Gender differences in the link between depressive symptoms and inflammatory responses are associated with markers of endotoxemia.

Depressive symptoms are often linked with higher inflammation and inflammatory responses, although these associations are not always consistent. In a recent study (N=160, 25-65 years, 67% women), our group reported gender differences relevant to this association: In men higher depressive symptoms were related to heightened ex vivo inflammatory responses to lipopolysaccharide (LPS), whereas in women higher depressive symptoms were related to attenuated inflammatory responses. In the present manuscript, we investigate markers of endotoxemia - i.e., markers of the presence of endotoxin in the blood, presumably due to bacterial translocation from the gut - as factors that elicit gender-dependent immune responses that may be associated with links between depressive symptoms and inflammation. We examined inflammatory responses in whole blood via a composite index of LPS-stimulated cytokines. The ratio of LPS-binding protein to soluble CD14 receptor (LBP:sCD14) was quantified as an index of endotoxemia that captures the relative reliance on pro-inflammatory versus non-inflammatory pathways for bacterial clearance. Levels of endotoxemia markers in blood were found to moderate gender differences in the link between depressive symptoms and stimulated inflammation (Gender × Depressive Symptoms × Endotoxemia: = -0.039, 95%CI [-0.068, 0.009], = 0.010). At lower LBP:sCD14 levels, depressive symptoms and stimulated inflammation were unrelated in both men and women. However, with higher levels of LBP:sCD14, men showed an increasingly positive correlation and women showed a negative correlation between depressive symptoms and stimulated inflammation. Hence, men and women exhibited similar associations between depressive symptoms and inflammatory responses at lower endotoxin marker levels, but these associations became divergent at higher levels of endotoxin markers. This information provides a novel perspective on risk factors for depression-linked alterations in inflammation, which may help to determine susceptibility to the downstream physical consequences of depressive symptomatology.