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Review article
01 2022
:16;
104435
doi:
10.1016/j.arabjc.2022.104435

Biodiversity and application prospects of fungal endophytes in the agarwood-producing genera, Aquilaria and Gyrinops (Thymelaeaceae): A review

, , , , , , ,
a National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
b Department of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou 510006, China
c Faculty of Health and Life Sciences, INTI International University, 71800 Nilai, Negeri Sembilan, Malaysia
d Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 301617 Tianjin, China

⁎Corresponding authors at: No. 16, Dongzhimen Southern Street, Beijing 100700, China. huangluqi01@126.com (Luqi Huang), juanliu126@126.com (Juan Liu)

Received: , Accepted: ,
© The Author(s) 2022
Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

Peer review under responsibility of King Saud University.

Abstract

Agarwood is originated from the resinous part of Aquilaria and Gyrinops plants and has been a precious biomaterial for applications in traditional medicine, perfumery, cosmetics, and religious purposes all over the world. In the wild, the formation of agarwood is related to the defense mechanism of the tree in response to physical damage that allows further microbial infestation into its wood, while having the whole tree covered with agarwood would take up a long time, and it rarely happens. For Aquilaria and Gyrinops, the presence of endophytes is mainly found derived from the tree. The isolated endophytes could be important sources of natural products, while some could contribute to the formation of agarwood in the tree, which is safe for the environment and human health. This review summarized the biodiversity of fungal endophytes recorded in Aquilaria and Gyrinops and their potential effects on host trees. Till now, 67 endophytic genera have been isolated from Aquilaria and Gyrinops, and 18 ones were found responsible for the promotion of agarwood formation. Additionally, 92 compounds have been reported to be produced by the agarwood endophytes, and 52 ones displayed biological activities, most of which have anti-inflammatory, anti-bacterial, and anti-cancer activities. Nevertheless, fungal endophytes are promising agents that deserved to be further studied and scaled up to a commercial level for the production of agarwood oil, but the role of endophytes in the agarwood host trees needs to be furtherly investigated in future studies.

Keywords

Agarwood
Fungal endophytes
Aquilaria
Gyrinops
1

1 Introduction

Members of the agarwood-producing genera, Aquilaria and Gyrinops, are tropical evergreen trees commonly grown in the lowland forest regions, which are mainly distributed in southeast Asia. Agarwood is a highly valuable fragrance derived from the resinous wood of Aquilaria and Gyrinops trees. The intriguing aroma of agarwood makes it a valuable ingredient that has a long history record in the production of traditional medicines as well as used in religious activities, while at present, it is regarded as a luxury biomaterial in perfumery and cosmeceutical industries (Huang et al., 2013; Sun et al., 2020; Xie et al., 2020). Although all 30 species (21 Aquilaria species and 9 Gyrinops species) are believed to be able to produce agarwood, to date, evidence of agarwood formation was only reported for 14 species of Aquilaria and eight species of Gyrinops (Auri et al., 2021; Compton and Zich, 2002; Hou 1964; Kiet et al., 2005; Lee and Mohamed, 2016; Ng et al., 1997; Subasinghe et al., 2012; Turjaman et al., 2016) (Table 1). The high demand but rare occurrence of agarwood in the wild has led to the over-exploitation of these valuable species in the past, causing the decline in the population size of these agarwood-producing species in the wild. As a consequence, some of these species are classified as “Vulnerable”, “Endangered”, and “Critically Endangered” (IUCN 2022), as well as to aid in conserving the resources, all members of the agarwood-producing genera, Aquilaria and Gyrinops, are currently placed under strict monitoring by the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES) in Appendix II (UNEP-WCMC, 2022).

