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Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity.

ABSTRACT: Chronic stress manifests as depressive- and anxiety-like behavior while recurrent stress elicits disproportionate behavioral impairments linked to stress-induced immunological priming. The gut-brain-microbiota-axis is a promising therapeutic target for stress-induced behavioral impairments as it simultaneously modulates peripheral and brain immunological landscapes. In this study, a combination of probiotics and prebiotics, known as a synbiotic, promoted behavioral resilience to chronic and recurrent stress by normalizing gut microbiota populations and promoting regulatory T cell (Treg) expansion through modulation of ileal innate lymphoid cell (ILC)3 activity, an impact reflecting behavioral responses better than limbic brain region neuroinflammation. Supporting this conclusion, a multivariate machine learning model correlatively predicted a cross-tissue immunological signature of stress-induced behavioral impairment where the ileal Treg/T helper17 cell ratio associated to hippocampal chemotactic chemokine and prefrontal cortex IL-1β production in the context of stress-induced behavioral deficits. In conclusion, stress-induced behavioral impairments depend on the gut-brain-microbiota-axis and through ileal immune regulation, synbiotics attenuate the associated depressive- and anxiety-like behavior.

SUBMITTER: Westfall S

PROVIDER: S-EPMC8264434 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity.

Westfall Susan S Caracci Francesca F Estill Molly M Frolinger Tal T Shen Li L Pasinetti Giulio M GM

Frontiers in immunology 20210624

Chronic stress manifests as depressive- and anxiety-like behavior while recurrent stress elicits disproportionate behavioral impairments linked to stress-induced immunological priming. The gut-brain-microbiota-axis is a promising therapeutic target for stress-induced behavioral impairments as it simultaneously modulates peripheral and brain immunological landscapes. In this study, a combination of probiotics and prebiotics, known as a synbiotic, promoted behavioral resilience to chronic and recu ...[more]

PMID: 34248950

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Project description:BackgroundThe effect of chronic psychological stress on hepatitis and liver fibrosis is concerned. However, its mechanism remains unclear. We investigated the effect and mechanism of chronic psychological stress in promoting liver injury and fibrosis through gut.MethodsSixty male SD rats were randomly assigned to 6 groups. Rat models of chronic psychological stress (4 weeks) and liver fibrosis (8 weeks) were established. The diversity of gut microbiota in intestinal feces, permeability of intestinal mucosa, pathologies of intestinal and liver tissues, collagen fibers, protein expressions of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), nuclear factor kappa β (NF-κβ), tumor necrosis factor α (TNF-α) and interleukin 1 (IL-1) in liver tissue, liver function and coagulation function in blood and lipopolysaccharide (LPS) in portal vein blood were detected and analyzed.ResultsThe diversities and abundances of gut microbiota were significant differences in rats among each group. The pathological lesions of intestinal and liver tissues, decreased expression of occludin protein in intestinal mucosa, deposition of collagen fibers and increased protein expression of TLR4, MyD88, NF-κβ, TNF-α and IL-1 in liver tissue, increased LPS level in portal vein blood, and abnormalities of liver function and coagulation function, were observed in rats exposed to chronic psychological stress or liver fibrosis. There were significant differences with normal rats. When the dual intervention factors of chronic psychological stress and liver fibrosis were superimposed, the above indicators were further aggravated.ConclusionChronic psychological stress promotes liver injury and fibrosis, depending on changes in the diversity of gut microbiota and increased intestinal permeability caused by psychological stress, LPS that enters liver and acts on TLR4, and active LPS-TLR4 pathway depend on MyD88. It demonstrates the possibility of existence of brain-gut-liver axis.

Project description:BackgroundMost of the previous studies have demonstrated the potential antidepressive and anxiolytic role of prebiotic supplement in male subjects, yet few have females enrolled. Herein, we explored whether prebiotics administration during chronic stress prevented depression-like and anxiety-like behavior in a sex-specific manner and the mechanism of behavioral differences caused by sex.MethodsFemale and male C57 BL/J mice on normal diet were supplemented with or without a combination of fructo-oligosaccharides (FOS) and galacto-oligosaccharides (GOS) during 3- and 4-week chronic restraint stress (CRS) treatment, respectively. C57 BL/J mice on normal diet without CRS were used as controls. Behavior consequences, gut microbiota, dysfunction of gut and brain-blood barriers, and inflammatory profiles were measured.ResultsIn the 3rd week, FOS + GOS administration attenuated stress-induced anxiety-like behavior in female, but not in male mice, and the anxiolytic effects in males were observed until the 4th week. However, protective effects of prebiotics on CRS-induced depression were not observed. Changes in the gene expression of tight junction proteins in the distal colon and hippocampus, and decreased number of colon goblet cells following CRS were restored by prebiotics only in females. In both female and male mice, prebiotics alleviated stress-induced BBB dysfunction and elevation in pro-inflammatory cytokines levels, and modulated gut microbiota caused by stress. Furthermore, correlation analysis revealed that anxiety-like behaviors were significantly correlated with levels of pro-inflammatory cytokines and gene expression of tight junction proteins in the hippocampus of female mice, and the abundance of specific gut microbes was also correlated with anxiety-like behaviors, pro-inflammatory cytokines, and gene expression of tight junction proteins in the hippocampus of female mice.ConclusionFemale mice were more vulnerable to stress and prebiotics than males. The gut microbiota, gut and blood-brain barrier, and inflammatory response may mediate the protective effects of prebiotics on anxiety-like behaviors in female mice.

Project description:Emerging evidence suggests that the gut microbiota may interact with the host brain and play pivotal roles in the pathogenesis of neuropsychiatric disorders. However, the mechanism underlying reciprocal interactions along the microbiota-gut-brain axis in depression remains unclear. In this study, a murine model of chronic restraint stress (CRS) was established to investigate the metabolic signaling of tryptophan (Trp) neurotransmission at the intestinal and central levels in depression. The results showed that CRS mice displayed depression- and anxiety-like behaviors. Additionally, kynurenine (Kyn) and its metabolites, an important Trp metabolic pathway, were strongly activated in the brain. Intriguingly, the Kyn toxic signaling was exacerbated in the gut, especially in the colon. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme responsible for Kyn metabolic pathway initiation, was significantly upregulated in the brain and gut in CRS mice compared with control mice, promoting transfer of Trp metabolic pathway to Kyn signaling. Additionally, administration of IDO inhibitor, 1-methyl-tryptophan (1-MT), partially rescued CRS-induced depression- and anxiety-like changes. Moreover, the enhanced intestinal permeability mediated by CRS allowed toxic metabolites to "leak" into the bloodstream. The microbiome profiles of CRS mice displayed obviously altered taxonomic composition and negative correlations were observed between Enterorhabdus, Parabacteroides and Kyn levels in the brain. Reciprocal crosstalk between the brain and gut was further validated by citalopram treatment, IDO inhibitor and microbiota intervention, which counteracted depression-like behavior, Kyn metabolic signaling and microbiota composition in CRS mice. Meanwhile, Parabacteroides treatment affected Trp metabolism in mouse hippocampus, manifesting as elevated concentration of 5-HT as well as ratio of 5-HT to Trp. These results suggest that long-term stress disrupts Kyn metabolism and endocrine function along the gut-brain axis, accompanied by the disrupted homeostasis of certain microbiota, which collectively contribute to the development of depression-like behavior.

Dataset Information

Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity.

Publications

Chronic Stress-Induced Depression and Anxiety Priming Modulated by Gut-Brain-Axis Immunity.

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