Harnessing Trichoderma in Agriculture for Productivity and Sustainability

: Increased agricultural activities driven by rising food demand have led to environmental problems mostly arising from the high levels of external inputs and resources that are required. Additionally, environmental changes, such as global warming, can lead to various biotic and abiotic stresses, which have negative impacts on crop production. Numerous solutions and agricultural strategies have been introduced to overcome these problems. One of the ways to improve plant production as well as to increase resistance towards biotic and abiotic stresses is by utilizing beneﬁcial microbes as soil inoculants. A better understanding of the ability of Trichoderma to enhance crop production and the mechanisms that are involved are important for deriving maximum beneﬁts from their exploitation. These versatile fungi hold great promise for the development of viable commercial products that can be used widely in agriculture for increasing crop productivity in a more sustainable way. Many previous reviews on Trichoderma have tended to focus on the mechanisms of Trichoderma in enhancing plant growth and yield. This current review discusses the sustainability aspect of using Trichoderma as plant growth regulators, the impact on plant growth and yield as well as their effects in regulating biotic and abiotic stresses.


Introduction
Continuous growth in the world's population has led to a corresponding increase in food demand, which has necessitated the mass production of agricultural products [1]. By 2050, the population to be fed will be over 9 billion people. Not only do we have to increase food availability, but we also must ensure that supplies are sustainably produced by not compromising the services that nature is able to provide [2]. Intensive large-scale industrial agriculture requires high-external input and resources, and these ultimately cause environmental problems such as water shortages, destruction of biodiversity, a decline in soil fertility, and elevated levels of greenhouse gases, leading to an increase in biotic and abiotic stresses, which threaten agricultural productivity and food security [3,4].
Beneficial microbes employ various mechanisms of action that increase plant productivity through the promotion of plant growth and health, such as (a) colonizing soil and/or plant parts, thereby occupying space and limiting the proliferation of phytopathogens; (b) producing enzymes, antibiotic substances, and volatile organic compounds that suppress the phytopathogens; (c) facilitating nutrient and water uptake; (d) producing phytohormone; (e) inducing local or systemic resistance responses in plants; and (f) improving various physiological and molecular processes [5][6][7]. Trichoderma is among the most widespread fungi in the world and is a plant symbiont that resides in varying habitats, including the rhizosphere and plant tissue (as an endophyte). Trichoderma is also widely used as biocontrol agent against phytopathogenic microorganisms. For example, Trichoderma was found to endophytically colonize Brassica oleracea (kale) and activated the systemic resistance of kale plants against the bacterial pathogen, Xanthomonas campestris [8]. Some of the mechanisms involved in promoting plant growth and disease protection by means of endophytic fungi include increasing access to nutrients (nitrogen, phosphorus, potassium, zinc, iron, etc.), the production of antibiotics, the production of plant hormones, a reduction in ethylene, or an increase in water acquisition rate [9].
Numerous studies have been conducted to elucidate the mechanisms by which Trichoderma confers resistance to plant pathogens and resilience against various kinds of biotic and abiotic stresses [10,11]. Over the years, scientists and agricultural practitioners have focused on the search for environmentally friendly options for the management of cropping systems. Finding the best method for improving crop production is crucial in order to achieve a sufficient food supply for the continuously rising population. Agroecology has been a prominent way of redesigning food systems to achieve greener agriculture approaches with higher sustainability [12,13]. One important agroecological approach for maximizing root and rhizosphere efficiency is the application of beneficial microbes, including Trichoderma [14,15]. This strategy can lead to improved crop productivity and better nutrient use efficiency while providing a friendlier option for human health and the environment [16,17].
This review discusses Trichoderma-plant interactions that result in improved plant production and resistance towards biotic and abiotic stresses as well as the potential applications for Trichoderma in sustainable crop production. We also highlight the ability of Trichoderma to resist those stresses, thereby contributing to better plant growth and development. Despite the advancements achieved through research studies, the application of Trichoderma as a commercialized biofertilizer is yet to attain a satisfactory level. Deeper knowledge on the roles of Trichoderma-plant relationships and the underlying mechanisms involved are essential for the better understanding and application of these fungi by agricultural practitioners for sustainable food production. Sustainable agriculture is important in order to practice cleaner and healthier food production without jeopardizing the environment and the ability of future generations to produce food.