Table 1 Basic information about agarwood-producing genera of Aquilaria and Gyrinops, including species name, distribution, basionyms and synonyms, and agarwood production report.
Species Name Distribution* Basionyms and synonyms Agarwood production report
Aquilaria apiculata Merr. Philippines –
Aquilaria baillonii Pierre ex Lecomte Cambodia; Viet Nam; Lao People's Democratic Republic – Ng et al., 1997
Aquilaria banaensis P.H. Hô Viet Nam Aquilaria banaensae
Aquilaria beccariana Tiegh. Brunei Darussalam; Indonesia; Malaysia Aquilaria cumingiana var parvifolia; Aquilaria grandifolia; Gyrinops brachyantha; Gyrinopsis grandifolia Faridah et al., 2009Compton and Zich, 2002Turjaman et al., 2016
Aquilaria brachyantha (Merr.) Hallier f. Phillipines Gyrinopsis brachyantha
Aquilaria citrinicarpa (Elmer) Hallier f. Phillipines Gyrinopsis citrinicarpa
Aquilaria crassna Pierre ex Lecomte Cambodia; Viet Nam; Thailand; China; Malaysia – Yoswathana, 2013Ng et al., 1997
Aquilaria cumingiana (Decne.) Ridl. Phillipines; Indonesia; United State; Malaysia Aquilaria pubescens; Decaisnella cumingiana; Gyrinopsis cumingiana; Gyrinopsis cumingiana var. pubescens; Gyrinopsis decemcostata; Gyrinopsis pubifolia Turjaman et al., 2016
Aquilaria decemcostata Hallier f. Phillippines –
Aquilaria filaria (Oken) Merr. Indonesia; Phillipines; Papua New Guinea Aquilaria cuminate; Aquilaria tomentosa; Gyrinopsis acuminate; Pittosporum filarium Compton and Zich, 2002Turjaman et al., 2016
Aquilaria hirta Ridl. Indonesia; Malaysia; Singapore; Thailand Aquilaria moszkowski Faridah et al., 2009Compton and Zich, 2002Turjaman et al., 2016
Aquilaria khasiana Hallier f. India – Hallier, 1992
Aquilaria malaccensis Lam. Bangladesh; Bhutan; China; France; India; Indonesia; Lao People's Democratic Republic; Mauritius; Malaysia; Philippines; Viet Nam; Thailand; Sri Lanka Agallochum malaccense; Aloexylum agallochum; Aquilaria agallocha; Aquilaria ovate; Aquilaria moluccensis; Aquilaria secundaria; Aquilariella malaccense; Aquilariella malaccensis Chowdhury et al., 2003Broad, 1995Rahayu and Putridan Juliarni, 2007Turjaman et al. 2016
Aquilaria microcarpa Baill. Brunei Darussalam; Indonesia; Malaysia; Italy Aquilaria borneensis; Aquilariella borneensis; Aquilariella microcarpa Santoso et al., 2011Faridah et al., 2009Compton and Zich, 2002Turjaman et al. 2016
Aquilaria parvifolia (Quisumb.) Ding Hou Philippines Gyrinopsis parvifolia
Aquilaria rostrata Ridl. Malaysia; Thailand – Faridah et al., 2009
Aquilaria rugosa K.Le-Cong & Kessler Thailand; Viet Nam – Kiet et al., 2005
Aquilaria sinensis (Lour.) Spreng. China; Thailand; Malaysia; Viet Nam Agallochum grandiflorum; Agallochum sinense; Aquilaria chinensis; Aquilaria grandiflora; Aquilaria ophispermum; Ophispermum sinense Liu et al., 2013Liu et al., 2022Ng et al., 1997Zhang et al., 2014
Aquilaria subintegra Ding Hou Thailand; Malaysia – Hou, 1964
Aquilaria urdanetensis (Elmer) Hallier f. Philippines Gyrinopsis urdanetense; Gyrinopsis urdanetensis
Aquilaria yunnanensis S.C.Huang China – Sun et al., 2019Zhang et al. 2019
Gyrinops caudata (Gilg) Domke Indonesia; Papua New Guinea Aquilaria caudata; Brachythalamus caudatus; Gyrinops audate Auri et al., 2021
Gyrinops decipiens Ding Hou Indonesia – Turjaman et al. 2016
Gyrinops ledermannii Domke Indonesia; Papua New Guinea – Compton and Zich 2002Turjaman et al. 2016
Gyrinops moluccana (Miq.) Baill. Indonesia Aquilaria moluccana; Lachnolepsis moluccana Turjaman et al. 2016
Gyrinops podocarpa (Gilg) Domke Indonesia; Papua New Guinea Aquilaria podocarpus; Brachythalamus podocarpus; Gyrinops ledermannii; Gyrinops podocarpus Turjaman et al. 2016
Gyrinops salicifolia Ridl. Indonesia; Papua New Guinea Gyrinopsis salicifolia Shao et al., 2016Dong et al., 2019Turjaman et al., 2016
Gyrinops versteegii (Gilg) Domke Indonesia; Papua New Guinea Aquilaria versteegii; Brachythalamus versteegii Faizal et al., 2020Faizal et al., 2022Turjaman et al., 2016Nasution et al., 2020
Gyrinops vidalii P.H.Hô Thailand; Lao People's Democratic Republic –
Gyrinops walla Gaertn. Indonesia; Papua New Guinea; India; Sri Lanka Aquilaria walla Subasinghe et al., 2012
* The distribution data of this table were calculated out from GBIF (the Global Biodiversity Information Facility, https://www.gbif.org) database and references (Lee and Mohamed, 2016; Lee et al., 2018; Lee et al., 2022).

