Secondary metabolites of higher plants are the main source of many natural medicines, and the plant origins of which are gradually occupying a dominant position in the field of medicine and healthcare on a global scale. Among these chemicals are ginsenosides [1], tanshinones [2], vinblastine [3], camptothecin [4], paclitaxel [5], and others with anti-fatigue, anti-blood pressure, anti-thrombotic, and anti-tumor properties, which serve as a foundation for novel medications development. However, the majority of these natural active components have distinct chemical structures, which means artificial synthesis to directly replace natural plant resources is difficult. The existing single extraction and separation method is far from satisfying the complex and diversified extraction of natural active compounds in medicinal plants, resulting in resource waste. In addition, the wave of economic development has also brought about the destruction of wild medicinal resources and unplanned and unregulated exploitation. This has accelerated the formation of the global shortage of herbal resources.

However, after medicinal plants are invaded by specific environmental microorganisms, they establish symbiotic relationships including partial symbiosis and mutualistic symbiosis, which was been accompanied by in-depth understanding and exploration of medicinal plant microbiota in recent years. Symbiosis includes offset symbiosis and mutualism. Endophytic bacteria and host plants have evolved a comparatively robust equilibrium maintenance symbiosis mechanism through ongoing synergistic evolution and balanced confrontation [6]. In the symbiotic system involving endophytic bacteria, the convenient generation of secondary metabolites of medicinal plants fully reflects the characteristics of high yield, rapid generation, high plasticity, convenient operation, and mild reaction. Therefore, endophytic bacteria act as a special "inducer" signal to regulate plant growth and metabolism [7] and biotic and abiotic resistance [8] and to induce specific secondary metabolites [9] in a mutualistic system with plants. The signaling molecules such as organic molecules and signaling hormones in the symbiotic system are also key to the processes of endophytic bacteria recruitment, infestation, colonization [10], signal integration [11], and regulation of plant secondary metabolite synthesis. 

2. Signaling Molecules Involved in the Interactions between Endophytic Bacteria and Medicinal Plants

Endophytes and host plants have formed a unique symbiotic system under long-term symbiotic synergy, becoming a functional symbiosis with diverse structures, complex composition, and dynamic change. The orderly operation of various signaling molecules and symbiotic systems provides a basis for subsequent research on the synthesis pathways of secondary metabolites in medicinal plants. Plants recognize endophytes through selective metabolic signals to restrict other microorganisms from entering the plant. After initiation of intracellular symbiotic signaling pathways, endophytes successfully colonize host plants.

2.1. Interaction of Metabolic Signaling Molecules in Endophytic Bacteria and Medicinal Plants

Symbiosis is a complex nutrient environment. In a symbiotic system, many chemicals can be used as signals to recruit and identify endophytic bacteria. These metabolites generally include (i) nutrients available only to specific microorganisms, (ii) antibacterial substances toxic to some microorganisms, and (iii) a metabolite that attracts specific microorganisms. For example, organic acids such as citric acid, malic acid, fumaric acid, and salicylic acid have been shown to play important roles as nutrients in the recruitment of endophytic bacteria [12]. Triterpenoids are another large and diverse group of plant metabolic nutrients that mediate the establishment of symbiotic systems by promoting and limiting the growth of endophytic bacteria [13]. Similarly, plants may produce a wide range of antimicrobial substances, but the regulatory mechanisms of how these molecules allow endophytic bacteria to proliferate while resisting pathogenic bacteria have not been fully described in studies. Plant-derived coumarins have antimicrobial activity against some pathogenic bacteria, but not against endophytic bacteria [14]. Similarly, rhizobacteria have evolved resistance to the toxic structural mimic of arginine (cotinine) produced by legumes, thus allowing proliferation in the inter-rhizosphere of legumes [15]. These examples show that plants can use antimicrobial products to select specific endophytes while excluding other microorganisms. Plant-secreted metabolites can also serve as signals used by hosts in symbiotic systems to attract specific endophytic bacteria. Nitrogen-fixing rhizobacteria can sense the presence of plant flavonoids through bacterial regulators that biosynthesize in conjunction with Nod factors [16]; the phytohormone strigolactone can trigger the germination of mycorrhizal (AM) fungal spores, thus signaling the presence of a potential plant host ^[17][18][17,18]. Symbionts can also use the presence of plant metabolites, including polyamines [19], amino acids, organic acids, or sugars [20], to indicate the presence of a plant host. Thus, the secretion of induced signals such as nutrients, antimicrobial substances, and metabolites provides the basis for plants to invoke only beneficial endophytes in a complex microbiota.The release of plant metabolic signals may be a major determinant of the formation of specific symbiotic systems between host plants and endophytes.

2.2. Receptor Signaling Molecules in the Interactions between Endophytic Bacteria and Medicinal Plants

Endophytic bacteria form a symbiosis with the host plant after successfully competing for nutrients in the host and surviving the attack of host antimicrobial metabolites. Plant receptors need to sense and integrate multiple signaling cues to successfully recognize the symbiont and determine the pathway to initiate symbiosis. Plant genomes encode hundreds of structure-specific membrane-associated pattern recognition receptors (PRRs) [21] to specifically recognize microbial-associated molecular patterns (MAMP). MAMPs that play a role in symbiotic pathways include chitosan, bacterial extracellular polysaccharides (EPS) [22], lipopolysaccharides (LPS) [23], and various protein components. In addition to this, endophytic bacteria have evolved effectors that can also act as receptor signaling molecules involved in the symbiotic pathway between endophytes and plants. The symbiosis between rhizobia and legumes begins when rhizobia secrete lipid chitooligosaccharides (LCO) and release Nod factors [24]. Both the effector and the host plant have multiple LysM structural domains, and the LysM structural domain receptors of the host plant need to recognize the correct Nod factor separately, regulating parallel signaling pathways [25]. For example, Tribulus Terrestris NFP and LYK3 recognize the non-reducing and reducing ends of Nod factors, respectively [26], and initiate the signaling pathways of NFP and LYK2 [27]. In summary, the symbiont signal can be selectively, and with high affinity, delivered to downstream intracellular signaling molecules through successful recognition of multiple receptors’ signaling molecules by host plants for MAMP signaling and effector signaling of endophytes, and transduction of invasion colonization signals by endophytes (schematized in Table 1).