Roles of Trichoderma in Sustainable Crop Production
The effects of root inoculation by Trichoderma are not restricted to the site of colonization but exist throughout the entire plant system. Colonization involves a complex system whereby the fungus is able to invade plant cells but can only live symbiotically without killing the plant. Trichoderma resides at the outermost layer of the roots and does not penetrate into the inner vascular tissue [18]. In Trichoderma studies with arabidopsis, the plants were seen to restrict the invasion of Trichoderma in the vascular bundle through the presence of metabolites such as salicylic acid (SA) and glucosinolates (GSLs) [19,20]. A successful Trichoderma-plant interaction results in improved plant growth and crop yield upon the cumulative positive effects induced by the fungus that subsequently improve nutrient uptake and transport in plants [21,22]. For instance, composted kitchen wastes comprising T. harzianum showed considerable promise as a biofertilizer for tomato plants with yield increases of up to 336.5% [23]. In a chickpea study, Trichoderma spp. caused an increase in the growth and yield parameters of the treated plants compared to the uninoculated controls. This result was found to be caused by the enhanced solubilisation and uptake of phosphate [24]. Furthermore, a maximum yield of chilies (69.55 q/ha) was recorded when the seeds were pre-treated with T. harzianum together with its foliar sprays. Nutrient solubility and availability are induced by the acidification of soils by plant roots upon inoculation with the fungus. The process occurs through the secretion of some organic acids such as gluconic, citric, and fumaric acids [25]. In the case of sugarcane, both T. harzianum and T. viride were significantly effective in enhancing the uptake of phosphorus as well as other micronutrients, thereby improving germination, tiller population, millable canes output, and commercial cane sugar yield (CCS t/ha) [26]. In tomato plants, shoot and root growth attributes as well as chlorophyll content were significantly increased when sown in Trichoderma-fortified soil. Mineral contents in both shoot and root were higher compared to control plants [27]. Upon the application of T. virens, the efficiency of nitrogen uptake in lettuce and rocket plants was greater with enhanced crop yield and quality. Those acids reduce soil pH, subsequently allowing better nutrients solubility and uptake [28]. Other than acidification, the induction of root growth by the fungus and the increase in root biomass contributed to better nutrient absorption. It was observed that the single inoculation of broccoli plants with T. viride significantly increased the above-ground fresh weight, root length, chlorophyll b, head diameter, root phosphorus content, and shoot nitrogen content compared to uninoculated control plants [29].
Trichoderma sp. also secretes secondary metabolites that play important roles in elevating plant growth and yield. For example, T. harzianum and T. atroviride, with their main secondary metabolites harzianic acid (HA) and 6-pentyl-α-pyrone (6PP), respectively, were observed to improve grape plant growth, yield, and quality [30]. Vinale et al. [31] showed that the 6PP produced by Trichoderma has an auxin-like mechanism of action that is involved in plant growth improvement. Further study demonstrated that 6PP is responsible for promoting plant growth and regulating root architecture, inhibiting primary root growth, and inducing lateral root formation [32]. This study showed that 6PP modulated the expression of PIN auxin-transport proteins in a specific and dose-dependent manner in primary roots. Other than that, T. harzianum was found to release a metabolite called harzianolide, which is a plant growth regulator that is responsible for improving the growth of tomato seedlings [33]. This study revealed that harzianolide enhances root length and tips as well as induces the expression of genes involved in the salicylic acid (PR1 and GLU) and jasmonate/ethylene (JERF3) signaling pathways that are related to the plant defence mechanism. In arabidopsis, T. virens and T. atroviride were found to secrete indole acetic acid (IAA) and auxin-related substances; these metabolites are important for root development [34]. Studies have shown that rice plants inoculated with T. asperellum produced better plant architecture, higher panicle number, longer panicle length, and increased plant height [35][36][37]. This is in agreement with previous study on the application of T. harzianum on maize plants. When applied to the soil or directly to the seeds, the fungus caused an increase in all of the measured parameters, including growth parameters and levels of chlorophyll, starch, nucleic acids, total protein, and phytohormones of the plants [38].
