Anti-depressive-like and cognitive impairment alleviation effects of Gastrodia elata Blume water extract is related to gut microbiome remodeling in ApoE−/− mice exposed to unpredictable chronic mild stress

Depression is a common mental disease, and approximately 280 million people worldwide suffer from it (Trautmann et al., 2016) Moreover, the World Health Organization (WHO) predicted that depression will become the world's first high-burden social disease and the first cause of disability by 2030 (World Health Organization, 2008). Several theories of depression pathophysiology have been proposed (Jesulola et al., 2018), including the monoamine deficiency hypothesis. Monoamine neurotransmitters, including serotonin (5-HT), dopamine (DA), adrenaline, and noradrenaline, play an indispensable role in normal physiological functions of the brain (Delgado, 2000). In particular, lower levels of cerebral 5-HT and DA are important pathogenic conditions of depression (Lopresti et al., 2012) and are involved in appetite, emotional constancy, and cognition (Roberts et al., 2020; Volkow et al., 2011).

The prefrontal cortex (PFC) is a brain region that correlates with major depressive disorder (MDD) (Pizzagalli and Roberts, 2022). Under stress intervention showing high levels of corticosteroids, synaptic plasticity impairment and synaptic selective atrophy results in PFC dysfunction, suggesting that the PFC is an important target region for stress-related psychiatric disorders, including depression (Cerqueira et al., 2005, 2007). Another study found that PFC dysfunction correlated with irregular cognitive control (CC), including abnormal behavior and cognition in several psychiatric disorders and neurological conditions (Friedman and Robbins, 2022). In a clinical study, people with a medical history of depression have a two-fold possibility of developing mild cognitive impairment (MCI) even dementia (Steffens et al., 2006), which suggested that depression can be a risk factor for MCI (Sanford, 2017; Swardfager and Black, 2013). MCI refers to lower cognitive ability, but the severity of the disease does not affect activities of daily living (Petersen et al., 1997). Patients with cognitive impairment, Alzheimer's disease, and dementia are found to have elevated levels of blood amyloid-β, a novel biomarker and risk factor for neurodegenerative diseases (Fandos et al., 2017).

Epidemiological studies found the link between depression and cardiovascular diseases (CVDs): Approximately 30% of patients with a history of myocardial infarction also have depression (Thombs et al., 2006), and nearly 20% percent of patients with a history of CVDs have comorbid depression (Carney and Freedland, 2017). In response to stress factors, the secretion of stress hormones such as glucocorticoids, including cortisol (human) and corticosterone (rodents) (Raff, 2016), results in elevation of the heart rate and blood pressure; moreover, these events increase the risk of CVDs (Nemeroff and Goldschmidt-Clermont, 2012). These findings indicate that depression and CVDs are risk factors for each other (Alcocer-Gomez and Cordero, 2017). Moreover, smoking, hypertension, and diabetes mellitus also are risk factors for cognitive impairment and CVDs, and CVDs involve the progression of cognitive impairment, resulting in cerebral hypoperfusion and hypoxia (Qiu and Fratiglioni, 2015). Notably, the current depression medications merely focus on monoamine neurotransmitter regulation, which may not be efficient in improving cognitive decline (Russo et al., 2015).

In recent years, the gut has been recognized as the second brain, and the gut microbiome and its metabolites have been linked to several neurological disorders (Carabotti et al., 2015). Gut microbiota transplantation in germ-free mice (GF) caused obvious depression-like behaviors in the open field test and forced swimming test (FST), indicating that the gut microbiota plays an essential role in the progression of depression (Zheng et al., 2016). Some beneficial bacteria such as Bifidobacterium and Lactobacillus are less abundant in patients with depression than in healthy patients (Aizawa et al., 2018). Interestingly, the administration of normal mouse microbiota can improve neurogenesis in GF mice (Ogbonnaya et al., 2015). Short-chain fatty acids (SCFAs) are bacterial products fermented by the gut microbiome from undigestible carbohydrates (Rios-Covian et al., 2016). Currently, acetic acid, propionic acid, and butyric acid are the three major SCFAs in the gut (Cummings et al., 1987; Canfora et al., 2015). The imbalance of SCFAs has been found to be associated with brain diseases such as depression, anxiety, and autism (Silva et al., 2020).

