Current Scenario and Future Prospects of Endophytic Microbes: Promising Candidates for Abiotic and Biotic Stress Management for Agricultural and Environmental Sustainability

Globally, substantial research into endophytic microbes is being conducted to increase agricultural and environmental sustainability. Endophytic microbes such as bacteria, actinomycetes, and fungi inhabit ubiquitously within the tissues of all plant species without causing any harm or disease. Endophytes form symbiotic relationships with diverse plant species and can regulate numerous host functions, including resistance to abiotic and biotic stresses, growth and development, and stimulating immune systems. Moreover, plant endophytes play a dominant role in nutrient cycling, biodegradation, and bioremediation, and are widely used in many industries. Endophytes have a stronger predisposition for enhancing mineral and metal solubility by cells through the secretion of organic acids with low molecular weight and metal-specific ligands (such as siderophores) that alter soil pH and boost binding activity. Finally, endophytes synthesize various bioactive compounds with high competence that are promising candidates for new drugs, antibiotics, and medicines. Bioprospecting of endophytic novel secondary metabolites has given momentum to sustainable agriculture for combating environmental stresses. Biotechnological interventions with the aid of endophytes played a pivotal role in crop improvement to mitigate biotic and abiotic stress conditions like drought, salinity, xenobiotic compounds, and heavy metals. Identification of putative genes from endophytes conferring resistance and tolerance to crop diseases, apart from those involved in the accumulation and degradation of contaminants, could open new avenues in agricultural research and development. Furthermore, a detailed molecular and biochemical understanding of endophyte entry and colonization strategy in the host would better help in manipulating crop productivity under changing climatic conditions. Therefore, the present review highlights current research trends based on the SCOPUS database, potential biotechnological interventions of endophytic microorganisms in combating environmental stresses influencing crop productivity, future opportunities of endophytes in improving plant stress tolerance, and their contribution to sustainable remediation of hazardous environmental contaminants. Graphical Abstract


Introduction
Plants interact with diverse microbial species thriving in the rhizosphere and phyllosphere, thereby resulting in altered vital biological activities together with defense strategies against various abiotic and biotic stresses [43,78,101,178]. Rhizosphere and phyllosphere plant growth-promoting bacteria (PGPB) and mycorrhizal fungi in the rhizosphere are capable to induce growth of the plants directly by increasing macronutrient and mineral uptake and concentrations of 1 3 essential hormones and/or indirectly through minimizing the negative impacts of a myriad of pathogens [18,35,79,147,161,162,171,186,240,263] (Fig. 1).
The microbial species surviving on plant surfaces are epiphytes, whereas endophytes are those that inhabit the plant tissues [149,203,253]. In 1866, De Barry introduced the term "endophyte" for those organisms, including bacteria, fungi, or their associations multiplying intracellularly or intercellularly into host plants at least once in a lifetime without producing any marked signs of disease. Recent studies have illustrated that the growth and development of host plants depend to a greater extent on such symbiotic microbial species [55]. For example, in the most widely studied endosymbiotic association of rhizobium and legume, the bacterial counterpart is reported to regulate and meet the host plant nitrogen requirement [200,201].
Endophytes facilitate the successful establishment of symbiotic association via the synthesis and secretion of plant growth-promoting compounds responsible for host adaptation under given environmental conditions. Several fungal, bacterial, and actinomycetes species are described to participate in the synthesis and secretion of biologically active compounds and secondary metabolites [7,14,46,56,64,144,189,198,230,273].
Biomolecules belonging to classes of alkaloids, phenols, peptides, etc. synthesized by bacterial endosymbionts show a promising future in agriculture and medicine [163,215]. For example, microbially synthesized bio-insecticide azadirachtin was found to be an effective inhibitor toward the desert locust (Schistocerca gregaria) [33]. Since its first discovery, azadirachtin has been found to be effective against more than 200 insect species and has become an active component of many commercial pesticides, including TreeAzin, AzaMax, BioNEEM, AzaGuard, and AzaSol [38,59,62,80,85,94,156,196]. Many experimental investigations have reported the differential impact of factors such as specific host tissue, climatic conditions, and soil characteristics on bioactive compounds synthesized by endophytic microbial species [205]. The clue about the important role of endophytic microorganisms in the governance of the composition of metabolic products of host plants has attracted plant biologists to decipher the complexities of endophytic associations to improve crop plants.