Numerous studies have been conducted to elaborate the mechanisms by which Trichoderma promotes plant growth and development [30,31,[39][40][41]. Some of these mechanisms can be explained by the upregulation of photosynthesis-related proteins resulting in a better photosynthetic rate, plant nitrogen use efficiency [39], and enhancement of plant nutrient uptake [42]. While molecular studies on Trichoderma effects are still in a nascent stage, some are showing promising results. For example, a large portion of the genes related to carbohydrate metabolism, stress modulation, and photosynthesis were up-regulated in maize plants upon inoculation with Trichoderma [43]. Similarly, in rice, the presence of T. asperellum was found to be correlated with the up-regulation of different genes, some of which have been identified to be involved in photosynthesis and chlorophyll biosynthesis. The up-regulation of genes related to CO 2 fixation, response to light, and stomatal complex development indicated an enhancement of the plant's efficiency in photosynthesis [44]. Table 1 summarizes the genes reported to be up-regulated in various plants upon Trichoderma inoculation.

Roles of Trichoderma in Sustainable Plant Disease Management
Since the 1920s, the very common, soil-inhabiting fungi, Trichoderma spp. have been recognized for their capability to act as biocontrol agents against many phytopathogens based on their abilities to parasitize other fungi and to produce antibiotics [42,52]. Later, their principal mechanism of action for plant protection was known to be based on the induction of disease resistance. Trichoderma has been documented to control many pathogenic microorganisms that affect plants, including bacteria (Pseudomonas and Xanthomonas), other fungi (e.g., Fusarium, Curvularia, Colletotrichum, Alternaria, Rhizoctonia, and Magnaporthe), the oomycetes (Pythium and Phytophthora), and at least one virulent virus (green mottle mosaic virus on cucumber) [42].

Trichoderma as Biocontrol Agents against Plant Pathogenic Bacteria
Plant diseases caused by bacteria are relatively difficult to control. However, the most common methods used to effectively control these diseases include plant breeding and cultural, chemical, biological, and physical control measures. Biocontrol agents are effective in controlling bacterial pathogens and are safer for the environment than chemical bactericides are. The excessive application of chemicals and consumer acceptance towards resistant cultivars can be very complex, which makes the use of biocontrol agents an attractive alternative [22].
Trichoderma showed an inhibitory effect on the growth and survival of the pathogenic Gram-negative bacterium, Ralstonia spp., in tomato plants, which was attributed to the secretion of various compounds such as lysosime, viridiofungin, and trichokonin [53]. Moreover, bacterial wilt caused by the soilborne bacterium R. solanacearum was inhibited by the application of T. asperellum, and the disease incidence was subsequently decreased with concomitant improvement in plant growth and yield under field conditions. This was achieved through the induction of a maximum level of defence enzyme activities, such as POX, PPO, and PAL, β-1,3-glucanase, and the total phenolic contents in plants [54]. Other examples of biocontrol of bacterial phytopathogens include the induction of resistance by Trichoderma conferred protection in tomato plants against Xanthomonas euvesicatoria (the causative agent of bacterial spot) and [55] cucumber plants grown in the presence of Trichoderma exhibiting greater protection against Pseudomonas syringae pv. lachrymans infection. T. harzianum activated separate metabolic pathways in cucumber that are involved in plant signaling and biosynthesis. Plant protection may be conferred by a combination of several modes of action provided by Trichoderma, such as phytoalexins biosynthesis, lignification, and the accumulation of pathogenesis related proteins and antimicrobial secondary metabolites [56].

Trichoderma as Biocontrol Agents against Phytopathogenic Fungi
Other than bacterial infections, fungal diseases are often associated with damage to crops, causing major losses in agricultural activities and food production. Thus, finding the best option to eradicate this problem is crucial. Trichoderma was found to have the ability to eliminate phytopathogenic fungi through a mechanism known as mycoparasitism. This involves the suppression of other microorganisms at the same site, thereby making it the dominant organism at the location [15,57].