Due to the conservation status and low yield of agarwood production in the wild, relying on the natural population as a source of agarwood to meet the increasing market demand is rather unviable (Deng et al., 2020; Wang et al., 2018). Therefore, the domestication of agarwood-producing trees was introduced and mass cultivation coupled with good agriculture practices was promoted (Liu et al., 2013; Persoon and Beek, 2008). In general, agarwood is naturally formed in Aquilaria and Gyrinops trees as a result of self-defense against physical damage or microbial infection on the trees (Soehartono and Newton, 2000; Xu et al., 2013). While physical damage to the tree is to introduce an opening; fungal infection has always been considered to be a key factor in agarwood formation (Rasool and Mohamed, 2016).

Endophytic fungi can live inside plant tissues without any disease symptoms. The evidence of the use of endophytic fungi to induce agarwood formation has been present for a long time, i.e. 1934 (Turjaman et al., 2016; Yoswathana, 2013), while the fungi that show promising results in the production of agarwood are developed into fungal inoculum. To mimic the mechanism of agarwood formation via microbial infestation, endophytic fungi are introduced into the cultivated stands via inoculation technique in hope that the time to form agarwood will be reduced and the yield could be increased at the same time. It is believed that the quality of the agarwood formed relies heavily on the species or strains selected among the different endophytic fungi; thus, research and exploration to discover additional useful endophytic fungi that could warrant better yield and quality of agarwood are still ongoing (Liu et al., 2022). Additionally, the secondary metabolites from endophytic fungi of agarwood lead the way as sources for various pharmacological properties.

In order to provide a comprehensive review of the information on endophytic fungi involved in the formation of agarwood, we mined various published scientific reports and summarized the distribution and biodiversity of fungal endophytes present in Aquilaria and Gyrinops. In addition, the secondary metabolites produced as well as the pharmacological values of these agarwood-related fungal endophytes in Aquilaria and Gyrinops were documented and discussed too. Finally, the effects on the host trees of Aquilaria and Gyrinops by fungal endophytes were discussed. We believe that our review could be useful for researchers to find innovative directions in the research field of agarwood endophytes.

2

2 Ecological distribution of Aquilaria and Gyrinops species

Aquilaria and Gyrinops species are widely distributed in southeast Asia, especially Indomalesia region (Lee and Mohamed, 2016). Recently, nine from the total of 21 species in the genus Aquilaria genus are known to grow in Malaysia (data from GBIF-Global Biodiversity Information Facility; Lee and Mohamed, 2016; Lee et al., 2018; Lee et al., 2022), including A. beccariana, A. crassna, A. cumingiana, A. hirta, A. malaccensis, A. microcarpa, A. rostrate, A. sinensis, and A. subintegra (Table 1), which is the country with the most species of Aquilaria. And five species of Aquilaria are naturally distributed in Malaysia, including A. beccariana, A. hirta, A. malaccensis, A. microcarpa, and A. rostrate (Lee et al., 2016). The other four are transplanted from China, Indonesia, Thailand, and Vietnam. Meanwhile, eight of the total of nine species in the Gyrinops genus are known to naturally grow in Indonesia, except for G. vidalii which is only distributed in Thailand and Lao People’s Democratic Republic (Table 1).

At present, the wild resources of Aquilaria and Gyrinops are rather limited. Thus, the reports on agarwood production are confined to 14 species of Aquilaria and eight species of Gyrinops (Table 1). More and more plantation areas are of larger scale, and A. sinensis occupies more than 5245 ha in China, which has the largest plantation size of all the species reported now (Turjaman et al., 2016; Yin et al., 2016). Additionally, A. malaccensis is the most widespread and cultivated species, including 13 countries (Table 1). Thus, A. malaccensis and A. sinensis are the most studied species recently. However, Gyrinops is less planted and studied for its slow-growing features (Lee et al., 2018). Among all the Gyrinops species, G. versteegii is the most popular species in eastern Indonesia, but it is less favored compared to A. malaccensis when it comes to agarwood cultivation in Indonesia (Faizal et al., 2022; Nasution et al., 2020; Turjaman et al., 2016).

