Stressor-Induced Reduction in Cognitive Behavior is Associated with Impaired Colonic Mucus Layer Integrity and is Dependent Upon the LPS-Binding Protein Receptor CD14

Abstract

Purpose Commensal microbes are impacted by stressor exposure and are known contributors to cognitive and social behaviors, but the pathways through which gut microbes influence stressor-induced behavioral changes are mostly unknown. A murine social stressor was used to determine whether host–microbe interactions are necessary for stressor-induced inflammation, including neuroinflammation, that leads to reduced cognitive and social behavior. Methods C57BL/6 male mice were exposed to a paired fighting social stressor over a 1 hr period for 6 consecutive days. Y-maze and social interaction behaviors were tested following the last day of the stressor. Serum cytokines and lipopolysaccharide binding protein (LBP) were measured and the number and morphology of hippocampal microglia determined via immunohistochemistry. Intestinal mucous thickness and antimicrobial peptide expression were determined via fluorescent staining and real-time PCR (respectively) and microbial community composition was assessed using 16S rRNA gene amplicon sequencing. To determine whether the microbiota or the LBP receptor (CD14) are necessary for stressor-induced behavioral changes, experiments were performed in mice treated with a broad-spectrum antibiotic cocktail or in CD14 −/− mice. Results The stressor reduced Y-maze spontaneous alternations, which was accompanied by increased microglia in the hippocampus, increased circulating cytokines (eg, IL-6, TNF-α) and LBP, and reduced intestinal mucus thickness while increasing antimicrobial peptides and cytokines. These stressor-induced changes were largely prevented in mice given broad-spectrum antibiotics and in CD14 −/− mice. In contrast, social stressor-induced alterations of social behavior were not microbe-dependent. Conclusion Stressor-induced cognitive deficits involve enhanced bacterial interaction with the intestine, leading to low-grade, CD14-dependent, inflammation.

The Alleviation of Gut Microbiota-Induced Depression and Colitis in Mice by Anti-Inflammatory Probiotics NK151, NK173, and NK175

“…The pathogenesis of IBD is strongly involved in the mucosal immune imbalance toward the gut microbiome as well as host genetic factors [ 5 , 6 ]. Exposure to immobilization stress (IS) or social defeat induces depression with neuroinflammation through the upregulated expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in mice, resulting in gut inflammation and dysbiosis [ 7 , 8 ]. Many patients with mood disorders are diagnosed with IBD in clinic studies [ 9 , 10 ].…”

Large-scale imputation models for multi-ancestry proteome-wide association analysis

“…Importantly, they regulated neuronal homeostasis and the plasticity of neurons in response to acute stress or trauma 68 . Moreover, studies have highlighted CD14 as a central mediator in the cognitive behavioral reductions induced by social stressors 69 .…”

“…Moreover, studies have highlighted CD14 as a central mediator in the cognitive behavioral reductions induced by social stressors 69 .…”

The impact of acute and chronic stress on gastrointestinal physiology and function: a microbiota–gut–brain axis perspective

“…In contrast to permeability which has been studied throughout the intestine, effects on mucous secretion are usually best documented for the colon by examining goblet cells, the specialised epithelial cells that secrete mucins. These studies show enlarged goblet cells (Machorro‐Rojas et al., 2019), inconsistent effects on goblet cell number (Arciniega‐Martínez et al., 2022; Machorro‐Rojas et al., 2019) and a reduced colonic mucus layer thickness (Allen et al., 2022; Chen et al., 2021; Da Silva et al., 2014; Jaggers et al., 2022). Dysregulation of transcellular junctions associated with goblet cells may underlie some of the effects of stress‐induced gut barrier dysfunction.…”