Mycoparasitism by Trichoderma species involves an attack on the pathogen's cell or structures [58]. It was reported that T. koningii did not invade healthy tissues but colonized infected or damaged onion root tissues as a secondary colonizer, where it reduced Sclerotium cepivorum infection by destroying the hyphae [59]. On the other hand, T. virens not only parasitized the hyphae of many pathogenic fungal species, but also penetrated and destroyed some of the resting structures of these fungi, thereby reducing their inoculum potential in soil [60]. The pre-emergence of damping-off diseases in cotton seedlings caused by Rhizopus oryzae was observed to be controlled upon T. virens treatment. This fungus metabolized the pathogen propagule germination stimulants that emanated from the germinating cotton seed [61].
Several species of Trichoderma also produce volatile and non-volatile antibiotics and enzymes, which have shown antagonistic effects towards phytopathogenic fungi [62]. Protease, endochitinases, β-glucosidases, mannosidases, and phosphatases released by T. harzianum were found to be involved in the biocontrol of various pathogens, including Guignardia citricarpa (the causative agent of citrus black spot). These enzymes are involved in the degradation of pathogen cell wall membranes and proteins [63]. Trichoderma also releases metabolites that are capable of diminishing or antagonizing pathogenic microbes [64]. Fungal terpenoids (desoxyhemigossypol, hemigossypol, and gossypol) synthesized in cotton roots by T. virens were found to be involved in combating R. solani-incited cotton seedling [65]. The application of Trichoderma on R. solani-infected chilies improved plant growth and yield. This was attributed to the reduction of the damping-off disease of seedlings as well as to reducing root and stem rot in chilies [66].
In another report, inoculation of T. harzianum inhibits R. solani growth by the induction and expression of lipoxygenase (Lox) and glutathione S-transferase (GST1) genes in the roots of potato plantlets that have been simultaneously inoculated with both organisms [50]. The Lox gene product is crucial for lipid peroxidation processes during plant defence responses to pathogen infection [67]. On the other hand, GST1 is a defence gene that is involved in the detoxification of toxic substances by their conjugation with glutathione, the attenuation of oxidative stress, and participation in hormone transport [68]. Biotic stresses can induce plants to produce higher levels of damaging reactive oxygen species (ROS). The excessive production of ROS causes oxidative stress resulting in the damage of cellular components, consequently leading to the death of plant cells [69]. A study conducted by Herrera-Téllez et al. [70] found that tomato plants pre-treated with T. asperellum and that were subsequently challenged with two fungal pathogens, Fusarium oxysporum and B. cinerea, experienced less severe wilting and stunting symptoms compared to non-treated plants due to the ROS modulation by Trichoderma.
Besides their direct antagonistic effects against fungal and bacterial plant pathogens, Trichoderma species have also been found to induce resistance against various plant diseases. This resistance induction can be either localized or systemic. The effects of systemic resistance induced by Trichoderma were recorded using a model rhizobacterium. For example, T. virens successfully induced plant-systemic resistance in maize against Colletotrichum graminicola [71]. Other than that, T. virens was capable of inducing localized resistance against R. solani infection of cotton roots through the stimulation of terpenoid synthesis by the plant [65]. The mechanisms involved in these inductions are associated with different kinds of changes at the biochemical and molecular levels in the plants [72].
The capability of Trichoderma to protect plants against different bacterial and fungal pathogens is summarized with examples in Table 2.

Trichoderma as Biocontrol Agents against Pests and Plant-Parasitic Nematodes
Plant diseases caused by insect pests and plant-parasitic nematodes (PPNs) are also considered to be a significant threat to global agricultural productivity and sustainability. Insect pests can cause agricultural losses of up to 70% [82], while 12% of worldwide food production is lost due to plant-parasitic nematodes (PPNs) [83].
