Repeated Social Defeat Stress Induces an Inflammatory Gut Milieu by Altering the Mucosal Barrier Integrity and Gut Microbiota Homeostasis

Yadav, Santosh Kumar; Ahmad, Rizwan; Moshfegh, Cassandra; Sankarasubramanian, Jagadesan; Joshi, Vineet V.; Elkhatib, Safwan; Chhonker, Yashpal S.; Murry, Daryl J.; Talmon, Geoffrey A.; Guda, Chittibabu; Case, Adam J.; Singh, Amar B.

doi:10.1016/j.bpsgos.2023.03.005

Cited by 3 publications

(3 citation statements)

References 78 publications

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“…The trans-epithelial resistance was determined as described previously and is represented as Ω xcm2. 71 …”

Section: Methodsmentioning

confidence: 99%

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Loss of claudin-3 expression increases colitis risk by promoting Gut Dysbiosis

Ahmad,

Kumar,

Thapa

et al. 2023

Gut Microbes

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Dysregulation of both the gut barrier and microbiota (dysbiosis) promotes susceptibility to and severity of Inflammatory Bowel Diseases (IBD). Leaky gut and dysbiosis often coexist; however, potential interdependence and molecular regulation are not well understood. Robust expression of claudin-3 (CLDN3) characterizes the gut epithelium, and studies have demonstrated a positive association between CLDN3 expression and gut barrier maturity and integrity, including in response to probiotics. However, the exact status and causal role of CLDN3 in IBD and regulation of gut dysbiosis remain unknown. Analysis of mouse and human IBD cohorts helped examine CLDN3 expression in IBD. The causal role was determined by modeling CLDN3 loss of expression during experimental colitis. 16S sequencing and in silico analysis helped examine gut microbiota diversity between Cldn3 KO and WT mice and potential host metabolic responses. Fecal microbiota transplant (FMT) studies were performed to assess the role of gut dysbiosis in the increased susceptibility of Cldn3 KO mice to colitis. A significant decrease in CLDN3 expression characterized IBD and CLDN3 loss of expression promoted colitis. 16S sequencing analysis suggested gut microbiota changes in Cldn3 KO mice that were capable of modulating fatty acid metabolism and oxidative stress response. FMT from naïve Cldn3 KO mice promoted colitis susceptibility in recipient germ-free mice (GFM) compared with GFM-receiving microbiota from WT mice. Our data demonstrate a critical role of CLDN3 in maintaining normal gut microbiota and inflammatory responses, which can be harnessed to develop novel therapeutic opportunities for patients with IBD.

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“…The trans-epithelial resistance was determined as described previously and is represented as Ω xcm2. 71 …”

Section: Methodsmentioning

confidence: 99%

“…Immunoblot, immunofluorescence, and immunohistochemistry analyses were performed as described previously. 71 …”

Section: Methodsmentioning

confidence: 99%

Loss of claudin-3 expression increases colitis risk by promoting Gut Dysbiosis

Ahmad,

Kumar,

Thapa

et al. 2023

Gut Microbes

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“…A majority of stressed mice develop a behavioural phenotype characterized by social avoidance 20 and reduced preference for natural rewards (anhedonia), including impaired social reward 23 . They also develop several physiological disturbances, such as metabolic syndrome, systemic inflammation and gastrointestinal disturbances 10 , 24 . These mice are termed stress-susceptible (SUS) mice.…”

Section: Chronic Stress Affects Monocytesmentioning

confidence: 99%

Circulating myeloid-derived MMP8 in stress susceptibility and depression

Cathomas,

Lin,

Chan

et al. 2024

Nature

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Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

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Resveratrol: A Multifaceted Guardian against Anxiety and Stress Disorders—An Overview of Experimental Evidence

Tseilikman,

Yegorov

et al. 2024

Nutrients

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The medicinal properties of resveratrol have garnered increasing attention from researchers. Extensive data have been accumulated on its use in treating cardiovascular diseases, immune system disorders, cancer, neurological diseases, and behavioral disorders. The protective mechanisms of resveratrol, particularly in anxiety-related stress disorders, have been well documented. However, less attention has been given to the side effects of resveratrol. This review explores not only the mechanisms underlying the anxiolytic effects of resveratrol but also the mechanisms that may lead to increased anxiety following resveratrol treatment. Understanding these mechanisms is crucial for enhancing the efficacy of resveratrol in managing anxiety disorders associated with stress and PTSD.

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Repeated Social Defeat Stress Induces an Inflammatory Gut Milieu by Altering the Mucosal Barrier Integrity and Gut Microbiota Homeostasis

Cited by 3 publications

References 78 publications

Loss of claudin-3 expression increases colitis risk by promoting Gut Dysbiosis

Loss of claudin-3 expression increases colitis risk by promoting Gut Dysbiosis

Circulating myeloid-derived MMP8 in stress susceptibility and depression

Resveratrol: A Multifaceted Guardian against Anxiety and Stress Disorders—An Overview of Experimental Evidence

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