Abnormal Distribution and Function of Circulating Monocytes and Enhanced Bacterial Translocation in Major Depressive Disorder

Abstract

Introduction: Major depressive disorder (MDD) patients experience a systemic inflammatory stage. Monocytes play an important role in innate inflammatory responses and may be modulated by bacterial translocation. Our aim was to investigate the subset distribution and function of circulating monocytes, levels of proinflammatory cytokines, gut barrier damage, and bacterial translocation in MDD patients.Methods: Twenty-two MDD patients without concomitant diseases and 14 sex- and age-matched healthy controls were studied. The levels of circulating CD14++CD16- (classical), CD14++CD16++ (intermediate) and CD14-CD16++ (nonclassical) monocytes and the intracytoplasmic tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10 expression in the presence or absence of lipopolysaccharide (LPS) stimulation were analyzed by polychromatic flow cytometry. The serum TNF-α, IL-1β, IL-6, and IL-10 levels were measured by Luminex. LPS-binding protein (LBP), intestinal fatty acid-binding protein (I-FABP), and zonulin were measured by enzyme-linked immunosorbent assay (ELISA).Results: MDD patients had a significant increase in the frequency of intermediate monocytes and a significant decrease in the frequency of classical monocytes compared to those in the healthy controls. MDD patients had a significantly increased percentage of classical monocytes that expressed IL-1β, intermediate monocytes that expressed IL-1β and IL6 and nonclassical monocytes that expressed IL-1β, and decreased levels of nonclassical monocytes that expressed IL6 compared to those in the healthy controls. MDD patients had significantly increased levels of circulating TNF-α, IL-1β, LBP, and I-FABP compared to those in the healthy controls. MDD patients with high LBP levels had a significant reduction in the number of circulating monocytes compared to that in the normal-LBP MDD patients, which can be mainly ascribed to a decrease in the number of intermediate and nonclassical monocytes.Conclusions: We have demonstrated that compared to the healthy controls, MDD patients show a marked alteration in circulating monocytes, with an expansion of the intermediate subset with increased frequency of IL-1β and IL-6 producing cells. These patients also exhibited a systemic proinflammatory state, which was characterized by the enhanced serum TNF-α and IL-1β levels compared to those in the healthy controls. Furthermore, MDD patients showed increased LBP and I-FABP levels compared to those in healthy controls, indicating increased bacterial translocation and gut barrier damage.

Blunted Expansion of Regulatory T Lymphocytes Is Associated With Increased Bacterial Translocation in Patients With Major Depressive Disorder

“…The clinical characteristics of the MDD patients included in this study exclude chronic viral or bacterial infections, as well as any existence of a concomitant or recent (at least 3 months prior to the study) bacterial infection. Thus, these results strengthen the connection between intestinal barrier dysfunction, bacterial translocation, and the immune-inflammatory system in MDD patients, with an expansion of activated monocytes in MDD patients ( 53 ). It is possible to suggest that the reduction of the expansion of Tregs might limit the gut migration of these cells.…”

“…The balance of effector lymphoid cells and Treg cells can have a profound influence on how the gut mucosa responds to stressors that elicit damage ( 51 ). Furthermore, MDD is associated with an enhanced intestinal permeability, or “leaky gut,” and increased bacterial translocation ( 52 , 53 ). In this subset of MDD patients, we have confirmed enhanced I-FABP serum levels, a proven peripheral blood marker of gut barrier function ( 54 ).…”

Nutritional Components in Western Diet Versus Mediterranean Diet at the Gut Microbiota–Immune System Interplay. Implications for Health and Disease

“…On the other hand, there is evidence supporting the interpretation that the interaction of the intestinal microbiota and the immune system cells may damage the intestinal barrier, increasing bacterial translocation with systemic pro-inflammatory effects [ 91 ]. This pathogenic mechanism has been observed in different diseases [ 92 , 93 , 94 ]. Here, we will summarize some of the mechanisms and signaling processes used by bacteria and the possible responses enacted by immune cells.…”

Single-cell mass cytometry of microglia in major depressive disorder reveals a non-inflammatory phenotype with increased homeostatic marker expression

“…However, it remains an unresolved question of high therapeutic relevance whether the inflammation in MDD originates primarily in the periphery or in the CNS. Peripheral blood monocytes of MDD patients express higher levels of inflammatory/immune mediators like IL-1β and IL-6, as well as TNF , TLR2 , CEBPA, and CCL2 mRNAs 19 – 24 . In contrast, studies of CNS microglia have resulted in contradictory findings.…”