Among the common nematode antagonistic fungi, also known as nematophagous fungi, T. harzianum. T. viride, and T. lignorum have been commercially produced as fungal biocontrol agents for the management of phytonematodes [84]. An experiment employing Trichoderma for the control of the root-feeding nematode Meloidogyne hapla in tomatoes revealed that tomato plants that were prior inoculated with Trichoderma exhibited a lower number of nematode eggs laid on or near the roots of about 1000 (2%) eggs compared to 50,000 eggs laid on the roots of untreated plant controls [85]. Earlier, an experiment in India showed that the bio-integration of T. harzianum in combination with oil cakes could significantly reduce the population of citrus nematode Tylenchulus semipenetrans in both soil and root [86].
Fungi belonging to the Trichoderma genus are also well-known for their beneficial effects in conferring plant protection against insect pests and parasitic nematodes. Based on previous studies on the mode of action of Trichoderma as the mycoparasite fungus, Trichoderma species can act directly as an entomopathogen through parasitism, and the production of insecticidal secondary metabolites, antifeedant compounds and repellent metabolites. On top of that, this versatile fungus can act indirectly as a mycoparasite through the activation of systemic plant defensive responses, the attraction of natural enemies, or the parasitism of insect-symbiotic microorganisms [82]. For example, T. longibrachiatum that was formulated into a biopesticide was reported to be able to control the insect pest Leucinodes orbonalis in brinjal plants as well as increasing crop yield by 56.02% [87]. Moreover, under laboratory conditions T. harzianum exhibited an inhibitory activity of around 70-80% towards Xylotrechus arvicola (an important pest in vineyards) and Acanthoscelides obtectus (a causal agent of severe post-harvest losses in the common bean) [88].
The application of T. gamsii to the roots of Arabidopsis thaliana decreased the feeding behaviour of herbivore Trichoplusia ni through the modulation of the metabolome as well as affecting the content of phytohormones in plant leaves. T. gamsii-inoculated plant leaves recorded higher levels of amino acids and abscisic acid and lower concentrations of sugars compared to untreated plants [89]. Maize plant roots associated with T. atroviride recorded higher resistance against the insect herbivore Spodoptera frugiperda compared to untreated plants. Further examination indicated that there was a significant increase with regards to the emission of volatile terpenes and the accumulation of jasmonic in roots of inoculated rice plants. Chemical analyses revealed that T. atroviride produced the volatiles 1-octen-3-ol and 6-pentyl-2H-pyran-2-one, which were believed to have an important role in reducing the consumption of the foliar tissue of maize plants by S. frugiperda [90].
The inoculation of T. atroviride in tomato plants induced plant resistance to the insects Spodoptera littorali and Macrosiphum euphorbiae. These protection capacities were attributed to a plant response induced by T. atroviride that was linked with molecular and biochemical changes in tomato plants. T. atroviride also produced alterations in plant metabolic pathways leading to the production and release of volatile organic compounds (VOCs) that are involved in the attraction of the aphid Aphidius ervi (a parasitoid with activity against many pests), thus reinforcing indirect plant defence barriers [91]. The insecticidal efficacy of T. harzianum with natural protectants was also found to be an acceptable approach for the management of stored product damage resulting from the insects Callosobruchus maculatus and C. chinensis in cowpea seeds. The T. harzianum-based biofungicide formulation caused complete insect mortality and inhibited progeny production. Thus, this eco-friendly product can be an effective strategy for the management of both insects on stored cowpea seeds [92].

Trichoderma Species as Abiotic Stress Relievers in Crops
Drought is one of the main abiotic stresses that occur due to water deficit and is escalated by increasing evapotranspiration [93]. Drought has deleterious effects that may reduce growth and cause plant death [94]. The inoculation of plants with Trichoderma activates a number of different kinds of responses toward drought. For example, T. harzianum was found to postpone or delay drought responses in rice. This was due to the enhancement of root growth regardless of the water deficit that was shown by the delayed increase of the stress-induced metabolites proline, malondialdehyde (MDA), and hydrogen peroxide content as well as increased phenolic compound concentration [95]. T. atroviride inoculation in maize plants could diminish the injurious effects of drought and might have a function in arranging resilience against stress by inducing the antioxidant machinery that helps to overcome the unfavourable conditions caused by the overproduction of ROS [96]. It was found that the maize plants inoculated with T. harzianum had a high starch content in their leaves [38]. This could be beneficial in drought conditions, where prolonged stomatal conductance leads to carbon starvation.
