The outer membrane of Gram-negative bacteria contains LPS, which consist of a hydrophobic domain-endotoxin-lipid A, a hydrophilic O-antigen, and a central polysaccharide (Brodzikowska et al., 2022). Two molecules of 3-hydroxy fatty acids are esterified to the glucosamine backbone of lipid A, and another two are connected via an amide linkage. Lipid A serves as the pathogen-associated molecular pattern of LPS. Increased LPS concentrations act as potent immune activators and toll-like receptor (TLR) 4 (TLR4) ligands, triggering inflammation (Chassaing and Gewirtz, 2014; Scott et al., 2017). Within the eye, various cells, such as perivascular macrophages, microglia, photoreceptors, dendritic cells, and RPE cells, exhibit proinflammatory signals via LPS (Tsioti et al., 2022). LPS-induced retinal explants exhibited a notable neuroinflammatory reaction, marked by deterioration of neurons and increased levels of various cytokines (Ghosh et al., 2018).

Furthermore, emerging evidence strongly suggests that low-grade inflammation caused by LPS plays a role in the progression of AMD. Larsen et al. (2023) observed increased levels of esterified 3-hydroxy fatty acids (indicative of LPS burden) in blood samples, indicating a potential role of LPS exposure in the early stages of AMD pathophysiology. The above suggests that LPS leads to a range of acute and chronic inflammatory responses, generating edema, exudation, and neovascularization, further affecting the development and progression of AMD (Ibbett et al., 2014).

Researchers have explained the risk of LPS-induced AMD via various mechanisms, such as immune inflammation, peroxidative damage, and RPE senescence. Liu et al. (2019) proposed that LPS promotes the production of inflammatory cytokines and apoptosis of RPE cells by inducing miR-21-3p expression, which can lead to AMD. LPS-induced miR-21-3p overexpression increased the protein and mRNA levels of the inflammatory cytokines monocyte chemoattractant protein-1 (MCP-1) and IL-6 in RPE cells while elevating apoptosis, caspase-3 activity, and levels of cleaved caspase-3 and poly-(ADP-ribose) polymerase proteins, which exacerbate inflammatory responses and apoptosis. LPS not only stimulates the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and nuclear factor kappa-B (NF-κB), but also strongly increases the expression levels of IL-1β, IL-6, IL-12, VEGF, TNF, and TNF-related apoptosis-inducing ligand. Furthermore, exposure to LPS increases the expression of glutathione peroxidase and mitochondrial manganese superoxide dismutase, leading to oxidative stress in the cells. However, Ozal et al. (2018) found that esculetin downregulates the secretion of proinflammatory cytokines and decreases NF-κB activation, ERK1/2 phosphorylation, and VEGF levels, consequently suppressing oxidative stress and inflammation, protecting against LPS-mediated RPE cell death, and preventing AMD development.

LPS production by Gram-negative bacteria in the intestinal flora is involved in HFD-induced obesity. Gram-negative bacteria secrete LPS, which binds to the complex receptor CD4/TLR4 on the surface of immune cells, releasing proinflammatory cytokines and developing inflammatory responses and metabolic disorders, ultimately leading to diseases such as obesity (Davis, 2016). Therefore, therapeutic options that balance LPS levels are of interest in AMD.

Oxysterols are cholesterol derivatives produced via enzymatic or free radical oxidation associated with oxidative stress, inflammation, and apoptosis (Testa et al., 2018; Zarrouk et al., 2020; de Medina et al., 2022). Several studies have suggested a correlation between retinal degeneration and cholesterol metabolism, specifically the transformation of cholesterol into oxysterols and the degeneration of the retina (Pfeffer et al., 2021; Zhang et al., 2021). Dasari et al. (2011) observed that providing rabbits with a diet high in cholesterol for 12 weeks resulted in heightened β-amyloid (Aβ) levels in the retina, oxidative harm, apoptosis, and elevated accumulation of cholesterol and oxysterols (24-hydroxycholesterol (24-OH), 27-hydroxycholesterol (27-OH), 4β-hydroxycholesterol, 7α-hydroxycholesterol, 25-hydroxycholesterol (25-OH), 7-ketocholesterol (7KC), and 7β-hydroxycholesterol (7β-OH)). A prior study (Dasari et al., 2010) revealed that 27-OH induced toxicity in RPE cells via the stimulation of Aβ1–42 peptide production, elevation of stress markers specific to the endoplasmic reticulum (cysteinyl asparaginase-12 and C/EBP homologous protein), reduction in dysregulation of Ca²⁺ homeostasis, mitochondrial membrane potential, oxidative stress (as indicated by glutathione depletion and reactive oxygen species (ROS) production), and apoptosis. Studies have demonstrated that cholesterol metabolism and its oxidation byproducts, including 7KC, can adversely affect RPE cells, as 7KC triggers oxidative stress and cell death. Various alterations have been noted in RPE cells in the presence of 7KC, such as damage to mtDNA, mitochondrial dysfunction, increased production of ROS/reactive nitrogen species (Gramajo et al., 2010), and activation of caspase-8, -12, and -3 (Neekhra et al., 2007). 7β-OH induces a caspase-3-independent mode of cell death related to lysosomal destabilization, which plays a significant role in the signaling pathways resulting in cell death (Malvitte et al., 2008). These findings collectively demonstrate the association between oxysterols and AMD.

