Prevention and Treatment of Alzheimer's Disease Via the Regulation of the Gut Microbiota With Traditional Chinese Medicine

Isoorientin, a natural C‐glucosyl flavonoid from Polygonum orientale, is a highly selective inhibitor of glycogen synthase kinase‐3β (GSK‐3β) [77]. Chronic administration of isoorientin to APP/PS1 mice significantly reduced GSK‐3β hyperactivation, tau protein hyperphosphorylation, and Aβ deposition in AD, and led to reverse prolonged synaptic activation and spatial memory impairment [78]. Isoorientin reduced the abundances of Alteromonas, Campylobacterales, and uncultured Bacteroidales bacterium and significantly reduced Aβ₄₂ deposition and p‐tau deposition in the hippocampus and cortex in APP/PS1 mice [79]. Isoorientin partially reversed the decreased abundances of Muribaculaceae and Prevotellaceae and the increased abundance of Erysipelotrichaceae in scopolamine‐induced AD mice [80]. These microorganisms were related to inflammatory factors and pathways, including the TNF‐α, IL‐4, IL‐10, GSK‐3β, MAPK, and NF‐κB pathways [79, 80].

Curcumin is isolated from Curcuma longa. It has antioxidant, anti‐inflammatory, and neuroprotective effects and has been proven to be a promising anti‐AD compound [81]. Curcumin was shown to alter the abundances of the families Lactobacillaceae and Rikenellaceae and the genera Prevotella, Bacteroides, and Parabacteroides in the intestines of APP/PS1 mice [82]. Bacteroides species increased the permeability of the gastrointestinal barrier. Through this process, Bacteroides species promoted the entry of pathogens, LPS, and certain metabolites into the bloodstream [83]. This resulted in a reduction in the number of amyloid plaques in the hippocampus and an improvement in spatial learning and memory in APP/PS1 mice [83]. Curcumin promoted neuroinflammation via the activation of the NF‐κB signaling pathway and this pathway may be a potential mechanism by which curcumin blocks the occurrence of AD [84].

Ginsenoside is one of the active components of Panax ginseng, and has been extensively used to treat dementia [85]. From the pharmacological perspective, ginsenoside significantly inhibits neurotoxicity, regulates nerve growth factor levels, and promotes neurological recovery [86]. In a study of AD tree shrews, the abundance of Lactobacillus salivarius and the ratio of Firmicutes/Bacteroides in the ginsenoside treatment group were markedly greater than those in the AD group [87]. Moreover, compared with those in the AD tree shrew model group, Bcl‐2‐associated X (Bax), beta‐secretase 1, Aβ_1‐42, and p‐tau levels were significantly lower and the learning and memory abilities were improved in the ginsenoside treatment group [87, 88].

Resveratrol is a neuroprotective polyphenolic compound. It is one of the main active ingredients of Reynoutria japonica. It has antioxidant, anti‐acetylcholinesterase, and antiapoptotic effects [89]. Resveratrol reduces the Aβ concentration by reducing the cleavage of APP and inhibiting amyloidogenic pathways, reversing the learning and memory impairments [90]. Besides, resveratrol supplementation facilitates the dephosphorylation of tau and inhibits its aggregation [91, 92]. When resveratrol was administered by gavage for 16 weeks in the D‐galactose (D‐gal)‐induced mice, researchers reported that resveratrol was able to regulate Aβ production associated with oxidative stress by modulating the gut microbiota, including Lactobacillus, Erysipeltrichales, and Faecalibaculum [93]. Resveratrol also significantly increased the abundances of Lactobacillus, Bifidobacterium, Allobaculum, Coriobacteriaceae_UCG‐002, Alloprevotella, Candidatus_Saccharimonas, Alistipes, and Parasutterella, and reduced the abundances of Rikenella, Anaerotruncus, Colidextribacter, and Helicobacter [91]. They decreased reactive oxygen species levels and insulin resistance and increased the synthesis of superoxide dismutase (SOD) to ameliorate cognitive decline and neuroinflammation [91, 93].

Cistanche deserticola polysaccharide (CDPS) is one compound of Cistanche deserticola that exerts anti‐inflammatory, antioxidant, antiaging, neuroprotective, and immunomodulatory effects [94]. CDPS also plays a significant role in improving the gut microbiota of AD. D‐gal‐induced aging mice were given CDPS by gavage, and the abundances of Bacillus, unidentified Actinobacteria and Fusobacteria were significantly decreased and the abundances of Methanobacteria, Deltaproteobacteria, Anaerolineae, and Erysipelotrichia were increased [95]. The levels of IL‐2 and TNF‐α were decreased and the IL‐4 and IL‐10 levels were significantly increased, moreover, the learning and memory functions were improved [95]. However, when triple antibiotics and cyclophosphamide were applied to sterilize the gut microbiota, the brain, and serum levels of proinflammatory cytokines, including TNF‐α, IL‐2, SOD, and malondialdehyde, were significantly increased [95].