Other than drought, cold is an example of extreme temperature conditions that constitute a serious threat to the sustainability of crop yields and that can lead to major crop losses. This stress happens when plants are exposed to low temperatures, such as those caused by sudden frosts in fall, freezing temperatures in winter, and late cold spring events [97]. The inhibition of decline in plant growth due to cold weather can be induced by Trichoderma. For example, T. harzianum colonization was found to alleviate the detrimental effects of cold stress on most commercial varieties of tomato, a cold-sensitive plant. Upon inoculation of T. harzianum, both the fresh and dry weights of tomato leaves and roots were enhanced compared to those of cold-treated plants. Other than that, improved photosynthesis and growth rate, leaf water content, and proline accumulation were observed, while indicators of cold injuries such as lipid peroxidation rate and electrolyte leakage were reduced [49].
Soil salinity stress is accompanied by high osmotic potential and specific ion toxicity and is another growth limiting factor for plants. However, treatment with T. harzianum on wheat plants was able to reduce the severity of saline conditions [98]. The application of T. asperelloides prior to salt stress imposition in both arabidopsis and cucumber plants showed significantly improved seed germination [45]. Increased salinity can lower the photosynthetic rate, thereby reducing the supply of carbohydrates needed for plant growth [99]. The inoculation of the Indian mustard plant with T. harzianum was able to restore the photosynthetic pigment to an appreciable level [100]. In saline or degenerated soils, T. asperellum was found to be involved in the solubilization of the large amounts of insoluble organic and inorganic phosphate compounds needed for cucumber growth. Cucumber plants inoculated with Trichoderma exhibited growth in both normal and saline conditions, indicating the role of the fungus in helping plants to overcome the inhibition of plant root development caused by high salt levels [101,102]. In addition, in response to biotic and abiotic stresses, several genes related to the rice plant response to these stresses were upregulated upon Trichoderma inoculation. For example, genes that are involved in plant defence response and ROS metabolism were up-regulated with T. asperellum inoculation [44]. Table 3 summarizes the effects of Trichoderma inoculation towards abiotic stresses in plants. Table 3. Trichoderma and their abiotic stress regulation mechanisms.

Trichoderma Species Mechanisms References
Rice T. harzianum Promotion of root growth in water deficit conditions. [95] Maize

T. atroviride
Improved drought-induced damages such as fresh and dry weights of maize roots, lipid peroxidation, photosynthetic machinery and inducing antioxidant enzyme activity and hydrogen peroxide. [96] Maize T. harzianum High starch content. [43] Tomato T. harzianum Maintained a high level of growth regulators, modulated plant secondary metabolites. [103] Tomato T. harzianum Improved growth attributes together with reduced cold injuries. [49] Arabidopsis, Cucumber T. asperelloides Improved seed germination. [45] Indian mustard T. harzianum Restored photosynthetic pigment level. [100]

Challenges and Future Prospects for Up-Scaling the Use of Trichoderma for Sustainable Crop Production
In summary, numerous studies have provided strong evidence that Trichoderma species integrated into crop production can achieve improved overall plant health, growth, yield, and disease resistance (Figure 1). Based on a study completed by Zhang et al. [104], the application of Trichoderma biofertilizer (composted cattle manure + inoculum) effectively regulated soil chemistry and microbial communities, which substantially improved aboveground plant biomass compared to the organic fertilizer alone. Furthermore, the presence of Trichoderma can increase the relative abundance of beneficial fungi while significantly decreasing the number of phytopathogenic microorganisms. This was shown by the increase of Archaeorhizomyces and Trichoderma while decreasing Ophiosphaerella abundance. In one in vitro study, Trichoderma was seen to inhibit the growth of Fusarium solani, but no inhibition area was observed when it was cultured together with Pseudomonas strains [105]. Trichoderma tends to be compatible and live mutually with beneficial microbes that contribute to plant growth rather than harmful ones.
