Shugan Hewei Decoction Alleviates Cecum Mucosal Injury and Improves Depressive- and Anxiety-Like Behaviors in Chronic Stress Model Rats by Regulating Cecal Microbiota and Inhibiting NLRP3 Inflammasome.

Yingying Yue,Xian Zhou,Miaoqi Chen,Xin Chen,Yunya Lin,Songlin Liu,Yu Chen,Hao Liu,Lesi Xu,Lin Liu,Yingqian Zhao,Hao Ming

doi:10.3389/fphar.2021.766474

Yingying Yue, Xian Zhou + Show 10 more

Open Access

https://doi.org/10.3389/fphar.2021.766474

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Abstract

Chronic stress is a significant cause of depression, anxiety, and intestinal mucosal injury. Gut microbiota disturbances are also associated with these disorders. Shugan Hewei Decoction (SHD), which is a traditional Chinese medicine formula developed by our team, has shown superior therapeutic effects in the treatment of depression, anxiety, and functional gastrointestinal diseases caused by chronic stress. In this study, we investigated the modulatory effect of SHD on the cecal microbiota and cecum mucosal NOD-like receptor protein 3 (NLRP3) inflammasome in a chronic unpredictable stress (CUS)/social isolation rat model. After the SHD intervention, the CUS model rats showed improvements in their depressive- and anxiety-like behaviors, as well as sustained body weight growth and improved fecal characteristics. SHD improved the cecal microbiota diversity and changed the abundance of six microbial genera. A Spearman’s correlation analysis showed a strong correlation between the NLRP3 inflammasome and CUS-perturbed cecal biomarker microbiota. SHD regulated the excessive expression of NLRP3, ASC, caspase-1, interleukin-1β (IL-1β), and IL-18 in the serum and cecum mucosa induced by CUS, as well as the activation of the Toll-like receptor 4/nuclear factor-κB signaling cascades. Our results reveal the pharmacological mechanisms of SHD and provide a validated therapeutic method for the treatment of depression, anxiety, and cecum mucosal injury.

Highlights

Chronic stress due to social pressure or negative emotional stimulation can lead to psychological and somatic manifestations, such as anxiety, depression, and functional gastrointestinal disorders (Qin et al, 2014; Stefanaki et al, 2018), all of which endanger public physical and psychological health (Baxter et al, 2013)
We demonstrated that Shugan Hewei Decoction (SHD) may alleviate cecum mucosal injury by maintaining intestinal microbiota homeostasis and inhibiting the excessive activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and Toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway, which improves depressive-like behaviors and the ability of SHD to regulate neurotransmitter release
The p-NF-κB/NF-κB and myeloid differentiation factor 88 (MyD88) protein expression levels were increased in the model group in comparison with the control group (p < 0.01 and p < 0.05, respectively), and they were further upregulated by the SHD-L and SHD-H interventions (p < 0.01 and p < 0.05, respectively), while they were downregulated by FOS (p < 0.01 and p < 0.05, respectively) in comparison with the model group (Figures 6N,O). These results indicate that SHD can modulate the TLR4/NF-κB signaling pathway, which is involved in NLRP3 inflammasome expression and the downstream production of IL-1β and IL-18 in serum and cecal tissue

Summary

Introduction

Chronic stress due to social pressure or negative emotional stimulation can lead to psychological and somatic manifestations, such as anxiety, depression, and functional gastrointestinal disorders (Qin et al, 2014; Stefanaki et al, 2018), all of which endanger public physical and psychological health (Baxter et al, 2013). Chronic stress-induced gastrointestinal symptoms are associated with intestinal mucosal injury, which further exacerbates inflammatory reactions (Wei et al, 2019). The intestinal microbiome plays an important role in the incidence of gastrointestinal diseases induced by mental and psychological factors (Karl et al, 2018). The NLRP3 inflammasome acts as a bridge between stress and the intestinal immune response, and it plays a dual role in promoting inflammation and maintaining intestinal homeostasis, both of which affect gastrointestinal function (Lamkanfi and Dixit, 2014). The intestinal microbiota and NLRP3 inflammasome are involved in the development of depression, anxiety, and functional gastrointestinal disorders that are induced by chronic stress; they are recognized as potential targets for managing stress-related diseases

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