Furthermore, oxysterols cause a rise in inflammatory cytokines in retinal cells. The presence of 25-OH (20–30 μg/mL) in human retinal pigment epithelium (ARPE-19) cells triggered the release of IL-8 (via the MEK/ERK1/2 pathway), VEGF, and MCP-1. The administration of 25-OH upregulated IL-8 transcription and secretion, facilitated by ERK1/2 and phosphoinositol-3 kinase activities and the involvement of transcription factor activator protein 1 and NF-κB. The presence of 7KC and 7β-OH elevated the secretion of IL-1β and IL-6 in ARPE-19 cells (Dugas et al., 2010). Huang et al. (2012) also demonstrated that 7KC (8 μM) enhanced levels of TNF-α, IL-1β, IL-6, IL-8, transforming growth factor beta 1 (TGF-β1), and VEGF by a mechanism that may involve endoplasmic reticulum stress. Larrayoz et al. (2010) found that 7KC induced cytokine production via the kinase signaling pathways ERK, p38MAPK, and AKT-PKCζ-NF-κB via interactions in the plasma membrane. The activation of NF-κB was linked to the MAPK/ERK pathway. These findings illustrate that oxysterols, particularly 25-OH, 7βOH, and 7KC, can trigger oxidative stress, apoptosis, and inflammation in RPE cells, thereby inducing retinal degeneration. Therefore, lowering oxysterol levels may be beneficial in preventing and treating AMD.

Organic fatty acids with a carbon chain length of less than six, known as short-chain fatty acids (SCFAs), are generated by bacteria in the gut, including 41 families, such as Lactobacillaceae, Clostridiaceae, Christensenellaceae Bifidobacteriaceae, Lachnospiraceae, and Akkermansia muciniphila. The main components of SCFAs are acetate, propionate, and butyrate. Acetate, constituting 50%–60% of SCFAs, is produced by Bifidobacteria and Lactobacilli, along with bacteria such as Clostridium spp., Anaerotruncus, Lachnospira, Akkermansia Muciniphila, and Streptococcus spp. The Bacteroidetes and Negativicutes class of Firmicutes synthesize propionate via a succinate route, utilizing vitamin B12 to transform succinate into propionate. Other Negativicutes bacteria form propionate from lactate via the succinate, such as Veillonella spp. or acrylate pathways, such as Coprococcus catus, Lachnospiraceae, and Megasphaera elsdenii. Eubacterium rectale and Roseburia spp., members of the Clostridium coccoides group (clostridial cluster XIVa), along with Faecalibacterium prausnitzii, a member of the Clostridium leptum group (clostridial cluster IV), are capable of producing butyrate. Besides the two prevalent human clusters, clostridial clusters I, III, XV, and XVI can also produce butyrate. SCFAs enter the bloodstream via the intestine, directly influencing the functioning of peripheral tissues and metabolic processes. SCFAs are crucial in regulating gene expression, controlling host metabolic processes (cell proliferation, diversification, and apoptosis), inflammatory reactions, and energy supply (Abdalkareem Jasim et al., 2022; Fillier et al., 2022; Rekha et al., 2022; Anachad et al., 2023; Ney et al., 2023). The metabolic responses mediated by SCFA receptors also influence obesity, contributing to AMD (Tian et al., 2023). Propionic acid increases peptide YY and glucagon-like peptide 1 (GLP-1) production and secretion, which helps to control obesity. Propionate and butyrate have the potential to combat obesity by stimulating intestinal gluconeogenesis, thereby enhancing metabolic wellbeing. Butyric acid upregulates the lipocalin-mediated AMP-activated protein kinase (AMPK) pathway, promoting mitochondrial biosynthesis and fatty acid oxidation by inhibiting histone deacetylases and augmenting peroxisome proliferator-activated receptor alpha (PPAR-α). SCFAs further ameliorate obesity by decreasing PPAR-α expression, increasing adipose tissue metabolism, and reducing body fat accumulation (Anachad et al., 2023).

Additionally, SCFAs may exert anti-inflammatory effects. SCFAs can traverse the blood–ocular barrier via the circulatory system. Chen et al. (2021) demonstrated the ability of high-dose, intraperitoneally administered SCFAs to reach the eye and impede LPS-induced endophthalmitis. SCFAs hinder TNF-α, IL-6, and the chemokines C-X-C motif chemokine ligand 1 and C-X-C motif chemokine ligand 12 when exposed to inflammatory stimuli in vitro, including ligands for TLR and IL-17. SCFAs reduce inflammatory mediators produced by LPS-stimulated retinal astrocytes and enhance the ability of retinal astrocytes to activate T cells, thereby treating AMD. Growing evidence indicates that SCFAs help to improve AMD and its associated risk factors. However, further clinical trials and animal experiments are required to validate these findings.