There are several depression-like animal models, such as chronic mild stress (CMS), FST, tail suspension test, and chronic social defeat stress (CSDS). CMS is a helpful model because it has the highest construct, predictive, and face validities (Abelaira et al., 2013). Unpredictable chronic mild stress (UCMS) is modified from CMS, and it applies several stress factors in an unpredictable program. It is also a practical animal model for depression research under chronic stress (Huang et al., 2019; Lin et al., 2016; Planchez et al., 2019).

ApoE−/− mice are a common CVDs animal model (Vasquez et al., 2012) because it lacks the ApoE gene, resulting in elevated blood lipid levels and spontaneous acceleration of atherosclerosis progression (Plump et al., 1992). Compared with wild-type mice, ApoE−/− mice develop fatty streaks in the proximal aorta at approximately 12 weeks of age, even when fed with a regular chow diet (Zhang et al., 1992). Under the normal chow diet, foam cell lesions were found in younger ApoE−/− mice (10 weeks-old), the pathological conditions of foam and smooth muscle cells at 15 weeks of age, and fibrous plaques emerged at approximately 20 weeks (Meir and Leitersdorf, 2004). There is currently no in-depth study on depression and cognitive impairment in ApoE−/− mice. Therefore, we used UCMS to induce depressive-like behavior and cognitive impairment in ApoE−/− mice, which mimics CVDs patients with depression and cognitive decline.

Gastrodia elata Blume (GE), commonly known as Tiān má (天麻), is a traditional Chinese dietary therapy ingredient in ancient Chinese medical books. GE has been used to a settle fright and tranquilize (藥性論 Yào xìng lùn), as written by Zhēn quán. GE could tranquillize and stabilize the essence-spirit (Complete Works of Jingyue (Jingyuequanshu), as written by Zhang Jiebin in 1640. Studies have shown that GE has a potent effect on neurological and mood disorders such as dizziness, epilepsy, headache, depression, and anxiety (Zhan et al., 2016). The active components of GE, such as gastrodin, 4-Hydroxybutyl acrylate, and vanillin, have been shown to have neuroprotective and anti-depressant-like effects, and the content of gastrodin is a quality indicator of GE (Tao et al., 2009). WGE has a practical antidepressant-like function in FST (Lin et al., 2014; Chen et al., 2016), UCMS (Lin et al., 2016), and CSDS models (Lin et al., 2018). WGE exhibits neuroprotective and anti-depressant-like effects via neurotransmitter regulation, hypothalamic-pituitary-adrenal axis modulation, neuroplasticity improvement (Chen and Sheen, 2011; Lin et al., 2014); Lin et al., 2016), and microbiome reconstruction (Hua et al., 2019; Huang et al., 2021). The active compound gastrodin alleviates chronic inflammatory pain and depression-like and anxiety-like behaviors in vivo (Xiao et al., 2016; Wang et al., 2014; Peng et al., 2013). Furthermore, it can detoxify and elevate the antioxidative ability of β-amyloid (Aβ)-induced Alzheimer's disease (AD) in vitro and in vivo (Zhao et al., 2012).

Therefore, WGE has the potential to alleviate depression. However, studies on the psychological disorders in ApoE−/− mice that mimic CVDs cases with depression/cognitive impairment that occur through the gut microbiota and its metabolite-related pathways are lacking. Therefore, this study aimed to investigate the role of the gut microbiome in the anti-depressive-like and cognitive impairment alleviation effects of WGE in ApoE−/− mice induced with UCMS.

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