Searching for host immune-microbiome mechanisms in obsessive-compulsive disorder: A narrative literature review and future directions

Abstract

Obsessive-compulsive disorder (OCD) is disabling and often treatment-refractory. Host immunity and gut microbiota have bidirectional communication with each other and with the brain. Perturbations to this axis have been implicated in neuropsychiatric disorders, but immune-microbiome signaling in OCD is relatively underexplored. We review support for further pursuing such investigations in OCD, including: 1) gut microbiota has been associated with OCD, but causal pathogenic mechanisms remain unclear; 2) early environmental risk factors for OCD overlap with critical periods of immune-microbiome development; 3) OCD is associated with increased risk of immune-mediated disorders and changes in immune parameters, which are separately associated with the microbiome; and 4) gut microbiome manipulations in animal models are associated with changes in immunity and some obsessive-compulsive symptoms. Theoretical pathogenic mechanisms could include microbiota programming of cytokine production, promotion of expansion and trafficking of peripheral immune cells to the CNS, and regulation of microglial function. Immune-microbiome signaling in OCD requires further exploration, and may offer novel insights into pathogenic mechanisms and potential treatment targets for this disabling disorder.

Keywords: Gut microbiome; Gut-brain-immune axis; Immune; Inflammation; Microbiota; Neuroinflammation; Obsessive-compulsive behavior; Obsessive-compulsive disorder.

Figure 1.. Select theoretical mechanisms by which host immune-microbiome signaling could influence OCD symptomatology

1. Gut microbiome can influence cytokine production capacity (1a) (Schirmer et al., 2016). Peripheral cytokines can influence afferent signaling to the central nervous system (CNS) via the vagus nerve (1b), or cross the blood brain barrier directly (1c), and cytokines are also produced by glial cells within the CNS. Cytokines of either peripheral or central origin can influence brain and behavior (1d) (Dantzer et al., 2008; Miller and Raison, 2016). Based on genetic studies, TNFα might be of particular relevance to OCD, but the relationship between TNFα and OCD remains to be fully elucidated (Cappi et al., 2012; Hounie et al., 2008; Jiang et al., 2018). 2. Gut microbes, specifically segmented filamentous bacteria (SFB), can participate in inflammatory and autoimmune processes by promoting expansion of T-helper 17 (Th17) cells (2a) (Lécuyer et al., 2014). In mice, auto-reactive Th17 cells can enter the CNS (2b) and have been shown to induce obsessive-compulsive behaviors (2c) (Kant et al., 2018). Other peripheral immune cell types, such as monocytes, may also exhibit dysregulated inflammatory responses in humans with OCD (Rodríguez et al., 2017), and can traffic to the CNS under conditions of increased blood brain barrier permeability (Wohleb et al., 2015), but are not included here, as their relationships with microbiome composition are less clear in the current literature. 3. Gut microbiota are needed for development and homeostasis of mature microglia (3a) (Erny et al., 2017). Microbiome manipulations, such as germ-free (GF) rearing and antibiotic treatment, are associated with microglial dysregulation and cognitive and behavioral changes in animal models, in an age- and sex-dependent manner (3b) (Thion et al., 2018).