Bile acids (BAs) are synthesized from cholesterol within hepatocytes. The gallbladder stores BAs, which are then released into the intestine, aiding in the absorption of dietary fats and vitamins. Research indicates that GM significantly influences BA metabolism (Wahlström et al., 2016). Primary BAs—cholic acid and chenodeoxycholic acid—are produced from liver cholesterol, whereas GM generates secondary BAs via hydroxylation, deconjugation, epimerization, or oxidation processes. Both primary and secondary BAs in the liver are typically linked to glycine or taurine. Research has demonstrated that BAs positively impact experimental models studying retinal disorders. Warden et al. (2020) found that tauroursodeoxycholic acid promotes the phagocytosis of outer segments of photoreceptor cells by RPE cells, inhibits human retinal endothelial cell proliferation in vitro, and inhibits choroidal neovascularization. The BA taurocholic acid shields HRPEpiC primary retinal epithelial cells from oxidative stress-induced damage to their structure and function while also inhibiting VEGF-induced angiogenesis in choroidal endothelial cells. Moreover, glycine-bound BAs protect RPE cells from oxidative harm and impede VEGF-triggered angiogenesis in choroidal endothelial cells. Glycine-bound BAs offer protection against both atrophic and neovascular AMD.

In summary, LPS and oxysterols can cause oxidative stress, cellular senescence, and various acute and chronic inflammatory responses that further affect the occurrence and development of AMD (Figure 3). SCFAs improve AMD symptoms by regulating cell proliferation, differentiation, and apoptosis, inhibiting inflammatory responses, and providing energy. BAs improve lipid metabolism, protect oxidative stress-induced RPE cells, and inhibit choroidal neoangiogenesis. Consequently, the progression of AMD can be significantly slowed and postponed via the regulation of intestinal flora metabolites, including LPS balance, oxysterol reduction, and an increase in SCFAs and BAs (Guo et al., 2023b).

Flavonoids are compounds that are abundantly found in plants (Table 1). They have different phenolic structures consisting of two benzene rings with phenolic hydroxyl groups, primarily in glycosidic and free forms. These compounds exhibit antioxidative, anti-inflammatory (Guo et al., 2023c), antimicrobial, anti-apoptotic, neovascularization inhibiting, and central nervous and cardiovascular system protective effects (Lan et al., 2023a). Typically, flavonoid glycosides contain glucose bonds. Glucosides with water-soluble sugar components have low pharmacological activity and are difficult to absorb in the intestine, leading to a lack of bioavailability. Nevertheless, enzymatic degradation, hydrolysis, reduction, dehydroxylation, and other reactions involving intestinal microbiota can convert most flavonoids into simple phenolic acids, leading to their absorption and subsequent bioavailability enhancement.

Flavonoids can be divided into two primary groups depending on how they control the GM. Some flavonoids can be metabolized by the GM and act as substrates for various catalytic reactions involving various enzyme systems produced by the GM. Consequently, the bacteria responsible for these reactions tend to propagate (Feng et al., 2018). In contrast, some flavonoids influence the cell membranes of specific bacteria (such as Staphylococcus aureus and Escherichia coli), either by directly disrupting the lipid bilayer of the cell membrane or by modifying the permeability of the cell membrane, ultimately hindering the proliferation of these bacteria (Xie et al., 2015). Flavonoids modulate the relative abundance of probiotic and harmful bacteria. Pan et al. (2023) found that certain flavonoids (particularly hesperidin-7-O-glucoside, prunin, and isoquercitrin) possess bactericidal, antiviral, and anti-inflammatory properties.

Moreover, flavonoids also modulate the abundance and number of intestinal microbiota, leading to a considerable reduction in total SCFA production. By using in vitro simulated fermentation technology to study the fecal microbial composition of healthy individuals, it has been demonstrated that hesperidin-7-O-glucoside, prunin, and isoquercetin increase Bifidobacterium and result in a decrease in the relative abundance of Bilophila, Lachnoclostridium, promoting intestinal mucosal absorption and digestion, biobarrier function (Odamaki et al., 2016), and immunomodulation (Milani et al., 2017). Flavonoids reduce the effects of harmful bacteria. Hesperidin-7-O-glucoside, naringenin, and lisin all significantly reduce the levels of Haemophilus and the relative abundance of harmful bacteria, such as Clostridium pullulans and Bacteroides, suggesting that flavonoids can regulate signaling pathways, such as TLR4/NF-κB, NOD-like receptor family pyrin domain containing 3, and MAPK, along with the expression of the genes encoding matrix metalloproteinase-9, IL-1β, IL-6, IL-8, soluble intercellular adhesion molecule-1, MCP-1, and other inflammatory factors, suppressing the inflammatory response (Sun et al., 2023). The presence of flavonols, a type of flavonoid, facilitates the proliferation of beneficial bacteria, such as Lactobacillus and Bifidobacterium, while diminishing the presence of Clostridium spp. Taken together, hesperidin-7-O-glucoside, lisinin, and isoquercitrin, which are flavonoid monoglycosides containing only one glucose group in their structures, can lead to an increase in beneficial intestinal bacteria and a decline in harmful intestinal bacteria. This action helps ameliorate intestinal dysbiosis and diminish the impact of other factors on the intestinal flora.