Realization of the beneficial capabilities of Trichoderma is important to meet current societal needs [106]. There are increasing concerns about the possible adverse effects of biological control agents (BCAs) and the risks associated with the use of these biological compounds on mammalian health. A study conducted by Santos et al. [107] analyzed and discussed the interaction between Trichoderma spp. and mammalian immune system cells. The study indicated that T. asperelloides spores in mice reduced the quantity of neutrophils (a type of white blood cell that involves in healing damaged tissues and resolving infections) and monocytes. However, these preliminary results indicated that the impact of Trichoderma on the immune system could be more significant than previously supposed. However, further studies are required to elucidate the effects of BCAs on mammalian immune responses that are possibly associated with infectious, inflammatory diseases and defective defences [108]. That said, the majority of BCAs products are safe for consumers and the environment [109]. Nevertheless, consumers need to handle BCAs properly and must comply with safety and health standards [37]. A number of Trichoderma-based products have been developed and marketed globally as BCAs and biofertilizers, a majority of the work on the BCAs has focused on isolation, identification, and the development of the selected isolates and only a few of such products are registered and commercialized. This is due to the fact that the commercialization of the end products is tedious, laborious, timeconsuming, and quite costly [84]. On top of that, the investigation on the long-term effect of BCAs and biofertilizers on consumers should always be included in order to prevent any potential harm from such compounds and to allow consumers to make informed decisions based on scientific data [110]. To translate early-stage BCA research, a suitable company that is capable of manufacturing and marketing products must be approached. As this is not easily achieved, researchers might have to resort to their personal means to develop and produce the intended product up until the commercialization process. Without proper instructions and knowledge passed to the consumers, such a product will not reach or stay relevant on the market. Realization of the beneficial capabilities of Trichoderma is important to meet current societal needs [106]. There are increasing concerns about the possible adverse effects of biological control agents (BCAs) and the risks associated with the use of these biological compounds on mammalian health. A study conducted by Santos et al. [107] analyzed and discussed the interaction between Trichoderma spp. and mammalian immune system cells. The study indicated that T. asperelloides spores in mice reduced the quantity of neutrophils (a type of white blood cell that involves in healing damaged tissues and resolving infections) and monocytes. However, these preliminary results indicated that the impact of Trichoderma on the immune system could be more significant than previously supposed. However, further studies are required to elucidate the effects of BCAs on mammalian immune responses that are possibly associated with infectious, inflammatory diseases and defective defences [108]. That said, the majority of BCAs products are safe for consumers and the environment [109]. Nevertheless, consumers need to handle BCAs properly and must comply with safety and health standards [37]. A number of Trichoderma-based products have been developed and marketed globally as BCAs and biofertilizers, a majority of the work on the BCAs has focused on isolation, identification, and the development of the selected isolates and only a few of such products are registered and commercialized. This is due to the fact that the commercialization of the end products is tedious, laborious, timeconsuming, and quite costly [84]. On top of that, the investigation on the long-term effect of BCAs and biofertilizers on consumers should always be included in order to prevent any potential harm from such compounds and to allow consumers to make informed decisions based on scientific data [110]. To translate early-stage BCA research, a suitable company that is capable of manufacturing and marketing products must be approached. As this is not easily achieved, researchers might have to resort to their personal means to develop and produce the intended product up until the commercialization process. Without proper instructions and knowledge passed to the consumers, such a product will not reach or stay relevant on the market. Despite the constraints, the Asian continent, particularly India, has seen the greatest commercialization of Trichoderma-based products, followed by South and Central America [111]. Several challenges have limited the full-scale commercialization of Trichoderma bioproducts, and these have also been major reasons for the relatively small number of registered products. In many countries, guidelines for microbial control agents are lacking; hence, regulatory requirements for the approval of these products are modelled after those of chemical agents. This approach makes it difficult due to the incompatibility of biocontrol agents with some of the criteria used for chemical agents [112]. Furthermore, the requirements for testing, validation, patenting, and other processes make the registration an expensive venture, thus discouraging aspiring entrepreneurs [112,113]. In developing countries, the required resources and expertise for the large-scale commercial production of Trichoderma products are also lacking [113,114].