Ginkgolide B is a diterpene lactone isolated from Ginkgo biloba. By regulating Aβ‐induced endoplasmic reticulum stress, it protects astrocytes and alleviates cognitive impairment in AD [96]. In addition, ginkgolide B treatment significantly reduced the levels of Bax and increased the level of Bcl‐2 in D‐gal and aluminum chloride (AlCl3/D‐gal)‐induced mice by decreasing the abundances of Bacteroidales, Muribaculaceae, and Alloprevotella, and increasing the abundance of Lactobacillus [97]. In this study, the mice were administered ginkgolide B by gavage for 2 weeks, the ability of learning and memory were significantly improved [97].

Xanthoceraside is a novel triterpenoid saponin obtained from the husks of Xanthoceras sorbifolia, which has been shown to ameliorate encephaledema and neuroinflammatory diseases [98]. Xanthoceraside also attenuates Aβ_1‐42‐induced memory impairment by suppressing the neuroinflammatory response [99]. AD rats injected with Aβ_1‐42 were administered xanthoceraside by gavage, and the abundances of Methanomassiliicoccus, Azoarcus, Phycisphaera, Clostridium IV, Enterorhabdus, Coriobacterium, Acetobacteroides, and Alloprevotella were regulated to decrease SCFA levels and improve the memory and cognitive impairment in AD rats [100].

At present, herbal monomers are a key type of TCMs used to treat diseases. This article searches herbal monomers with therapeutic effects on AD and list their pathway and targets on AD in the following (Table 2).

Forsythia suspensa exerts positive effects in AD patients [101]. However, the specific mechanism is not very clear. After extracts of Forsythia suspensa were administered by gavage at 200 mg/kg/day in Aβ‐induced AD rats for 50 days, the abundances of Erysipelotrichales, Clostridiales, Coriobacteriales, Desulfovibrionales Bacteroidales, Lactobacillales, and Bacillales were increased in the Forsythia suspensa group [102]. The Forsythia suspensa significantly inhibited the inflammatory response and tau deposition in the hippocampus and it also improved the memory function in AD rats [102]. There are several components of Forsythia suspensa that have been identified. Among these compounds, flavonoids and phenyl ethanol glycosides have neuroprotective effects and have significant effects on AD [103], whereas phenyl ethanol glycosides inhibit the LPS‐induced activation of BV2 microglia through the NF‐κB, MAPK, and other pathways [104]. These effects are accompanied by significant anti‐neuroinflammatory, antioxidant, antibacterial, and antiviral effects [105].

Rheum officinale has been proven to improve cognitive impairment in AD rats via several pathways, including the NF‐κB and PI3K‐AKT pathways [106]. Rheum officinale affected IL‐18, IL‐1, and TNF‐α concentrations by regulating the abundances of Bacillus and Anthropoid and it also ameliorated the pathological damage, such as oxidative stress and neuroinflammation in APP/PS1 mice [107]. The main active ingredients of Rheum officinale are the anthraquinone derivatives emodin, aloe‐emodin, chrysophanol, rhein, physcion, and danthron [108]. According to modern pharmacological studies, these ingredients could improve the cognitive function of AD patients by interfering with the PI3K‐AKT pathway and inflammatory factors [106]. Besides, they play roles in inhibiting microglial activation, reducing synaptic dysfunction, and decreasing tau phosphorylation [109].

Poria cocos has a good acetylcholinesterase inhibitory effect and affects AD [110]. Through antioxidant and antiapoptotic effects, Poria cocos protects neuronal cells from Aβ‐induced injury [111]. When Poria cocos extract was administered by gavage at 1.2 g/kg/day for 3 months, the abundances of Deferribacteraceae, Lachnospiraceae, and Enterobacteriales were decreased and cognitive impairment was alleviated in APP/PS1 mice [112]. Poria cocos directly interfered with the synthesis of Aβ plaques in the brain tissue of APP/PS1 mice by reversing the abnormal metabolism of β‐secretase and γ‐secretase [112, 113].