Natural flavonoid products also have antioxidant properties that reduce oxidative stress and inhibit the activation of various signaling pathways to ameliorate inflammatory diseases. By improving the dysregulation of intestinal dynamic homeostasis in vivo, ROS production is reduced, the AKT/glycogen synthase kinase-3-beta (GSK-3β) and Nuclear factor erythroid-derived-2-like 2 (Nrf2)/antioxidant response element (ARE) signaling pathways are directly altered, and the expression of antioxidant genes, such as NAD(P)H quinone oxidoreductase 1, heme oxygenase-1, glutamate-cysteine ligase modifier, glutathione, and superoxide dismutase (SOD), are regulated (Sun et al., 2023).

Increasingly, flavonoid metabolites, which are biologically active compounds, play a role in influencing the gut microbiome and reducing signs of obesity by hindering adipogenesis. Flavonoids, with their anti-inflammatory and antioxidant properties, impede the production of ROS and the cyclooxygenase (COX)-2 and NF-κB signaling pathways, thereby influencing obesity development and inflammatory responses (Carrera-Quintanar et al., 2018). Detaram et al. (2021) suggested that intake of higher levels of certain flavonoids may improve vision outcomes in patients with AMD. These findings were consistent with those of the Blue Mountains Eye Study, which revealed a connection between the overall consumption of flavonoids and reduced probability of AMD.

These findings suggest that flavonoids help control the development of AMD by modulating the gut microbial composition to slow inflammation, oxidative stress, dyslipidemia, and obesity.

Berberine (BBR) or BBR hydrochloride is an isoquinoline alkaloid derived from Coptis chinensis Franch. [Ranunculaceae; coptidis rhizoma]. It exhibits pharmacological properties, including anti-inflammatory, cardioprotective, and hypoglycemic effects (Miao and Cui, 2022; Saha et al., 2023). Intestinal flora enhances the bioavailability of orally administered BBR. The intestinal microbiota transforms BBR into absorbable dihydroberberine, which is five times more absorbable than BBR. Dihydroberberine is not stable in solution and can be reoxidized to BBR in intestinal tissues (Cheng et al., 2021).

BBR may inhibit inflammatory responses, oxidative stress, and apoptosis by altering the growth of various intestinal bacteria. It can reduce pathogenic bacteria and improve the metabolic and inflammatory state of organisms by inhibiting the LPS/NF-κB signaling pathway to promote the production of SCFAs, improving the relative abundance of GM, augmenting the relative abundance of SCFA-producing flora, and diminishing endotoxins (Shen et al., 2021). Yang et al. (2022) found that BBR modulates the GM and inhibits the initiation of the TLR4 signaling pathway, as well as the release of the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome and its cytokines. Li et al. (2018) also found that BBR inhibits oxidative damage caused by hydrogen peroxide (H₂O₂) in the human D407 RPE cell line. Pretreatment of D407 cells with BBR effectively inhibited apoptosis caused by H₂O₂ by rectifying irregular alterations in the nuclear structure, impeding the reduction in mitochondrial membrane potential, decreasing lactate dehydrogenase release, and impeding the activity of caspase 3/7 induced by H₂O₂. Western blot analysis revealed that BBR induced the phosphorylation and activation of AMPK in D407 cells in a manner that is dependent on the amount of time and dosage administered. In contrast, the action of BBR was inhibited by treating cells with compound C or reducing AMPK levels with specific siRNAs. Primary cultured human RPE cells yielded comparable outcomes. The collective findings indicate that BBR can protect RPE cells against oxidative stress via AMPK pathway activation, thereby addressing and slowing the progression of AMD.

Moreover, BBR can correct dyslipidemia by regulating the GM to improve AMD. BBR can boost the presence of Ruminococcus, Desulfovibrio vulnificus, Lactobacillus, and A. muciniphila, decline pathogenic bacteria, such as Aspergillus and Trematode spirochetes, promote the production of intestinal microbial metabolites such as SCFAs, and restore the breakdown and assimilation of glycolysis, amino acid metabolism, and carbohydrates (Liao et al., 2020), rectifying the imbalance in the rat intestinal flora ratio caused by a HFD, reducing the proportion of Firmicutes to Bacteroidetes, safeguarding the intestinal mucosal barrier, improving intestinal permeability, and preventing hyperlipidemia (Zhang et al., 2012).