Based on life strategies, endophytic bacteria were classified as facultative, obligate, opportunistic, and passenger endophytes [84] (Fig. 2). Currently, different biotic factors (e.g., insects and phytopathogens) and abiotic stress (e.g., extreme temperatures, salinity, drought, flood, low/excess nutrients, and organic/inorganic contamination) resulting from climate change have emerged as important limiting factors for agricultural and horticultural crop productivity worldwide [274]. Biotic stress has been estimated to reduce annual production of about 30% of crops [66]. In particular, combined effects of multiple abiotic stress factors such as drought and heat in a particular stage of growth of the plant are more detrimental than individual stress factors. Apart from abiotic stress factors, plants are constantly challenged with biological stresses through pathogenic bacteria, viruses, fungi, insects, and pests, causing considerable losses in food productivity worldwide [76,152,202,234]. Various approaches, such as the selection of tolerant varieties, molecular breeding, and genetic engineering are being used to improve crop varieties against different stressors. However, the majority of these methods are time consuming, costly, and not well accepted in some areas [12]. Therefore, to neutralize the negative consequences of various factors connected with abiotic and biotic stress, host plants have developed many biological mechanisms that can function simultaneously. In this context, the mutualistic association arising from interconnections between the host and the microbe is considered an effective and sustainable means of improving plant development and growth [54,132,173,195].
Unlike other plant growth-promoting microorganisms, endophytes have a direct relation with plants. They possess rapid adaptability under given conditions of biotic and abiotic stress, thereby improving host plant growth and survivability [9,25,61,101,149]. Furthermore, endophytic microbes can be an integral part of the rhizospheric region with the potential to synthesize and secrete metabolic products and enzymes [27,188]. They facilitate in neutralizing harmful impacts of plant pathogens. They may also allow the host plant to multiply even in polluted soil by degradation of contaminants in a manner similar to those harbored by plant growth-promoting rhizobacteria (PGPR) [31,37]. The application of highthroughput current "omics"-based technology such as gene sequencing, metabolomics, and microarray could comprehend the complex associations existing between plants and their endophytes and can be a promising tool for sustainable environmental development [40,105]. Their high colonization efficacy and stability against abiotic stress make them a potential candidate for environmental management [12,47,116,128].
The novelty of the present review is the current understanding pertaining to the colonization strategy of endophytes into host plants and their promising role in the alleviation of multiple abiotic and biotic environmental constraints limiting crop productivity. Noteworthy, the review has included comprehensive bibliometric information using the "SCOPUS" research database to illustrate the current research trend in the area of endophyte and possible implications in environmental stress management. In addition, the extensive information dealing with the possible roles of endophytes in eco-friendly removal of contaminants of hazardous nature including heavy metals, and diverse organic pollutants along with the future opportunities of endophytic microbes in crop improvement under changing climatic conditions, not considered in previously published reviews, are extensively taken into account.

Study Design
This review was designed after a literature search and analysis using the following criteria to provide a critical, effective, and comprehensive analysis of the literature on endophytic microbes. A search was carried out with the SCOPUS database considering titles, abstracts, and keywords fields of all available literature. The search contained only two keywords: "endophytic" (or "endophyte") and "stress." It showed the publication of 2949 papers starting from 1960. To highlight the more recent results, the review was specifically addressed to the publications of the last 10 years (from 2012 until December 3, 2022), resulting in a total of 2532 publications.
To obtain a suitable and systematic synthesis of all bibliographic information, including the article title, abstract, authors, and keywords, a cluster analysis was performed using VOSviewer software ("VOSviewer version 1.6.16," 2020).  -microbe interactions at  phyllospheric and rhizospheric  zone: endophytic microbes  and rhizospheric microbes are  capable to induce growth of  the plants directly by increasing macronutrient and mineral  uptake or indirectly through  plant protection against   3 reports the cluster analysis provided from the cooccurrence network of keywords of the papers extracted from the SCOPUS platform. The results can be grouped into five clusters. The first cluster (241 items), highlighted by green balls, is devoted to stress factors and adaptation. Keywords are related to abiotic stress (e.g., salinity and drought) and biotic (pathogen).
Cluster 2 (224 items) keywords highlight the reactivity of endophytes, the endophytic production of metabolites, and the antibacterial activity of the obtained bioactive compounds (blue balls highlight this cluster). The third cluster is represented by yellow balls (192 items), and mainly concerns colonization mechanisms, with several keywords devoted to culture, and bacterial and fungi growth.
Cluster 4 (175 items), represented by violet balls, is devoted to remediation, with keywords related to contamination and detoxification. The keywords contaminants refer to heavy metals and organic pollutants. Finally, cluster 5 (168 items), represented by red balls, is mainly devoted to genome and genetic expressions.
Based on the study design, the review was conceived in the following sections:

Impact of Stress Conditions on the Plant
The green revolution remarkably improved food availability in developing and developed countries. However, the indiscriminate use of chemical fertilizers reduced the biodiversity of soil microorganisms and frequently resulted in the loss of beneficial microbes necessary for soil health [126,138]. Meanwhile, the predicted expansion of the human population beyond 10 billion in the next half a century requires doubling food production [232]. Therefore, ensuring stable global food production and supply is among the main challenges of the twenty-first century.
