Discussion,on,the,treatment,of,Alzheimer's,disease,from,the,spleen,based,on,intestinal,flora

XIAO Yu-wen, WU Lin✉ , JIANG Jia-qiao, BIN Xin-ming, JIANG Yu-long, CHEN Wei

1. Guangxi University of Traditional Chinese Medicine, Nanning 530200, China

2. First Teaching Hospital of Guangxi University of Traditional Chinese Medicine, Nanning 530023, China

Keywords:Senile dementia Intestinal flora Treatment from the spleen

ABSTRACT Alzheimer"s disease (AD) is a clinically common degenerative disease of the central nervous system with a complex pathogenesis, which seriously endangers the physical and mental health of the elderly. In recent years, a large number of studies have shown that the intestinal flora can regulate the central nervous system through the brain-gut axis, thereby participating in the occurrence and development of AD. AD belongs to the category of "dementia" and"forgetfulness" in traditional Chinese medicine. It is caused by internal injury of seven emotions, old age and chronic illness, which can cause insufficient blood, deficiency of kidney essence, and blockage of phlegm and blood. To use, treat more from the heart, liver and kidney.We believe that phlegm turbidity blocking the orifice is the key to the pathogenesis of AD. It should be treated from the spleen, and according to the characteristics of the pathogenesis, the method of warming the spleen and dredging the collaterals and resuscitation is proposed to prevent AD. This article takes the intestinal flora as the starting point to discuss the research progress of treating AD from the spleen.✉Corresponding author:WU Lin, M.D., Chief Physician, Doctoral Supervisor,E-mail:358304005@qq.com.

AD progressive cognitive dysfunction and behavioral impairment are the main clinical features. Its main pathological changes are the aggregation of β-amyloid (amyloid-β, Aβ) to form senile plaques,and the hyperphosphorylation of Tau protein causes intracellular neurofibrillary tangles. Nodes (neurofibrillary tangles, NFTs)and apoptosis of neurons and their synapses [1]. The survey found that AD is the most common cause of cognitive impairment and behavioral disorders in the elderly, and the most common type of dementia in old age, accounting for about 60% of dementia [2].With the advent of an aging society, the incidence of AD has been increasing year by year, and it has become one of the public health problems of global concern. The intestinal flora colonizes the human intestine, which can regulate the host"s immune function and improve the intestinal barrier function, and participate in the maintenance of complex metabolic and behavioral processes mediated by the peripheral organ system and central nervous system neuronal groups [3]. The theoretical system of traditional Chinese medicine believes that the intestinal flora is closely related to the physiological functions and characteristics of the spleen, indicating that it is feasible to explore the treatment of AD from the spleen based on the intestinal flora.

The intestine and the central nervous system cross each other, and this pathway is called the brain-gut axis. The intestinal flora is large in number and diverse in variety, and it is the "second genome"of humans [4]. A variety of neurological and immunomodulatory substances produced by metabolism can participate in the activities of the central nervous system through the brain-gut axis. The integrity of the bidirectional brain-gut signaling pathway depends on a functionally active and healthy microbiota.

2.1 Intestinal flora participates in the mechanism of AD

The large accumulation of β-amyloid protein is the main pathological key to the cognitive dysfunction in AD patients. Studies have confirmed [5,6] that bacteria can synthesize and secrete a large amount of lipopolysaccharides (LPSs) and amyloid. These LPSs and amyloid will increase the level of Aβ in the hippocampus and promote the formation of amyloid fibrils. Induces the formation and aggregation of β-amyloid in the brain; in addition to LPS, many bacterial strains, including Escherichia coli, Staphylococcus aureus,Salmonella enteritidis, etc., can also accumulate protein-containing misfolded Aβ. A large amount of amyloid is produced, which may be the source of misfolding due to activation of neuroinflammation [7,8].All these indicate that the intestinal flora is related to the production of β-amyloid that causes AD. The neurofibrillary tangles formed by the accumulation of hyperphosphorylated Tau protein in neurons lead to a neuroinflammatory response, leading to a large number of glial cells and neuronal apoptosis, and cognitive behavioral impairment [9].Tau protein phosphorylation mainly occurs on the residues of serine and threonine. In phosphorylated Tau protein kinases containing a large number of serine and threonine residues, proline-directed Tau protein kinase glycogen synthase kinase-3 Cyclin-dependent protein kinase-5 is the main kinase that induces phosphorylation of Tau protein, and the intestinal flora is the main participant in the synthesis of amino acids such as serine, threonine and proline[10], indicating that the intestine The tract flora and AD can communicate with each other through serine, threonine and proline.In addition, neuroinflammation is also an important participant in the pathogenesis of AD, among which astrocytes and microglia have largely driven the production of neuroinflammation. Wang et al. [11]experimentally found that in the progress of AD, intestinal flora disorder will increase the concentration of phenylalanine and isoleucine in the peripheral blood, and stimulate pro-inflammatory cells Proliferation and differentiation, thereby activating M1 microglia, which continuously activates to become reactive microglia, participates in the occurrence of neuroinflammation, and thus mediates the apoptosis of brain tissue and neurons; at the same time, microglia Activation promotes the activation of astrocytes.The activation of the two types of cells increases the permeability of the blood-brain barrier (BBB), leading to the invasion of different bacteria, viruses and their neuroactive products that lead to neuroinflammatory reactions, further aggravating neuroinflammation Response, reducing synapse remodeling and causing neuron death, cognitive dysfunction [12,13]. It is also for this reason that improving intestinal disorders and reducing the accumulation of related phenylalanine and isoleucine can reduce neuro-inflammatory responses and improve cognitive impairment. As explained above,intestinal microbes participate in the pathological changes of AD by regulating the accumulation of β-amyloid protein, Tau protein overacidification and neuroinflammation.