Resveratrol is a polyphenolic compound with a low molecular weight naturally found in grapes, berries, and mulberries. It is recognized as a natural anti-inflammatory agent with a broad spectrum of medicinal effects, including anti-inflammatory, antimicrobial, antioxidant, immune-modulatory, anti-cardiovascular, and hepatocyte-protective activities (Boldyreva et al., 2023; Ghavidel et al., 2023; Santos et al., 2023). However, its notably low bioavailability poses a challenge in explaining the material basis of its in vivo pharmacodynamic effects. Several recent studies have shown that the exertion of its pharmacodynamic effects is associated with intestinal flora. Regarding intestinal flora regulation, resveratrol reduces the number of Bacteroidetes, promotes the metabolism of SCFAs, increases the level of butyric acid, and restores the intestinal flora to a homeostatic level (Alrafas et al., 2019).

Resveratrol has the potential to regulate the abundance of GM, thereby exerting antioxidant, anti-inflammatory, and anti-VEGF properties. Dull et al. (2019) showed that resveratrol can regulate the composition of gut bacteria, such as raising the amount of Bifidobacterium, Bacillus anthropophilus, and Lactobacillus and decreasing the amount of Enterococcus faecalis and Firmicutes. It may also exert anti-metabolic and anti-inflammatory effects via various pathways, such as NF-κB, arachidonic acid, activator protein-1, or aryl hydrocarbon receptor (AHR), diminishing proinflammatory elements and moderate granulocyte infiltration, functioning as an anti-proliferative and anti-inflammatory agent (Li et al., 2022b). Simultaneously, resveratrol can diminish the amount of oxidative stress damage in RPE cells by scavenging excess ROS, enhancing antioxidant enzyme activity, improving mitochondrial function, agonizing PPAR-α and peroxisome proliferator-activated receptor-δ, and up-regulating the mRNA expression of antioxidant genes BCL2 and HO1, thereby inhibiting the development of AMD. Maugeri et al. (2018) found that resveratrol restored the methylation levels of long-interspersed nuclear element-1 and reduced the oxidative stress and inflammatory response in ARPE-19 cells by regulating the functions of Sirtuin 1 and DNA methyltransferase. Resveratrol can also inhibit the phosphorylation and activation of vascular endothelial growth factor receptor 2 in endothelial cells and exert anti-AMD effects by activating SIRT1, as well as down-regulating the expression level of hypoxia-inducible factor-1α (HIF-1α) and VEGF secretion in RPE cells (Zhang et al., 2015).

Resveratrol can ameliorate intestinal flora dysbiosis caused by a HFD in mice, increase the amount of Bacteroidetes and Firmicutes, stimulate the propagation of Lactobacillus and Bifidobacterium, restore the imbalance in lipid metabolism, and significantly boost the expression of FIAF to reduce the number of blood lipids (Qiao et al., 2014). Chen et al. (2016) observed the impact of resveratrol on the GM and trimethylamine-N-oxide (TMAO) levels in apolipoprotein E knockout and choline-fed C57BL/6J mice. They found that plasma trimethylamine and TMAO levels decreased in the choline-fed resveratrol-treated group. Additionally, resveratrol intervention caused a decrease in Firmicutes and an increase in Bacteroidetes in the intestinal tracts of these mice, which indicated that resveratrol could reduce the abundance of detrimental bacteria, as well as effectively increase the relative abundance of advantageous microorganisms and the amount of intestinal pathogenic metabolites. These actions significantly enhance the hyperlipidemic state, restore the normal level of blood lipids, and could aid in preventing and controlling AMD by regulating its risk factors.

Poria is a common botanical drug (Table 2). Its main chemical components are polysaccharides, triterpenoids, sterols, and trace elements, such as calcium, iron, zinc, selenium, potassium, sodium, and phosphorus. Poria polysaccharides and triterpenoids have major pharmacological activities. Contemporary pharmacological research has demonstrated that Poria coccinea has antioxidant, immunomodulatory, anti-inflammatory, and intestinal microbiota-regulatory effects (Xu et al., 2023). Poria increases the beneficial bacteria Lactobacillus and Bifidobacterium and decreases Vibrio desulfuricans, inflammation-associated bacteria Mucor spp., and Staphylococcus to attenuate oxidative stress, inflammatory responses, and apoptosis (Ye et al., 2023). Huai et al. (2023) evaluated the unique ability of Poria to promote water metabolism in the body for the treatment of diabetic macular edema. They ranked it high among the therapeutic drugs for proliferative diabetic retinopathy.