The biotic and abiotic stresses have a negative impact on agricultural productivity. Biotic stress includes pathogens that cause plant diseases (e.g., fungi, bacteria, viruses, and nematodes) and insects that feed on plant parts and compete with plants to get nutrients [178]. Phytopathogens can cause various plant diseases such as leaf spot, necrosis, wilt, head rot, fruit rot, root rot, and black foot [122,146,165]. In addition, insect feeding can cause bore formation on leaves, stems, flowers, and bark. Some insects are also potential vectors of microbial pathogens, so the disease becomes epiphytotic to healthy plant populations.
The main abiotic stress includes salinity, drought, nutrient-deficient, temperature (low/high), flood, heavy metal contamination stress, and ultraviolet radiation, which massively limit the overall yield and growth of crop plants [86,231,238,246,264,271]. Drought stress alters the diffusion of nutrients, and the relationship between plants and water, and hampers normal functions, altering the plant morphological and physiological features. For example, drought stress can decrease chlorophyll content and cause an excess of reactive oxygen species (ROS) that can damage nucleic acids, proteins, and lipids [3, 41,241,255,256]. The keywords cooccurrence network, obtained from the articles extracted by SCOPUS, selecting two keywords: "endophytic" (or "endophyte") and "stress," in the titles, abstracts, and keywords fields of all available literature. The review was specifically addressed to the publications of the last 10 years (from 2012 until December 3, 2022). The map highlights the most frequently used bibliographic terms to understand the most active research fields that are grouped into 5 clusters. Data analysis was performed by "VOSviewer version 1.6.16," 2020 Furthermore, salinity stress reduces the growth of plants and productivity through specific ion toxicity and osmotic effects that lead to nutritional imbalance, changes in morphology and biochemistry, and a decrease in photosynthesis [102,137,214]. In addition, the acidic condition can produce a nutrient deficiency in plants, leading to an acute loss of the physiological growth and development sequence. Heavy metals have a similar effect on plants,they are released into the soil, water, and atmosphere as a result of various anthropogenic activities such as industrialization, mining, and agricultural activities such as the use of fungicides, pesticides, and fertilizers, including organic ones. The concentration of heavy metals in the environment depends on different activities, then it can become toxic when it exceeds acceptable limits [199]. Finally, high-and low-temperature stress diminishes enzyme functioning, cell division, and excessive denaturation of membranous proteins that leads to cell death when the condition persists in the case of long-term conditions [28,169]. Therefore, researchers need to develop sustainable microbe-based strategies to cope with difficult stress situations for food security and crop productivity. In this regard, endophytic microorganisms are the alternative that can contribute to plant health, nutrient supply, soil productivity, and protection against biotic and abiotic stress [49,174,176,183].

Colonization of Endophytes in the Host Plant
Plant endophyte colonization cannot be considered an abrupt phenomenon, but a series of complex and organized events determined by chemotactic responses. The intracellular colony development mechanism adopted by bacteria and fungi is almost the same, but their strategies and modes differ considerably. For example, bacterial endophytes colonize intercellularly the host plant system vasculature, whereas fungal endophytes colonize inter-and intracellularly within the entire root system [103,114,129,149,179,259]. The entry and colonization of endophytes involve different mechanisms comprising of (1) host availability and identification through a receptor and specific plant protein interaction, and (2) interaction with the phyllosphere followed by entry into the cellular environment (Fig. 4). Successful colonization by microbial endophytes is influenced by various factors such as the host plant genotype, the type of plant tissue, the microbial taxon and species, as well as abiotic and biotic stresses [135,136]. Plant root exudates serve as chemical signals to attract bacterial endophytes. Bacteria use flagella to move toward the root surface and eventually leading to interaction with the plant system through pili and fibers [34,113,153]. During the moving process from the rhizosphere environment to the endosphere region, microbial endophytes can rapidly adapt to the contrasting environment (e.g., redox status, oxygen availability, nutrient composition, and the osmotic balance of the host cell system). Furthermore, microbial endophytes invading the endosphere region must cope with the host's antioxidant defense machinery to internalize and colonize successfully [32,113,170]. In conclusion, the successful endophyte invasion and colonization within the host plant are largely determined by the timely identification of signaling substances, quorum responses, the potential to invade host defense machinery, and, most strikingly, the efficiency of tuning up with the entirely different complex host cellular system [119,153].