Gastrodia elata (GE) is a commonly used TCM for treating neurological diseases such as headache, AD, and Parkinson's disease [114]. After treatment with GE by gavage for 4 months, the abundances of probiotic bacteria, such as Bifidobacterium, Akkermansia, and Alloprevotella increased in ApoE mice and these changes in the gut microbiota increased the SCFAs concentration and decreased the serum corticosterone concentration [115]. By regulating brain monoamine neurotransmitter and Aβ levels, GE alleviated exploratory behavior and recognition ability in ApoE mice [115]. In the modern pharmacological studies, GE promotes synaptic regeneration and exerts neuroprotective effects by interfering with signal transduction [116]. GE can also reduce the levels of oxidative stress‐related products such as malondialdehyde and glutathione disulfide [117]. GE also has an important effect on reducing neuronal loss and apoptosis in AD, and this process is achieved mainly through activation of the PI3K/AKT/mTOR pathway, suppression of the NLRP3/NF‐κB pathway and the release of the apoptotic proteins Bcl‐2 and Bax [118]. GE ameliorates cognitive impairment by inhibiting oxidative stress and anti‐inflammatory pathways [119]. Gastrodin and gastrodigenin are the two active components of GE, and they can also reduce mitochondrial dysfunction caused by oxidative damage [120].

The purification of herbal monomers and the development of formulas are based on an understanding in the efficacy of single herbs. The following table lists the roles and related pathways of single drugs in the gut microbiota of AD patients (Table 3).

Huang Lian Jie Du (HLJD) contains four herbs, including Coptis chinensis, Scutellaria baicalensis, Phellodendron amurense, and Gardenia jasminoides. HLJD is a representative decoction for heat‐clearing and detoxicating, and has been widely used to treat neurological disorders [122, 123] HLJD can improve cognitive function, reduce the plaque burden, decrease inflammation and oxidative stress [124, 125, 126]. Through these effects, HLJD can alleviate learning and memory deficits in AD mice [127]. When HLJD was administered by gavage for 4 months, the gut microbiota was regulated especially by increasing the abundances of Prevotellaceae, Lactobacillaceae, Peptococcaceae, Alcaligenaceae, and Helicobacteraceae and reducing the abundances of BacteroidalesS24‐7_group, Lachnospiraceae, and Porphyromonadaceae, which ameliorated the memory and spatial learning deficits in APP/PS1 mice [76]. Coptis chinensis is the monarch herb of HLJD. By increasing the abundances of Firmicutes, Bacteroidetes, and Lachnospiraceae and decreasing the abundance of Verrucomicrobia, Coptis chinensis significantly promotes the production of SCFAs [128] and its therapeutic effects can also be achieved via SCFAs [129].

Liuwei Dihuang (LWDH) is a classical formula that is widely used to treat AD [130]. It contains six herbs, including Rehmannia glutinosa, Dioscorea oppositifolia, Cornus officinalis, Alisma plantago‐aquatica, Poria cocos, and Paeonia × suffruticosa [131]. According to modern pharmacological studies, LWDH can regulate the neuroimmune network by reducing the levels of interleukins, colony‐stimulating factors, TNF‐α and chemotactic factors [132]. Moreover, it can improve cognitive ability and neuronal synaptic function in animal models of aging or AD [133]. LWDH may exert a neuroprotective effect on AD by regulating the gut microbiota. When senescence‐accelerated mouse prone 8 (SAMP8) mice were given LWDH by gavage for 90 days, the abundances of Bacteroidales, Clostridiales, and Desulfovibrionales were altered and spatial learning and object recognition memory were improved in SAMP8 mice [134]. As a monarch medicine of LWDH, Rehmannia glutinosa can improve cognitive function by decreasing the levels of IL‐1β and TNF‐α [135]. Cornus officinalis is one of the minister herbs in LWDH, and it can increase the levels of SCFAs and regulate the levels of IL‐1β and TNF‐α by decreasing the abundances of Bacteroidetes and Proteobacteria [136]. The interaction between Rehmannia glutinosa and Cornus officinalis makes MGBA play an important role in AD [137].

Qisheng Wan (QSW) has been widely used to treat patients with amnesia or dementia [138]. It consists of seven substances, including Poria cocos, Neolitsea cassia, Panax ginseng, Polygala tenuifolia, Asparagus cochinchinensis, Acorus gramineus, and Lycium chinense. The abundances of Akkermansia, Lactobacillus, and Bifidobacterium were increased and the abundance of Lactobacillus was reduced in Aβ_1‐42‐induced AD rats after being administrated QSW by gavage for 4 weeks [139]. Changes in these microorganisms were accompanied by the increased levels of NF‐κB, IL‐6, and TNF‐α, and improved the spatial learning and memory abilities of AD rats [139].