2.2 The regulation of intestinal flora and the prevention and treatment of AD

Experiments such as Akbari [14] confirmed that after 12 weeks of probiotic milk feeding, compared with the normal milk control group, the results found that the MMSE score of Alzheimer"s disease patients in the experimental group was significantly improved (P<0.001), learning and memory Ability is significantly higher than the control group. After the intervention of fecal bacteria transplantation(FMT), the learning and memory ability and Aβ deposition of dementia mice were tested, and it was found that compared with AD mice, the FMT group mice had a significant increase in the number of crossing platforms, extended residence time in the target quadrant,and shortened the escape latency. The decrease of neurofibrillary tangles caused by β-like protein plaques and Tau protein hyperphosphorylation, and the decrease in the expression of agingrelated proteins in brain tissue. In addition, the fecal microbiota can also inhibit the abnormality of inflammatory cells in the blood of AD mice The expression indicates that FMT intervention can improve the glial responsiveness and learning and memory ability of Alzheimer"s disease mice by reducing Aβ deposition in brain tissue [15,16]. Therefore, restoring the balance of intestinal microbes in the human body may have a positive effect on the treatment of AD. Clostridium prasutii is a butyrate-producing bacterium,which has anti-inflammatory effects, regulates the intestinal flora,and the content of Clostridium pruritus in the intestine increases significantly, reduces the body"s inflammatory response, and is of great significance for preventing the occurrence of AD[17].Ingestion of bioactive food (BF) can restore the composition of the intestinal microbiota, reduce Aβ aggregation, and inhibit Tau protein hyperphosphorylation, significantly reduce the activation level of astrocytes and microglia, and reduce neuroinflammation. Improve cognition [18]. This article believes that by adjusting the intestinal microecological balance, it can promote neuronal repair, inhibit neuroinflammation and neuronal apoptosis, and achieve the purpose of preventing AD.

Traditional Chinese medicine generally believes that the main disease location of AD is located in the brain, and is closely related to the heart, liver, spleen, and kidneys. The main pathogenesis is divided into two ends of deficiency and excess, one is deficiency of Qi, blood, and essence, one is deficiency of marrow sea, and the other is sputum. , Blood stasis, qi, fire, etc. are caused by obstructing the clear orifice. However, it is not difficult to see from the above articles that the occurrence and development of dementia are closely related to the spleen. The Chinese medicine theory believes that the five elements of the spleen belong to the soil, and the soil conceives everything. It can irrigate the liver, heart, lungs, and kidneys by turning water into body fluid. Zang, "The spleen is a solitary viscera,and the central soil is used to irrigate all four sides" in "Suwen. On the True Zangs of Jade Machine" is for this purpose. The spleen can transport and transform the essence of water and valley, transform vitality and blood, and nourish the internal organs. If the spleen is not healthy, the qi and blood can not be transformed, the brain orifice is lost, the marrow sea is empty, and the mental machine is ineffective;"the spleen is the source of phlegm", the spleen The dysfunction of Yunhua water will cause dampness to accumulate and phlegm will grow. Phlegm will block the airway and qi will be stagnant. Phlegm will block the vasculature and blood flow will cause blood stasis.Phlegm, qi and stasis will harm each other, blinding and clearing the orifice. dementia.

