesity, insulin resistance, and cardiovascular disease, while also regulating SIRT1 activity, a major regulator of metabolism (Sharigyn et al., 2023).

Another interesting finding in this population is the significant associations between FABP2 with glucose and HbA1c, suggesting that it could be a potential marker of early metabolic disturbance, especially among MHO individuals. The significant inverse association of FABP2 with glucose levels contradicts its positive correlation with HbA1c, the latter of which is more aligned with previous observations on its role in long-term glucose dysregulation. Previous studies on FABP2 indicate that higher levels were associated with increased diabetes-related complications and sub-atherosclerosis in children (El-Asrar et al., 2023). FABP2, which is primarily a marker of intestinal lipid disturbance, has been studied mostly in genetics, since its polymorphisms have been associated with various cardiometabolic disorders in different ethnic groups such as MetS in Caucasians (Turkovic et al., 2012) and ischemic stroke in ethnic Han Chinese (Cao et al., 2023). The significant association between FABP2 and triglycerides in the present study are closely aligned with the findings from ethnic North Indians, where FABP2 polymorphisms have been associated with hypertriglyceridemia (Meena et al., 2023).

Findings of the present study provide valuable insights into the complex interplay between gut barrier markers and metabolic health in this population, highlighting several important associations not seen in previous investigations.

Lastly, no significant predictors were found for endotoxin, indicating that other factors, such as gut microbiota composition or dietary influences, may be involved in determining endotoxin levels. This highlights the complexity of the gut barrier’s role in metabolism and suggests that endotoxin levels may not be as strongly influenced by traditional metabolic parameters in this population. It is worthy to note, however, that at least in interventional studies done in the same Arab population, endotoxin was strongly associated with triglycerides and total cholesterol, most notably among obese participants with type 2 diabetes (Al-Daghri et al., 2022). The lack of consistency in observations may also be attributed to the differences in assays used in these studies, apart from the fact that the participants had MHO in this study and no diabetes. Larger studies are needed to confirm these findings.

The authors recognize several limitations. The design of the study prevents causal conclusions on the relationship between gut barrier function and metabolic health. Longitudinal studies are needed to determine whether changes in gut barrier over time lead to metabolic dysfunction. Furthermore, the findings are only applicable to women with MHO, and as such, larger studies using diverse populations are necessary to validate and examine how the present findings apply to other groups. Lastly, several confounders not included in the study, such as diet and physical activity, may influence gut microbiota composition and should be considered in future studies for a more comprehensive understanding. Nevertheless, several strengths are noted in this study, as it is the only study to investigate the link between cardiometabolic parameters and gut barrier function in Arab women with MHO. The exclusion of several comorbidities and medications eliminates potential confounders and ensures that the results reflect the true associations of the studied parameters with metabolic status among MHO women. The study also collected a wide array of clinical parameters, which can lead to hypothesis generation in future studies.

5. Conclusions

In summary, the study provided preliminary evidence of a link between gut barrier function markers and metabolic parameters, particularly insulin resistance, in Arab women with MHO. The findings suggest that CD14 and FABP2, markers of gut permeability, may serve as early indicators of metabolic risk even in individuals who are not overtly unhealthy. Given the rising obesity rates in the Arab world, this study underscores the importance of exploring gut health as a potential therapeutic target in the management of obesity and metabolic disorders. Further research is needed to better understand the mechanisms underlying these associations, particularly in diverse populations like Arab women, where genetic, dietary, and lifestyle factors may uniquely influence gut health and metabolic outcomes. Interventions that have positive modulatory effects on the gut microbiome, such as the consumption of the Mediterranean diet, may also provide additional understanding of how markers of gut permeability can be manipulated.