Further, a computerized search of clinical cases related to the treatment of macular edema in the Chinese full-text journal database and Wanfang database ranked Poria in first place, with a recurrence rate of 60 times. Kim et al. (2018) reported improved visual acuity and disappearance of retinal and optic disk hemorrhages in patients with non-proliferative glycoconjugate network after administration of Poria-containing Modified-Goshajinkigan (Niucheshenqiwan in Chinese). Lan et al. (2023b) found that Poria selectively modulated the abundance of Odoribacter, Muribaculum, Oscillibacter, E. coli, and Turicibacter, leading to a reduction of the inflammation levels caused by dextran sodium sulfate (DSS) in mice. Poria aqueous extract improves metabolic homeostasis and inflammation by restoring intestinal homeostasis, controlling the relationship between GM and host metabolites, modulating hypothalamic neurotransmitters, decreasing proinflammatory cytokines, and inhibiting the expression of TNF-α/NF-κB signaling pathway proteins. Additionally, Poria can improve AMD risk factors, such as hyperlipidemia and obesity, by regulating intestinal bacterial communities.

Moreover, water-insoluble Poria polysaccharides could improve intestinal mucosal integrity by regulating the intestinal bacterial community and increasing the butyrate-producing biomass of Clostridium perfringens (Sun et al., 2020a), thereby promoting glucose-stimulated lipid metabolism, alleviating hyperlipidemia and reducing inflammation and steatosis. Zhu et al. (2022) investigated the effects of Poria oligosaccharides on glucose and lipid metabolism disorders in HFD-induced obese mice. Compared to controls, Poria oligosaccharides improved insulin resistance and glucose intolerance and reduced insulin and blood glucose levels in HFD-fed mice. Additionally, Poria oligosaccharides treatment inhibited the mRNA expression of fatty acid synthesis regulators in epididymal fat and the expression of proinflammatory factors, such as TNF-α, IL-1β, IL-6, and MCP-1. Moreover, Poria oligosaccharides partially rectified the imbalance of GM in HFD-fed mice, accompanied by decreased various gut metabolites of significant importance in impairing the intestinal barrier, such as BAs, SCFAs, and tryptophan.

Ginseng, derived from the desiccated root and rhizome of Panax ginseng C. A. Meyer, a member of the Wujiaceae family, possesses several health benefits. It comprises a diverse range of active components, including ginsenosides, polysaccharides, and volatile oils (Su et al., 2023; Zhou et al., 2023), significantly affecting immunity, oxidative stress, inflammation, apoptosis, and coagulation (Zhou et al., 2023). Lee et al. (2015) utilized the ginsenoside targeted transport pathway to improve nutrient exchange in Bruch’s membrane of human donors, delaying its aging and preventing the onset and progression of AMD. Betts et al. (2012) reported that ginsenoside Rb1 from ginseng root extract increases the number of cultured adult ARPE-19 cells while decreasing the release of the angiogenic factor VEGF produced by ARPE-19 cells, suggesting that Rb1 plays a role in the prevention of angiogenic ophthalmopathies such as AMD. Cho et al. (2001) demonstrated that ginsenosides inhibited TNF-α production in mouse or human macrophages stimulated by LPS, suggesting that ginseng has a preventive effect on AMD.

Additionally, ginseng ameliorates AMD risk factors by modulating gut microbes. The ginsenoside Rg5 significantly lowered the F/B ratio and markedly attenuated inflammatory responses caused by metabolic endotoxemia. Moreover, Rg5 markedly decreased the abundance of Firmicutes and Verrucomicrobia. It augmented the abundance of Proteobacteria and Bacteroidetes in a mouse model of diabetes at the phylum level, ameliorating diabetes-associated dysbiosis and metabolic disorders of the intestinal microbiota. Ginseng saponins inhibit obesity and its complications by improving the metabolism of endogenous substances in the gut, reducing inflammation, and altering the composition of the GM. Ginseng pectin, a mixed pectin containing the structural domains of rhamnogalacturonan-I and homogalacturonan, improves the intestinal flora by increasing Bifidobacterium, Akkermansia, Prevotella, and Bacteroides, which increases the levels of propionic, acetic, and butyric acids and valine. These, in turn, participate in cinnamonoside-, 10-hydroxy-8-fen-2-fenuglone glucoside-, leucovorin-, 24-propylcholesterol-3-ol-, and other lipid regulation-related pathways in serum metabolite alterations, and activation of the AMP-activated protein kinase pathway, to ameliorate lipid disorders in obese rats (Zhuang et al., 2021; Ren et al., 2023).