3.1 The physiological functions and characteristics of the spleen and AD

3.1.1 The spleen governs transportationSpleen transports and transforms cereals: the spleen promotes the digestion of food, absorbs its subtleties, transmits to the heart and lungs, transforms vitality and blood, spreads the whole body, nurtures the viscera, body, and organs, and the body functions normally, so the spleen is " "The foundation of acquired", "the source of qi and blood biochemistry". The brain is the home of the primordial spirit,the lord of the body, and the source of the divine machine. Its normal operation is mainly nourished and supplemented by the essence of the sky. Inability to metabolize, leading to a series of symptoms such as forgetfulness, sluggishness, clumsiness, dullness, etc., which lead to a series of symptoms of mental retardation and abnormal thinking activities, such as loss of fullness and nourishment of the clear orifice, and empty marrow sea.

The spleen transports and transforms the water: the spleen will drink the water into water and body fluid, and then absorb and transport it to the internal organs of the whole body. "Su Wen · Zhi Zhen Yao Da Lun" stated that "all dampness and swelling belong to the spleen", indicating that the spleen is an important organ involved in the metabolism of water and fluid, and the spleen is the hub for the movement of water and fluid. "The spleen is the source of phlegm."The spleen should be blamed for the phlegm. The spleen loses its vitality, the dampness does not become phlegm, and the phlegm dampness blocks the circulation of qi and blood, which eventually leads to stagnation of qi, phlegm coagulation, and blood stasis, and disturbs the orifices of clearing the spirit, making the mind unclear,and dementia .

3.1.2 The Spleen Masters Purification

The "Huangdi Nei Jing" states that "drink into the stomach,overflow essence and qi, and lose essence on the spleen, and the spleen disperses essence." "Shengqing" means that the spleen absorbs nutrients such as the essence of water and grains, and then transports them upwards to the head, eyes, heart, lungs, etc. The "Lei Jing" points out: "The essence of the five internal organs and six fuorgans rise above the head for the purpose of forming seven orifices.Therefore, the spleen absorbs and transfers water to the spleen and the essence of the spleen is normal, and the smart house can perform its normal physiological functions. "If the spleen should rise, then the spleen will be healthy." If the spleen is weak, the function of transporting and dissolving the water will be ineffective, phlegm will become over time, and the phlegm will become heavy and turbid,causing the clearing of the qi to not rise, and the turbid yin will be disturbed. Seeing dizziness, speaking less laziness, in severe cases,unconsciousness, indifferent expression, impermanence of crying and laughing, and development of dementia.

3.2 Clinical experience in the treatment of dementia from the spleen

Chen Shiduo, a physician in the Qing Dynasty, believed that"phlegm is the most vigorous and dullness is the deepest", and put forward the view that "there is no strange way to treat dullness, and that treatment of dullness means treating dullness. On the basis of previous experience, Professor Wu Lin summed up his own clinical practice, proposed "treatment of dementia from the spleen", and used"Wenpi Tongluo Kaiqiao method" to prevent and treat AD (Wenpi Tongluo Kaiqiao Decoction: Astragalus 30g, Shichangpu 10g ,Panax notoginseng 10g, Gynostemma 10g, Yizhiren 10g, Polygonum multiflorum 10g). Jiang Lingfei et al. [19] found that after the intervention of Wenpi Tongluo Kaiqiao Decoction, the total effective rate (87.50%) of the observation group was significantly better than that of the control group (77.50%) (P<0.05); the MMSE score and Hcy concentration of the observation group were also higher The control group was significantly improved (P<0.05), indicating that Wenpi Tongluo Kaiqiao Decoction has a definite effect on the clinical symptoms and neurological deficits of AD patients with phlegm turbidity blocking orifice syndrome. Chen Wei, Wang Qingbi [20] and other experiments found that Wenpi Tongluo Kaiqiao Decoction can inhibit the β-secretase activity of AD model rats,reduce neuronal apoptosis and hippocampal neuron damage, and improve the learning and memory ability of dementia rats . Wu Lin and Yang Jinping [21,22] found that Wenpi Tongluo Kaiqiao Recipe has a significant effect on improving the learning and memory impairment of AD rats. The mechanism of action may be to reduce the activation of GSK-3β and increase the activity of PP2A, thereby increasing the activity of PP2A. Inhibit abnormal phosphorylation of tau protein. Wen Huijuan et al [23] found through in vitro cell culture that the method of warming the spleen and collaterals for resuscitation can inhibit the secretion of potentially neurotoxic IL-1β, IL-6 and TNF-α inflammatory factors, reduce microglia inflammation, and exert nerves Protective effect, which may be one of the mechanisms for the treatment of AD.