3

3 Biodiversity of fungal endophytes in Aquilaria and Gyrinops

Endophytes are microorganisms that maintain endosymbiotic relationship within plants (Turjaman et al., 2016). At present, studies on endophytic biodiversity on Aquilaria received more attention than that of Gyrinops. Eventually, species that are involved in such studies are mainly those selected as cultivation species, including A. crassna, A. malaccensis, A. microcarpa, A. sinensis, A. subintegra, G. caudata, G. verstegii, and G. walla. However, the biodiversity of fungal endophytes has not been investigated in the other species of Aquilaria and Gyrinops due to the limited plantations, slow-growing features, and difficult species-identification (Hidayat et al., 2021; Lee et al., 2018; Turjaman et al., 2016). Based on our knowledge, a total of 42 fungal families and 67 fungal genera were isolated and identified in these eight agarwood-producing taxa, and 82.8 % of fungal species belonged to Ascomycota (Table 2). Among all the above endophytic genera, Fusarium is the most encountered species recorded in all studied taxa, except for A. microcarpa and G. caudata.

Table 2 Host species distribution of fungal genera isolated from Aquilaria and Gyrinops, and their agarwood-inducing effects.
Fungal taxa Host species Distribution percentagesa Agarwood-inducing methods Inducing time Inducing effects References
Ascomycota
1. Apiosporaceae
1. Arthrinium A. subintegra 12.5 % --- --- --- Monggoot et al., 2017
2. Nigrospora A. sinensis 12.5 % --- --- --- Li et al., 2014
2. Ascomycota incertae sedis
3. Gonytrichum A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
3. Aspergillaceae
4. Aspergillus * G. walla 25.0 % --- --- --- Vidurangi et al., 2018
A. crassna Solid inoculation 1 year Tissue discoloration and resin content improved (Subasinghe et al., 2019)
--- --- Inducing agarwood formation Bose, 1938
5. Penicillium * A. sinensis 25.0 % Solid inoculation 30 days Promoting sesquiterpene accumulation Liu et al., 2022
Infusion 10 months Promoting the accumulation of active ingredients Wang et al., 2016
--- --- --- Gong and Guo, 2009
A. malaccensis --- --- --- (Chhipa et al., 2017)
4. Botryosphaeriaceae
6. Endomelanconiopsis A. sinensis 12.5 % --- --- --- Chen et al., 2018
7. Diplodia * Aquilaria sp. --- --- --- Inducing agar formation Bose, 1938
8. Lasiodiplodia * A. sinensis 37.5 % Inoculating the fermentation broth 2 months Promoting the agarwood formation Chen et al., 2017a
--- --- --- Cui et al., 2011
Inoculation of solid strains 6 months Promotion of 34 sesquiterpenes and 4 aromatic compounds Zhang et al., 2014
Infusion 10 months Promoting the accumulation of active ingredients Wang et al., 2016
A. malaccensis --- --- --- Mohamed et al., 2010
A. crassna --- --- --- Chi et al., 2016
--- --- --- Wang et al., 2019
9. Botryosphaeria * A. sinensis 37.5 % Formic acid and pinhole-infusion 1 ∼ 2 years Producing high yield and high quality artificial agarwood in a relatively short time Tian et al., 2013
Infusion 10 months Promoting the accumulation of active ingredients Wang et al., 2016
Liquid injection 160 days Promote the formation of the main components of agarwood and incenses Feng, 2008
A. crassna --- --- Inducing agar formation Bose, 1938
G. walla --- --- --- Vidurangi et al., 2018
5. Chaetomiaceae
10. Chaetomium * A. malaccensis 25.0 % Artificial boring onto the plants 30 days It is different between the oils obtained from naturally infected and healthy plants with regards to their quality. Tamuli et al., 2005
A. sinensis --- --- --- Tian et al., 2013
6. Chaetothyriales incertae sedis
11. Sarcinomyces G. walla 12.5 % --- --- --- Vidurangi et al., 2018
7. Cladosporiaceae