Processed ginseng is categorized into white (dried ginseng) (WEWG) and red (steamed ginseng) (WERG). In HFD-induced obese mice, aqueous extracts of WEWG and WERG demonstrated the ability to alleviate intestinal dysbiosis and exhibited anti-obesity effects, particularly the aqueous extract of WEWG. WEWG markedly decreased the F/B ratio and the amount of Ruminiclostridium while augmenting the amount of Parabacteroides and Lactobacillus. WERG decreased the amount of Desulfovibrio and augmented the amounts of S24-7 and Gastrococcus (Zhou et al., 2020). A separate in vitro experiment demonstrated that WERG stimulated the growth of the probiotics Lactobacillus and Bifidobacterium bifidum and curbed the overgrowth of E. coli, thereby enhancing the microbiological structure of the intestinal tract and reducing in vivo inflammation (Guo et al., 2015). Peng et al. (2021) revealed that WERG treatment caused a more pronounced enhancement of probiotic levels, such as those of B. bifidum and Akkermansia, than WEWG, indicating the increased anti-aging efficacy of WERG.

Additionally, research on elderly Korean women showed that the consumption of fermented red ginseng (RG) modified 20 distinct bacterial species, thereby enhancing overall wellbeing via its impact on defecation, biochemical parameters, and metabolism (Lee et al., 2022). Eun et al. (2023) found that the addition of WERG and its subsequent microbial conversion via the fermentation of RG resulted in alterations in the composition of the GM, exhibiting characteristics of both RG and fermented RG, which were linked to an improved obesity phenotype and glucose balance. These modifications were also linked to the enhanced integrity of the gut barrier, thus safeguarding against inflammation caused by heart failure at both local and systemic levels.

Astragalus is the dried root of Astragalus membranaceus. Its main components are polysaccharides, saponins, flavonoids, amino acids, and other compounds. Additionally, it contains alkaloids, glucuronic acid, iodine, silicon, zinc, and other trace elements. Astragalus polysaccharide (APS) (Zheng et al., 2020) and astragaloside (Yang et al., 2022) are the main active components of Astragalus. It has antioxidant, anti-inflammatory, anti-aging, anti-apoptosis, immunomodulatory, intestinal mucosa protective, and intestinal flora regulatory effects and modulates signaling pathways (Zheng et al., 2020; Liang et al., 2023). Li et al. (2002) studied a mouse model of retinal photoreceptor degeneration induced by exposure to bright light and the DNA alkylating agent methyl methanesulfonate. They found that astragaloside A reduced the expression of genes involved in necroptosis and inflammatory responses, inhibited microglia activation, and attenuated retinal oxidative stress and inflammation, thereby protecting photoreceptor cells. Similarly, Sun et al. (2020b) discovered that ultrasmall astragaloside-loaded lipid nanocapsule eye drops improved retinal morphology and function in sodium iodate (NaIO3)- induced dry AMD mice and protected retinal function from oxidative stress and apoptosis.

Astragalus can exert anti-inflammatory, antioxidant, and immunomodulatory effects by regulating GM abundance. APS altered its composition, enhancing the variety of GM, leading to the reduction in the relative prevalence of Pseudoflavonifractor and Parapovella and the increase of Parabacteroides, Parasutterella, Butyricicoccus, Clostridium perfringens XIVb, and Dorea. APS also increased the immune organ indexes and body weights, reduced IL-6, IL-1β, and endotoxin levels, inhibited the TLR4/NF-κB pathway, and improved immune disorders in rats via modulating their GM, particularly certain bacteria implicated in immune and inflammatory responses and production of SCFAs (Zhao et al., 2023). Wei et al. (2023) found that APS regulated GM abundance, enhanced the abundance of anti-inflammatory bacteria, generation of SCFAs, reversed the aberrant expression of NF-κB, NrF2, and their downstream factors in the brain-gut axis, and exerted anti-inflammatory and antioxidant effects on neuronal cells. Li et al. (2023) found that APS significantly activated intestinal TLR4 and MAPK pathways, reversing intestinal flora disorders in immunocompromised mice. APS resulted in an increase in bacterial populations at the genus level, including Lactobacillus, Bifidobacterium, Rousselaeria, and Desulfovibrio, and a decrease in the abundances of Tyzzerella and Lachnoclostridium. However, APS did not enhance the immune system of immunocompromised mice with GM depletion. Li et al. (2022c) discovered that supplementing mice with fermented Astragalus (FA) controlled abnormal activation of the intestinal immune barrier, resulting in decreased levels of MPO and immunoglobulin E and increased levels of immunoglobulin A. The levels of TNF-α, IL-1β, IL-6, and IL-17 were downregulated in the intestines, and those of TGF-β and IL-10, which are anti-inflammatory, were increased, indicating that FA may affect the inflammatory process by controlling Th1/Th2/Th17/Treg-related cytokines.

Furthermore, fatty acid supplementation modified the composition of the GM and enhanced the presence of Akkermansia and Aristochthys spp., both of which were associated with the generation of SCFAs. Fermented Astragalus-induced microorganisms and their metabolites play a role in preserving the intestinal mucosal barrier’s integrity by affecting intestinal mucosal immunity. Mice supplemented with FA exhibited greater expression of intestinal tight junction protein and mucous-secreting protein ZO-1 and occludin, as well as MUC2 genes, than those supplemented with unfermented Astragalus. Repair of the intestinal mucosal barrier by FA has been validated by regulating apoptosis in intestinal epithelial cells Li et al. (2022c).