Endophytes and Their Role in Mitigation of Drought and Temperature Stress
Plants in natural environments are bound to expose to different abiotic stresses. Drought is one of the main limiting factors for the growth and productivity of crops around the world [58,67,177,231]. Under water-limiting conditions, crop growth and productivity in the early stages are arrested due to low energy supply, low water uptake, and hindered functions of enzymes [52,60,121]. Furthermore, all considerable characters of plant-water relations, such as leaf relative water content (RWC), phenology, osmotic potential, water potential, pressure potential, photosynthesis, respiration, nutrition uptake, and rate of transpiration, are significantly impacted by drought, leading to decreased crop productivity ( Fig. 5) [69,83,229]. Considerable research has been conducted for the development of resistance in various model and crop plant species using conventional and molecular techniques that are tedious and expensive. Therefore, researchers are seeking a sustainable approach and numerous studies recognize that plant-associated microbes have tremendous potential to develop resistance against drought.
The literature so far revealed that endophytes induce tolerance to drought by certain molecular and biochemical changes in plants [70,208,265,269]. In field tests, the Bukholderia phytofirmans PsJN bacteria endophyte was inoculated in wheat plants that maintained metabolic balance due to higher antioxidant activity compared to control under drought conditions (Table 1) [164]. Furthermore, inoculation of the Piriformospora indica fungal endophyte also demonstrates drought resistance by upregulating antioxidant enzymes, drought-regulated genes, and CAS mRNA levels in drought-challenged leaves [223]. The pot experiment conducted on rice inoculated with Trichoderma harzianum TH-56 showed better drought tolerance by modulating SOD, proline, lipid peroxidation, and growth attributes, and the level of DHN/AQU transcript, under drought stress [181].
The accumulation of total soluble sugars, glucose, fructose, and starch content during endophyte infection plays an important role in increasing the resistance and improving plant tolerance to drought stress. Bacillus subtilis B26 has been found to reduce the negative effects of drought stress, which was linked to an increased level of starch content and total soluble sugars in inoculated stressed Brachypodium distachyon [71] and in Phleum pratense grasses [70]. The inoculation of the Bacillus subtilis B26 endophytic bacterium with Phleum pratense was found to have a significant effect on metabolism of plants. For instance, higher levels of fructans and sucrose, and key amino acids such as glutamic acid, glutamine, and asparagine were found in the roots and shoots of plants colonized compared to non-colonized ones. Furthermore, inoculation of plants with endophytes resulted in an increased level of a non-protein amino acid, i.e., gamma-aminobutyric acid (GABA), in shoots and roots [70,92]. A Trichoderma hamatum DIS 219b fungal endophyte delayed the onset of drought response in Theobroma cacao by changing gene expression, possibly corresponding to changes in net photosynthesis, stomatal conductance, and green fluorescence emissions [21]. A recent study indicated that Ampelomyces sp. colonized tomato plants and improved the promotion of plant growth under drought conditions, representing a sustainable form of biofertilizer that could improve agronomic production [160]. The recent finding revealed that P. indica confers drought tolerance by the regulation of promoter genes, resulting in morphophysiological changes in tomatoes [19]. In summary, the endophyte-mediated drought resistance mechanism is based on phytohormone production, antioxidant-mediated ROS scavenging activity, induction of microbial genes, and accumulation of compatible solutes (Fig. 5).
In turn, to alleviate heat/temperature stress (HS), some studies have identified the potential role of plant hormones and other secondary metabolites produced by Entry and colonization of endophytes into the host plant include several events that occur within the host plant, including endophytic population entrance, motility, transmission, and multiplication fungi endophytes such as Paecilomyces formosus LWL1 in the Dongjin japonica rice cultivar. This fungus protected rice plants against HS compared to the control, as shown by lower endogenous stress signaling compounds, such as jasmonic acid (34.57%) and abscisic acid (25.71%), and the overall protein content increased (18.76-33.22%) [245]. The Rhizopus oryzae endophytic fungus inoculated in soybean (Glycine max L.) and sunflower (Helianthus annuus L.) also has the potential to alleviate thermal stress. Namely, both crops also showed low levels of abscisic acid (ABA), while high levels of catalase (CAT), ascorbic acid oxidase (AAO), phenolics, proline, sugars, flavonoids, lipids, and proteins were also observed. It was also found that the endophytic fungus stimulates chlorophyll content, length of shoots and roots, and dry and fresh biomass compared to uninoculated plants [97].