Conceivably, the most serious hindrance against the commercialization of Trichodermabased products is their poor shelf life [111]. Several strategies have been attempted and have shown great promise for extending the shelf life of such products without severely impacting their beneficial properties. Among the measures that have been used to extend the shelf life of Trichoderma preparations are the use of carrier materials [115] such as starch and pH and copper amendments [116] and encapsulation in granules [117]. Recently, a novel biodegradable lignin shell was used to encapsulate T. reesei spores in a layer-by-layer assembly [118]. This strategy prevented the unwanted germination of the spores and permitted their selective germination upon contact with a lignin-degrading fungal pathogen.
Hence, efforts targeted at addressing these problems will facilitate commercialization and will increase the accessibility of bioproducts derived from this versatile fungal genus. Other than that, since biofertilizers normally depend on soil conditions, continuous study and refinement on the product design and workability are needed to allow different environmental areas to gain the same benefits [119]. Ultimately, both subsistent and large-scale agriculture would benefit from such measures.

Industrial Production of Trichoderma
The main characteristic for a selected endophytic fungal to be commercialized as a biocontrol or biofertilizer product is the ability to be mass produced through the economical generation of the utmost amount of effective propagules (chlamydospores, conidia, microsclerotia) in the shortest period of time. A higher cost of production due to expensive substrate, low biomass output, or restricted economies of scale can be a limiting factor in the commercialization of the end products [120].
Prior to the biomass production, practical research has been initiated with the isolation and identification of the specific Trichoderma species. After the isolation and characterization of pure culture of the selected Trichoderma, the propagules can be in the form of hyphae, chlamydospores, and conidia [37,84]. The mass production of Trichoderma propagules can be completed through solid state as well as by submersed fermentation [121]. Substrates for mass production can be obtained from crop residues, livestock wastes, industrial wastes, and any organic material [122].
The industrial production of Trichoderma can be conducted in the following steps: (1) optimization of the culture condition at a laboratory scale in order to obtain high yield and active biomass, (2) optimization of biomass production at pilot-plant level to determine and solve various engineering variables; the resulting products can be tested for field application, (3) integration of selected unit operations from fermentation, bioseparation, and formulation into a single process, and (4) industrial plant-scale production of propagules of Trichoderma [120,123]. The production process of Trichoderma-based biofertilizer from laboratory to industrial scale is summarized in Figure 2. (c) field testing from optimized product; (d) operation integration of fermentation, bioseparation, and formulation into a single process; (e) industrial plan-scale production of Trichoderma propagules; (f) assessment of product quality and standard; (g) commercialization and distribution for public use.

Conclusions
Trichoderma is able to enhance the growth and development of various plant species safely and sustainably. This includes combating both biotic and abiotic stresses that often deteriorate plant normal development and cause crop losses. The positive effects of Tricho- (c) field testing from optimized product; (d) operation integration of fermentation, bioseparation, and formulation into a single process; (e) industrial plan-scale production of Trichoderma propagules; (f) assessment of product quality and standard; (g) commercialization and distribution for public use.

Conclusions
Trichoderma is able to enhance the growth and development of various plant species safely and sustainably. This includes combating both biotic and abiotic stresses that often deteriorate plant normal development and cause crop losses. The positive effects of Trichoderma towards plant growth and development have proven that these fungi can be used extensively for the advancement of sustainable agriculture. Currently, there are intensive efforts to hasten their integration into agricultural production systems to achieve the development of successful inoculation systems and workable modes of delivery. An improved understanding of the mechanisms involved in various processes by Trichoderma is important to develop practicable products for a sustainable agriculture sector. Furthermore, the application of different omics approaches in phytobiome studies has become invaluable for unveiling a comprehensive interaction among Trichoderma, plants, and their environment. The acceptance of workable Trichoderma-based products will help to reduce the use of chemical fertilizers and pesticides and will subsequently lead to healthier, cleaner food production, and sustainable agricultural practice.