Pharmacological studies have shown that the normal function of intestinal flora is closely related to traditional Chinese medicine, and the absorption and metabolism of many traditional Chinese medicines require the intestinal flora to fully exert their pharmacological effects. Conversely, the active ingredients of traditional Chinese medicine can also directly affect the types and abundance of intestinal flora, and regulate the body through the intestinal flora and its metabolites as a medium to regulate the central system. Studies have shown that the traditional Chinese medicines in Wenpi Kaiqiao Tongluo Decoction: Astragalus, Shichangpu,Polygonum multiflorum, Yizhiren, Panax notoginseng, Gynostemma pentaphyllum can regulate the intestinal microecological diversity[24,29].

Astragalus is sweet and warm in nature, and it is returned to the spleen and lung meridian. It has a good effect of invigorating the spleen and replenishing qi. He Yixin et al. [30] experiments confirmed that astragaloside can reduce the activation of microglia and astrocytes in the hippocampus of mice, inhibit neuroinflammation,protect the integrity of the blood-brain barrier, and reduce the central nervous system. In addition, Astragalus can also regulate the relative expression of Bcl-2, Bax, p53 and caspase 3 proteins, significantly reducing the phosphorylation of tau protein, and its main active substance is metabolized by the intestine, indicating the intestinal flora It may be an important material basis for participating in the effectiveness of the drug. Shichangpu is pungent, bitter, dry and warm, and can enter the stomach meridian. It is a good product for refreshing the mind, improving the mind, and resuscitating the phlegm. Wu Qiduan et al [31] found that Shichangpu has the effects of anti-hypoxia, scavenging free radicals, inhibiting cell apoptosis of brain tissue cortex and hippocampus, and improving memory and cognitive dysfunction. Studies have also pointed out that Shichangpu"s improvement of the symptoms of dementia mice is mainly related to the three components of α-asarone, β-asarone and eugenol. The mechanism of action may be to accelerate the decomposition of APP or reduce the expression of APP to make Aβ The accumulation of Aβ is reduced, thereby inhibiting the damage of Aβ to nerve cells and synaptic structure, and improving the ability of learning and memory[32]. Studies have found that the effect of Shichangpu in improving learning and memory impairment may be achieved by regulating the function of intestinal flora[33]. Yizhiren enters the spleen meridian, has the effect of warming the spleen and the kidney, and is commonly used in the treatment of AD. The monomer compound protocatechuic acid isolated from Yizhiren can improve the memory ability of old rats. The protective mechanism is to reduce the cytotoxicity of Aβ1-42 and reduce the damage of hippocampal neurons [34]. Gynostemma pentaphyllum has a cool,bitter and slightly sweet taste, which can invigorate the spleen,nourish qi and resolve phlegm. Recent studies have found that AD model mice fed with gypenosides for 3 consecutive months have significantly reduced levels of hyperphosphorylated Tau protein and Aβ expression, and cognitive ability has been improved [35].In addition, the total saponins of Gynostemma pentaphyllum can also promote the conversion of microglia from type M1 to type M2,reduce the activity of microglia induced by Aβ, inhibit nerve cell inflammation, and improve AD symptoms [36].

The prevention and treatment of AD has been a problem in the medical field since ancient times, and there is still no breakthrough progress. Currently, the main drugs used to treat AD and prevent further deterioration of the disease are divided into two categories:cholinesterase inhibitors and NMDA receptor antagonist memantine.Although these drugs can improve the cognitive dysfunction of AD to a certain extent, they cannot Effectively reverse the progress of AD without achieving a definite cure effect. The self-care ability and overall function of AD patients have not been effectively improved.Some drugs have even been banned from clinical use due to their serious side effects [37] Therefore, it is particularly important to find new drugs to prevent and treat AD. Traditional Chinese medicine is a treasure of the Chinese nation. The prevention and treatment of diseases in TCM emphasizes a holistic view and pays attention to dialectical treatment. We believe that the weakness of the spleen and stomach is the root cause of AD. Phlegm and blood stasis are the key link in the pathogenesis of AD. Therefore, TCM treatment AD can be treated from the spleen. Since the spleen and stomach of Chinese medicine have similar properties to the digestive system of modern medicine, the theory of "treatment of dementia from the spleen"coincides with the modern medical viewpoint that AD originated from the intestinal tract. Explore the relationship between central nervous system diseases and intestinal flora, provide new ideas and new methods for the treatment of AD, and promote the development of traditional Chinese medicine culture.

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