Endophytic Microorganisms and Their Role in Alleviating Salinity Stress
Salinity is one of the most important environmental problems affecting plant productivity in dry and semi-dry climates [6, 216,102,133,260]. The high salt content of the soil has been described as the result of natural and human activities leading to soil sodium salt accumulation. Furthermore, soil high salt concentration is frequently correlated with the reduction in seedling formation and imbalance in cellular homeostasis culminating in diminished photosynthetic activities [13,204,222,267]. Endophytic microorganisms develop strategies against salinity, similar to drought-resistant mechanisms. Endophytes stimulate the synthesis of antioxidant enzymes to balance various free radicals and maintain the normal functioning of the cell under salinity stress (Table 1). For example, inoculation of poplar tree with Curvularia sp. stimulates plant production of ascorbate peroxidase (APX) and superoxide dismutase (SOD) [180]. Furthermore, exposure of endophytic microbes to high salinity may stimulate the synthesis of the ACC deaminase. For instance, Barnawal et al. [23] observed an increase in the growth rate of saltsensitive spider plants (Chlorophytum sp., Asparagaceae) with the presence of the bacterium Brachybacterium An overview of plant response to abiotic stress (left): prolonged abiotic stress (drought, salinity, and heavy metals) causes regeneration of ROS, desiccation, cellular dehydration, hormonal imbalance etc. that limit plant growth and productivity. Endophytic mediated abiotic stress tolerance mechanism (right): under abiotic conditions, endophytes trigger the production of osmolytes (proline, glycine betaine, etc.), secretion of phytohormones (IAA, cytokinins, GAs), and induce gene expressions for plant defense  [160,192] [ 266] paraconglomeratum that produce ACC deaminase and diminishing the negative impact of gaseous hormone ethylene. Similar studies on the involvement of ACC deaminase for improved rice plant growth and stress mitigation were recently described [98,193,254]. In addition, osmolyte production was also recorded in maintaining the sodium-potassium ratio to overcome the osmotic effect of salinity ( Table 1).
The pot experiment demonstrated that colonization with P. pseudoalcaligenes improved Arabidopsis sp. growth under salt stress conditions by likely modulating the expression levels of K + and Na + ion channels and genes involved in Na + /K + homeostasiss [4]. Colonization of P. indica in salinity-sensitive Brassica rapa (= B. campestris subsp. chinensis) confers salinity tolerance by significantly higher production of antioxidant enzymes such as catalase (CAT), peroxidase (POD), and SOD and increased the plant hormone level such as gibberellic acid (GA) and salicylic acid (SA) [107]. Further study by Ravi et al. (2022) suggested that fungal root endophyte (Fusarium haematococcum) can resist salt stress and produces extracellular enzymes such as amylase, cellulase, and protease under in vitro conditions in addition to antioxidant production [192].
Recently, Eida et al. [50] have illustrated the role of endophytes isolated from desert plants in mitigating plant stress caused in the soil by the high salt content. The model plant Arabidopsis thaliana exposed to different salt levels exhibited tolerance to salinity after inoculation of isolated endophytes. Recent findings of Zhang et al. [266] concluded that apart from higher antioxidative enzymes of proline content, upregulation of key genes involved in IAA synthase and ethylene signaling were observed in B. cereus KP120 inoculated with A. thaliana under salt-stressed condition. In addition, a number of recent research have shown that isolated endophytes are very effective in enhancing physiological performance, plant growth, root and shoot biomass, symbiotic performance, energy production, osmoregulation, Na + sequestration, and ion homeostasis under salt-stressed conditions [30, 48,110,111,123,125,157,160,219].

Role of Endophytes in the Management of Biotic Stress
Plants are often exposed to harmful molecules produced by microorganisms. These molecules alter plant metabolism, causing diseases and significant crop loss [53,76,217]. Beneficial interactions between plants and microbes play an important role in plant protection against phytopathogens. Plant-beneficial microorganisms release elicitors that alter biochemical and physiological plant properties in changing environments [5,34,99]. Plants have physical and chemical barriers able to react to pathogens: they activate signal transduction in response to pathogen attacks directed to induce defenses. Important mechanisms of tolerance to biotic and abiotic stress are ROS production, antioxidative defense, and oxidative burst [72,87,151,218,261]. Like rhizosphere microbes, endophytes trigger direct and indirect mechanisms of disease resistance (Fig. 6). Direct mechanisms include the production of antimicrobial compounds and the lytic enzymes of the cell wall of fungi are capable of inhibiting plant pathogen growth and act as biological controls (Table 2). For example, a study suggested that chitinase produced by endophytic Streptomyces sp. can control plant pathogenic fungi [187].
A variety of microbial phyla, including Pseudomonas sp., Bacillus sp., and Trichoderma sp., have been shown to lead to systemic resistance in plants against pathogen attacks [117,150,168,175,184]. Microorganisms activate defense reaction mechanisms that involve the induction of systemic acquired resistance (SAR) and systemic resistance (ISR) pathways. SAR is activated by pathogen infection, which is connected with the activation of salicylic acid signaling and the accumulation of pathogenesis-related proteins (PR). For example, activation of β-1,3-glucanase (PR 2) was increased in oilseed rape infected with Plasmodiophora brassicae after colonization with Heteroconium chaetospira, a dark septate endophyte [120]. Similarly, the endophyte Fusarium solani, recovered from tomato, triggered ISR across the Septoria lycopersici tomato foliar pathogen and activated the expressions of PR7 and PR5 in roots [106]. Experimental studies on resistance induction mediated by the endophyte Serendipita indica revealed that Blumeria graminis f. sp. hordei inoculation resulted in induction of gene expressions (notably Hsp70, PR1, PR2, and PR5, and barley chemically induced 7 (BCI-7)) in barley foliage, which is supposed to be involved in various functions including defense reactions and protein synthesis and apoptosis [158].