12. Cladosporium * A. sinensis 37.5 % --- --- --- Cui et al., 2011
--- --- --- Gong and Guo, 2009
Solid inoculation 30 days C. cladosporioides promotes the accumulation of agarwood sesquiterpenes and chromones, while C. parahalotolerans could not promote agarwood formation. Liu et al., 2022
A. malaccensis --- --- --- Premalatha and Kalra, 2013
A. subintegra --- --- --- Monggoot et al., 2017
8. Coniothyriaceae
13. Coniothyrium A. sinensis 12.5 % --- --- --- Cui et al., 2011
9. Diaporthaceae
14. Diaporthe A. sinensis 50.0 % --- --- --- Chen et al, 2018
A. microcarpa --- --- --- (Vidurangi et al., 2018)
A. subintegra --- --- --- Monggoot et al.,2017
G. verstegii --- --- --- Mega et al., 2016
10. Didymellaceae
15. Epicoccum A. malaccensis 25.0 % --- --- --- Bhattacharyya et al, 1952
A. sinensis --- --- --- Gong and Guo, 2009Cui et al., 2011
16. Leptosphaerulina A. sinensis 12.5 % --- --- --- Cui et al., 2011
11. Didymosphaeriaceae
17. Paraconiothyrium A. sinensis 12.5 % --- --- --- Cui et al., 2011
18. Montagnulaceae A. sinensis 12.5 % --- --- --- Wang et al., 2016
12. Dipodascaceae
19. Geotrichum A. crassna 25.0 % --- --- --- Chi et al., 2016
A. sinensis --- --- --- Gong and Guo, 2009
20. Galactomyces A. crassna 12.5 % --- --- --- Chi et al., 2016
13. Dissoconiaceae
21. Ramichloridium A. sinensis 12.5 % --- --- --- Tian et al., 2013
14. Erysiphaceae
22. Ovulariopsis A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
15. Glomerellaceae
23. Colletotrichum A. crassna 50.0 % --- --- --- Chi et al, 2016
A. sinensis --- --- --- Tian et al. 2013
A. subintegra --- --- --- Monggoot et al., 2017
G. walla --- --- --- Vidurangi et al., 2018
16. Herpotrichiellaceae
24. Rhinocladiella A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
25. Cladophialophora A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
17. Hypocreaceae
26. Trichoderma * A. sinensis 50.0 % --- --- --- Li et al., 2012
Infusion 10 months Promoting the accumulation of active ingredients Wang et al., 2016
A. malaccensis --- --- --- Mohamed et al.,2010
G. versteegii --- --- Contributing to the formation of agarwood sapwood Mega et al., 2020
G. walla --- --- --- Vidurangi et al., 2018
27. Hypocrea * A. malaccensis 25.0 % --- --- --- Mohamed et al., 2010
A. sinensis --- --- --- Cui et al., 2011
Liquid injection 160 days Promoting the transformation of agarwood and speeding up the process of making incense Feng, 2008
18. Hypocreales incertae sedis
28. Acremonium * A. microcarpa 37.5 % --- --- The wood color and terpenoid compounds were changed. Rahayu and Putridan Juliarni, 2007
G. verstegii --- --- --- Mega et al., 2016
G. caudata Fungal-induction with pruning 3–6 months Showing a considerable effect in wood internal tissue and fragrance. Auri et al., 2021
29. Cephalosporium A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
30. Verticillium A. sinensis 12.5 % --- --- --- Wang et al., 2016
19. Hypocreaceae
31. Diplocladium G. walla 12.5 % --- --- --- Subasinghe et al., 2019
20. Lasiosphaeriaceae
32. Fimetariella A. sinensis 12.5 % --- --- --- Tao et al., 2011aTao et al., 2011b
21. Mycosphaerellaceae
33. Mycosphaerella (Synonym: Davidiella) A. sinensis 25.0 % --- --- --- Tian et al., 2013
A. malaccensis --- --- --- Premalatha and Kalra, 2013
34. Botryodyplodis * (Synonym: Physalospora) Aquilaria sp. --- --- --- Inducing agar formation Bose, 1938
22. Nectriaceae
35. Cylindrocladium A. sinensis 12.5 % --- --- --- Tian et al., 2013
36. Fusarium * A. crassna 75.0 % --- --- --- Chi et al., 2016
--- 0.5 ∼ 1.5 years Inducing the formation of agarwood Nobuchi and Siripatanadilok, 1991
A. sinensis Formic acid and pinhole-infusion 1 ∼ 2 years Producing high yield and high quality artificial agarwood in a relatively short time Tian et al., 2013