Atractylodes macrocephala, commonly referred to as “Yuzhu,” “Xizhu,” or “Wuzhu,” functions as the desiccated rhizome of A. macrocephala within the Asteraceae family. Atractylodes macrocephala contains sesquiterpenes, lactones, polysaccharides, flavonoids, and other chemical components that have antioxidant, anti-apoptosis, and anti-inflammatory effects, improve gastrointestinal function and immunity, and lowers blood lipids (Xie et al., 2023). In a study involving a macular edema formula containing A. macrocephala, the total volume of the macular center area in diameter of the patients was significantly reduced, and the visual acuity and visual field were significantly improved (Zhu et al., 2016). In addition, Atractylodes may improve AMD risk factors by modulating gut microbes to act as an anti-inflammatory and lipid-lowering agents. Atractylodes macrocephala volatile oil reduces harmful bacteria, such as Parasutterella, Turicibacter, and Erysipelatoclostridium. It increases the number of beneficial bacteria, such as Parvibacter, Enterorhabdus, and Akkermansia, attenuating the inflammatory response in DSS-induced mouse models (Cheng et al., 2023). Kai et al. (2022) found that Atractylodes polysaccharide modulates the intestinal flora by increasing the abundance and diversity of intestinal flora, decreasing the proportion of harmful bacteria, such as Clostridium strictum 1 and Shigella coli, and increasing the relative abundance of potentially beneficial bacteria, such as B. bifidum, thereby alleviating DSS-induced weight loss. It also prevented the overexpression of proinflammatory cytokines TNF-α, IL-1β, and IL-6, reduced neutrophil infiltration, and upregulated the expression of MUC2 and the tight junction protein claudin-1, thus attenuating DSS-induced intestinal mucosal barrier damage in mice. In a rat model administered A. macrocephala, He et al. (2023b) observed an abundance of Lactobacillus and Rhodococcus species in the intestine, as well as an increase in tryptophan metabolites, such as indole, indole-3-propionic acid, and tryptophan. This, in turn, increased the expression of the intestinal AHR. The activation of AHR caused the upregulation of GLP-1 and IL-22 at proteins and mRNA levels, decreased systemic LPS, improved gut barrier function, activated the hepatic STAT3/IL-22R/peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) and pancreatic GLP-1R/p-CREB signaling pathways, and improved lipid metabolism and insulin resistance.

Shenling Baizhu powder comprises ginseng, Poria, A. macrocephala, Glycyrrhiza glabra L. [Fabaceae; radix et rhizoma glycyrrhizae], Dioscorea polystachya Turcz [Dioscoreaceae; dioscoreae rhizoma], Coix lacryma-jobi var. ma-yuen (Rom.Caill.) Stapf [Poaceae; coicis semen], Nelumbo nucifera Gaertn. [Nelumbonaceae; lotus seed], Lablab purpureus subsp. Purpureus [Fabaceae; semen lablab album], Wurfbainia villosa (Lour.) Skornick. & A.D.Poulsen [Zingiberaceae; amomi fructus], and Platycodon grandiflorus (Jacq.) A.DC. [Campanulaceae; platycodonis radix]. Recent research has shown that this powder possesses anti-inflammatory, antiviral, and antioxidative properties, improves immune function, regulates blood lipids, balances intestinal flora, and safeguards the intestinal mucosal barrier. Ginseng and Atractylodes Maculatus San protect the blood-retinal barrier, inhibit the expression of inflammatory factors, balance the ecological stability of the intestinal tract by regulating the intestinal bacterial flora, and improve the risk factors for macular edema (Bai et al., 2023). Polysaccharides of Shenling Baizhu powder alleviate inflammation by regulating tryptophan metabolism in Bacteroides, B. bifidum, and Ruminococcus. The tryptophan metabolite kynurenine activates the expression of polypeptide 1 (CYP1A1) and AHR and promotes the expression of anti-inflammatory IL-10 (Lv et al., 2022). Botanical drugs that strengthen the spleen and benefit qi have demonstrated a significant impact in regulating intestinal flora and enhancing immunity in animal models of spleen deficiency and clinical studies (Lima-Fontes et al., 2022). Shenling Baizhu powder has the potential to enhance the prevalence of the SCFA-producing bacteria Puccinia and Treponema and decrease the prevalence of the opportunistic pathogens Vibrio desulfuricans and Cholera spp. It significantly reduces the level of myeloperoxidase, increases the levels of catalase and SOD in the serum of rats, and exerts antimicrobial effects by enhancing the antioxidant capacity and modulating the intestinal microbiota (Gu et al., 2021).