Phytoremediation of Heavy Metals
Currently, the management of environmental pollutants based on living agents has achieved considerable progress worldwide. Pollutant removal by photosynthetic organisms (e.g., phytoremediation) has emerged as an attractive and light-driven decontamination technique and also an emerging green sustainable technology [44,63,65,89,118,185,221,226,233,236]. However, the low multiplication rate along with the low amount of cell mass, phytotoxic impacts, and release of pollutants of gaseous nature are the main drawbacks associated with phytoremediation technology, making the process inefficient at field scale [26, 73,242,252]. The solution to these limitations lies in the development of microbe-assisted phytoremediation. Previous studies have illustrated the use of rhizospheredwelling microbes to improve pollutant removal [77,81,190,250,275]. Furthermore, it was suggested that endophytes could facilitate phytoremediation more efficiently [44,112,154].
The negative impacts of heavy metals on plants can be described as reduced crop productivity resulting from changes in growth rate, nutrient accumulation capacity, and leaf area. In addition, heavy metal pollutions can cause considerable changes in community structure of diverse microbial populations and function associated with host plants [29,42,224]. Numerous studies have discussed the impact of various heavy metals on the diversity of endophytes, biological processes, and biomass production [57,68,123,125,127,172].
However, current studies dealing with the interactions between hyperaccumulator plants and endophytes have attracted attention worldwide because of inherent pollutant removal ability and possibilities for large-scale applications [91,109,123,125,130,131,197,225,243]. Furthermore, hyperaccumulators sequester a significantly high content of hazardous heavy metals and therefore create the internal environmental conditions suitable for the development of metal resistance in endophytes exposed to high heavy metal concentrations [172].
In terms of endophytic application, various metalresistant endophytic bacteria were isolated from leaves, stem, and roots of plant hyperaccumulators, including Thlaspi caerulescens, Th. goesingense, Alyssum bertolonii (all Brassicaceae), and Nicotiana tabacum (Solanaceae) ( Table 3). The association of these endophytes with hyperaccumulators suggests the widespread habitat choice of these microbes. For example, Thlaspi goesingense stems under field conditions harbor different bacteria including α-proteobacteria, γ-proteobacteria, Acidobacterium sp., Bacillus sp., Blastococcus sp., Curtobacterium sp., Desulfitobacterium metallireductans, Flavobacterium sp., Holophaga sp., M. mesophilicum, M. extorquens, Plantibacter flavus, Propionibacterium acnes, Rhodococcus sp., and Sphingomonas sp. These isolates were shown to be resistant to nickel (Ni) concentrations between 5 and 12 mM [95]. The same results were obtained in the field site experiment that the total Ni uptake by Alyssum serpyllifolium (Brassicaceae) was significantly enhanced by heavy metal-resistant endophytic bacterial strains Microbacterium sp., Pseudomonas sp., and Staphylococcus sp. [24]. In the line of the same experiment, Ma et al. [134] found that inoculation with the plant growth-promoting Pseudomonas sp. A3R3 endophytic bacterium significantly increased Ni uptake by 10% in A. serpyllifolium. In a later experiment, Achromobacter piechaudii was documented to sequester more than 60% of zinc (Zn), lead (Pb), and cadmium (Cd) from the corresponding hyperaccumulators, namely, Sedum plumbizincicola (Crassulaceae), Alnus firma (Betulaceae), and Solanum nigrum (Solanaceae), respectively [135,136]. Similarly, another study reported arsenic (As)-tolerant Bacillus sp. endophytes isolated from the leaves, stem, and root of Pteris vittata and P. multifida (Pteridaceae) [270] and concluded that bacteria with less biomass had greater tolerance to As. Surprisingly, fungal endophytes Fusarium sp. CBRF44, Alternaria sp. CBSF68, and Penicillium sp. CBRF65 isolated from the hyperaccumulators Brassica napus (Brassicaceae) showed significant tolerance to Cd and Pb [211]. This finding supported the result of Zhu et al. [272] where dark septate endophytes Phialophora mustea inoculated tomato roots established remarkable tolerance to Cd and Zn and promoted the tomato seedlings' growth under all metal stresses tested.