Qi‐Fu‐Yin (QFY) is a typical prescription used to treat dementia [140, 141], and it is composed mainly of seven herbs, including Panax ginseng, Rehmannia glutinosa, Angelica sinensis, Atractylodes macrocephala, Polygala tenuifolia, Glycyrrhiza uralensis, and Ziziphus jujuba. QFY can reduce the ratio of Aβ_1‐42 to Aβ_1‐40 and the concentrations of IL‐1β and TNF‐α [142]. The anti‐inflammatory effect inhibited the excessive activation of microglia and increased synaptic plasticity in the hippocampus [143]. QFY improves object recognition ability, passive avoidance responses, and spatial learning and memory abilities in AD animals [144, 145]. When QFY was administered by gavage for 3 months, the abundances of Bacteroides, Bacteroidaceae, and Rikenellaceae were significantly reduced and the abundance of Erysipelotrichaceae was increased in APP/PS1 mice [146]. QFY also inhibits the activation of aspartyl‐tRNA synthesis and improves spatial learning and memory abilities and promotes the recovery of motor coordination in AD mice [146].

Modified Huang‐Lian‐Jie‐Du (M‐HLJD) is a form of HLJD without Scutellaria baicalensis but with Salvia miltiorrhiza, Curcuma longa, and Acorus gramineus. Many studies have shown its well‐improvement effects in AD [147]. M‐HLJD relieves neuroinflammation and decreases Aβ deposition and tau phosphorylation in AD [148]. When M‐HLJD was administered intragastrically for 3 weeks, glutamate energy transmission and adenosine‐related signaling pathways were regulated through a process mediated by the N‐methyl‐D‐aspartate receptor in C57BL/6 mice injected with Aβ_1‐42 [149]. In addition, M‐HLJD significantly reduced the abundances of Bacteroides, Paraacteroides, Mycoplasmataceae, and Firmicutes and increased the abundances of Rikenella and Oscillospira. By altering the abundance of the gut microorganisms, M‐HLJD inhibited adenosine signaling, which further ameliorates synaptic plasticity and learning and memory deficits in AD models [149]. Salvia miltiorhiza plays an important role in anti‐AD effects by binding to Aβ and inhibiting its aggregation [150]. Tanshinone IIA is a compound of Salvia miltiorhiza that upregulates the expression of insulin‐degrading enzymes and reduces the deposition of Aβ in the brain. By reducing oxidative stress and inhibiting neuronal apoptosis, tanshinone IIA increased cholinergic system activity and led to improvements in learning ability in APP/PS1 mice [151]. Thus, tanshinone IIA is one such agent and has a key effect on the treatment of AD.

Jiedu‐Yizhi (JDYZ) has been proven to alleviate the cognitive impairment in AD [152]. JDYZ is composed of Coptis chinensis, wine‐treated Rheum officinale, Conioselinum anthriscoides, Kummerowia striata, Persicaria perfoliata, Cornus officinalis, and Alpinia oxyphylla. JDYZ can reduce the levels of the anti‐inflammatory factors, increased the number of neurons and decreased the deposition of Aβ in the hippocampus of Aβ_25‐35‐induced rats [153]. The anti‐inflammatory effects of JDYZ in AD may be related to its regulation of the gut microbiota [154]. When JDYZ was administered intragastrically for 8 weeks, the abundances of Firmicutes, Campilobacterota and Desulfobacterota were reduced while the abundances of Bacteroidoota and Actinobacterota were significantly increased in AD rats injected with Aβ_25‐35 [155]. These microorganisms maintained the integrity of the intestinal mucosal barrier, which was achieved mainly through reducing the expressions of Caspase‐1 and Caspase‐11, apoptosis‐related proteins, and the inflammatory pathways [155]. By intervening aforementioned factors, JDYZ significantly improved the learning and memory abilities of AD model rats.

Ling Gui Zhu Gan (LGZG) contains four herbs, including Poria cocos, Cinnamomum verum, Atractylodes macrocephala, and Glycyrrhiza glabra, and has anti‐inflammatory and antioxidative stress effects [156]. It exerts anti‐inflammatory effects by reducing the generation of TNF‐α, IL‐1β, IL‐6, malondialdehyde, and ROS in Aβ_25‐35‐induced cells [157]. Besides, LGZG can inhibit the overexpression of inflammatory factors and activate microglia to protect cells against Aβ_25‐35‐induced injury [158]. Numerous studies have shown that LGZG can exert its effects by regulating the gut microbiota and its metabolites [159, 160, 161]. When the LGZG decoction was administered by gavage for 9 weeks, the abundances of Bifidobacterium, Paraprevotella, and Dubosiella were increased, along with increased SCFAs and anti‐inflammatory effects mediated by the MAPK signaling pathway in AlCl3/D‐gal‐induced mice [162].

In the perspective of TCM treatment for AD, the treatment direction can be varied at different stages. Sometimes it needs to supplement deficiency, and sometimes it needs to relieve excess. The formulas for supplementing deficiency and relieving excess also have different effects on the changes in the gut microbiota of AD. The following table lists the different formulas regulating the gut microbiota in AD (Table 4).