In addition, evidence of phytoremediation of Pb by plants grown in soils contaminated by heavy metals has also been confirmed. [209,210] reported that Brassica napus inoculated with Pseudomonas fluorescens G10 improved the total uptake of Pb from 76 to 131% of the shoot, while it was 59 to 80% (p < 0.05) for Microbacterium sp. G16, respectively. Mastretta et al. [148] supported the same finding and reported that Sanguibacter sp. Cd-resistant endophyte inoculated Nicotiana tabacum (Solanaceae) increased Cd concentration in shoot tissues. Yamaji et al. [257] revealed that Clethra barbinervis (Clethraceae) could tolerate high metal concentrations (Zn, 21-2600 μg/g; Cu, 2-1123 μg/g; Pb, 32-1506 μg/g) due to the support of root fungal endophytes, including Rhizodermea veluwensis, Phialocephala fortinii, and Rhizoscyphus sp. through K uptake promotion, growth enhancement, and decrease of heavy metal concentrations. Further studies revealed that the metal resistance mechanisms in endophytes surviving within hyperaccumulators can be attributed to activities such as metal extracellular precipitation, intracellular storage and sequestration [20,212], conversion of hazardous metal into less or non-hazardous forms [270], and surface binding/detachment of metal [82,130,131].
In addition, some endophytes were isolated from different parts of non-hyperaccumulators, such as Salix caprea (Salicaceae) and Oryza sativa (Poaceae). The reported metal-resistant endophytes belonged to numerous taxa, including Burkholderia sp., Methylobacterium oryzae, Frigoribacterium sp., Microbacterium sp., and Sphingomonas sp. (Table 3). Kuffner et al. [115] revealed that inoculation of Salix caprea with Microbacterium sp., Frigoribacterium sp., Sphingomonas sp., and Methylobacterium sp. increase leaves Cd and Zn accumulation. Sharma et al. [207] concluded that seed endophytes FXZ2 inoculation in Dysphania ambrosioides induced increased Zn/Cd tolerance by changing Zn/Cd speciation in rhizospheric soils, as well as exogenous production of phytohormones to promote growth, lowering oxidative damage while enhancing antioxidant properties. Enhanced metal bioaccumulation in the inoculated plant was attributed to siderophores, indole acetic acid, and ACC deaminase secretion.
In general, the basic mechanism of metal adsorption involves two distinct steps: (1) passive binding/loading of metals onto the wall of dead/inactive cell without integrating energy [239] and (2) active removal (bioaccumulation), involving the movement of metals through the plasma membrane driven by energy input and followed by intracellular storage [143].

Phytoremediation of Water and Soil Contaminated with Organic Pollutants
Industrialization and intensive agriculture are the main sources of hazardous contaminants that have deteriorated the quality of the natural ecosystem [15]. Even a small quantity of contaminants can reduce plant growth performance coupled with significant changes in soil microbe physiological processes, thus affecting critical soil biological processes [1,139]. Phytoremediation can be used to detoxify or stabilize organic and inorganic pollutants. It is considered to be the most promising technology because it is the least disturbed at the site, cheap, and eco-friendly in nature compared to conventional remediation technologies [166,247,258]. Despite public acceptance, the application in the field of phytoremediation faces several obstacles, such as low biomass and slow growth, volatile contaminant evapotranspiration, and plant toxicity. Further research experiments revealed that microbe-assisted phytoremediation enhances the efficiency of phytoremediation due to its plant growth-promoting activity (e.g., siderophore production) [247]. Compared to rhizosphere microbes, endophytic microbes have been considered a better candidate for the remediation process due to their internal inhabitation that offers the opportunity to adaptation inside host cells [16,262]. In addition, once plant growth-promoting endophytes (PGPEs) are formed in plant tissues, they are less susceptible to soil conditions' changes but depend more on plant tissues and physiological status, such as plant health, plant growth stage, and the nutritional state [74,191,194,200,201].
Generally, the endophyte-associated phytoremediation process involves three distinct steps: (1) development, plant growth, and biomass production; (2) availability of pollutants to the host system; (3) rapid increase in endophyte population responsible for contaminant degradation. So far, many endophytic microorganisms are isolated from contaminated and non-contaminated soils capable of degrading herbicides and polyaromatic hydrocarbons pollutants (Table 4). Moore et al. (159) found that bacterial genera belonging to Arthrobacter, Pseudomonas, Bacillus, and Enterobacter recovered from different organs of poplar inhabiting near the automobile industries could remove a volatile organic compound BTEX, a component of petroleum product [159]. The mineralization of the herbicide 2,4-D was also documented by Pseudomonas putida VM1450 [75]. The results confirmed that 2,4-D was not detected in the soil of inoculated plants exposed to 7 or 13 mg of 2,4-D. Pseudomonas ITRI53 inoculated Lolium multiflorum var. taurus greatly degrades 68% of diesel-contaminated soil compared to control treatments [17]. Other bacterial endophytes such as Achromobacter xylosoxidans    [115] F3B and Pantoea sp. noted similar degradation capacity of diesel/petroleum products ITSI10 and inoculated in Arabidopsis thaliana and Italian ryegrass under controlled conditions, respectively [8, 90,262]. Endophytic bacteria have also been studied to remove other aromatic compounds such as naphthalene and toluene. The inoculated pea plant with P. putida VM1441 (pNAH7) degraded 40% more naphthalene than the non-inoculated plant [74]. The toluene volatilization experiment suggested less toluene released from the leaves of the inoculated poplar plant with B. cepacia FX2 [244,249]. Moreover, pyrene degradation increased by 43-65% in the live Enterobacter sp. 12J1 inoculated planted soils compared to dead bacterium inoculated planted soils [209,210]. Furthermore, microbial species that catalyze the degradation of volatile organic contaminants, including trichloroethylene (TCE) degrading microbes, are described from Quercus robur (Fagaceae), Fraxinus excelsior (Oleaceae), and poplar growing in sites enriched with TCE [104,248,251]. The results of all these studies indicated that endophytic inoculation such as B. cepacia VM1468, P. putida W619-TCE, and Enterobacter PDN3, respectively, highly resist the release of TCE vapor in the environment, indicating the increased degradation efficiency.
In addition to soil remediation, plant endophyte associations have also been deployed to manage ground and surface water contaminated with organic contaminants (Table 5). An experimental investigation described a more than 50-70% reduction in toluene volatilization through inoculated yellow lupine with engineered B. cepacia VM 1330 compared to control plants grown in a hydroponic culture system [22]. Taghavi et al. [227] revealed that B. cepacia VM1468 inoculated poplar plants released five times less toluene in the air through the leaves. Furthermore, this study also concluded that horizontal gene transfer in natural endophytes could improve the phytoremediation of environmental contaminants. In addition, genetic modification of endophytes carrying foreign genes with degradation capacity has been proven to improve the phytoremediation of contaminants of aromatic and organic substances. An engineered P. putida W619TCE endophytic bacterium inoculated to poplar cuttings alleviated growth promotion and reduced TCE toxicity when grown in water that was contaminated with TCE [251].
Comprehensive research on endophytes proposed that the use of bacteria (preferably endophytes) that promote both plant growth and pollutant-degrading activities is superior to the use of bacteria that only promote plant growth or have pollutant-degrading activities. Therefore, an attempt is made to isolate and characterize endophytic bacteria that have plant growth-promoting and pollutant-degrading activities when growing on a contaminated site.

Conclusion and Future Perspectives
The application of microbial endophytes in agriculture, as well as environmental sustainability, is a growing research field. During the past two and a half decades, many studies have revealed rising interest in endophytic microbes. Endophytic microbes are known to improve host plant performance under abiotic and biotic stress conditions by altering the plants' response. Recent advances in biotechnology and bioinformatic tools such as CRISPR (Clustered Regularly Interspaced Palindromic Repeats)-Cas system, RNA interference (RNAi), metabolomics, and next-generation sequencing systems have made the possibility of studying endophytes at the molecular level [167]. The present concept of isolation, purification, and characterization of endophytes and the research connecting biology to chemistry is now being developed. This opens new interdisciplinary dimensions and actively allows bachelor and master research students to participate in this domain of research. Research must focus on microbial endophytes to come up with new ideas to improve crop productivity on a pilot scale. Endophytes play an important role in producing a wide variety of naturally occurring secondary metabolites (such as tyrosol, saadamycin, and munumbicins) showing the industrial application in pharmaceutics and thus human health. In this regard, researchers from all over the world are continuously exploring hidden endophytic microbes for novel potent bioactive compounds that can be used as potential therapeutics. Figure 7 shows the importance of the biological activities of endophytic metabolites. Endophytes are reported to be a warehouse of new metabolites that can be widely used as antimicrobial, anticancer, immunosuppressant, antiarthritic, and anti-insect drugs.
Although several bioactive compounds produced by endophytes, such as camptothecin, vinblastine, hypericin, and podophyllotoxin, have already been commercialized, novel bioactive compounds seem promising in the case of most pathogenic microorganisms in overcoming the problem of antibiotic resistance. Taken together, new bioactive compounds emitted by endophytes, particularly endophytic actinomycetes, could make a significant contribution to the current and future challenges of agriculture, the environment, and medicine. To isolate and characterize new endophytes with specific features that could be useful for crop production, comprehensive bioprospecting research of endophytic microbes from various ecological niches (e.g., harsh habitats, the marine environment, etc.) is required. We anticipate a shift in practice in the future, with a greater emphasis on optimizing the interaction between plants and soil microorganisms and endophytes. However, molecular mechanisms that explain the interaction between plants and endophytes have yet to be discovered. They will open a new door to the isolation and characterization of new molecules for humans and provide a new way to improve crops and environmental sustainability.

Declarations
Ethics Approval This review article does not contain any studies with human participants or animals performed by any of the listed authors.  (1)