--- --- --- Cui et al., 2011
Infusion 10 months Promoting the accumulation of active ingredients Wang et al., 2016
Inoculating the fermentation broth 2 months Promoting the agarwood formation at the initial stage Chen et al., 2017a
A. malaccensis --- --- --- Mohamed et al., 2010
A. subintegra --- --- --- Monggoot et al., 2017
G. walla --- --- --- Vidurangi et al., 2018
Solid inoculation method 1 year Promoting the tissue discoloration and resin content Subasinghe et al., 2019
G. versteegii --- --- Contributing to the formation of agarwood sapwood Mega et al., 2020
Fungal inoculant formulation 16 months Producing the agarwood with good quality. Mega et al., 2016
37. Nectria A. sinensis 12.5 % --- --- --- Wang et al., 2016
23. Phyllostictaceae
38. Guignardia A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
24. Pichiaceae
39. Pichia A. malaccensis 25.0 % --- --- --- Premalatha and Kalra, 2013
A. sinensis --- --- --- Cui et al., 2011
25. Pleosporaceae
40. Curvularia A. crassna 37.5 % --- --- --- Chi et al., 2016
A. malaccensis --- --- --- Mohamed et al., 2010
G. verstegii --- --- --- Mega et al., 2016
41. Alternaria A. malaccensis 25.0 % --- --- --- Premalatha and Kalra, 2013
A. sinensis --- --- --- Tian et al., 2013
42. Pleospora A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
43. Cochliobolus A. malaccensis 12.5 % --- --- --- Mohamed et al., 2010
44. Phoma A. sinensis 12.5 % --- --- --- Cui et al., 2011Tian et al., 2013
26. Saccharomycetaceae
45. Lodderomycetes A. malaccensis 12.5 % --- --- --- Premalatha and Kalra, 2013
27. Sclerotiniaceae
46. Monilia A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
28. Sporocadaceae
47. Pestalotiopsis * A. sinensis 25.0 % Infusion method 6 months Promoting the agarwood production Chen et al., 2014Tian et al., 2013
A. subintegra --- --- --- Monggoot et al., 2017
48. Preussia A. malaccensis 12.5 % --- --- --- Premalatha and Kalra, 2013
29. Togniniaceae
49. Phaeoacremonium * A. malaccensis 25.0 % --- --- --- Premalatha and Kalra, 2013
A. sinensis --- --- --- Cui et al., 2011
Solid inoculation 30 days Promoting the agarwood sesquiterpene accumulation Liu et al., 2022
30. Trichocomaceae
50. Sagenomella A. sinensis 12.5 % --- --- --- Tian et al., 2013
31. Valsaceae
51. Phomopsis A. sinensis 12.5 % --- --- --- Tian et al., 2013
32. Xylariaceae
52. Xylaria * A. sinensis 12.5 % --- --- --- Cui et al., 2011
--- --- --- Tian et al., 2013
Solid inoculation 2 ∼ 8 months Promoting agilawood accumulation Cui et al., 2013
53. Nemania A. sinensis 12.5 % --- --- --- Tibpromma et al, 2021
54. Nodulisporium A. sinensis 12.5 % --- --- --- Tian et al., 2013Wu et al., 2010
33. Massarinaceae
55. Massarina A. malaccensis 12.5 % --- --- --- Premalatha and Kalra, 2013
Mucoromycota
34. Cunninghamellaceae
56. Cunninghamella A. malaccensis 12.5 % --- --- --- Mohamed et al., 2010
35. Lichtheimiaceae
57. Rhizomucor A. sinensis 12.5 % --- --- --- Cui et al., 2011
36. Mortierellaceae
58. Mortierella A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
37. Mucoraceae
59. Mucor G. walla 12.5 % --- --- --- Subasinghe et al., 2019
60. Rhizopus * G. versteegii 12.5 % --- --- Promoting the formation of agarwood sapwood Mega et al., 2020
Mixture of fungal liquid with Fusarium solani --- Promoting the production of agarwood with best quality Mega et al., 2016
Basidiomycota
38. Exobasidiaceae
61. Glomerularia A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
39. Fomitopsidaceae
62. Fomitopsis * A. sinensis 12.5 % Infusion method 6 months Promoting the agarwood production Chen et al., 2017b
40. Meripilaceae
63. Rigidoporus * A. sinensis 12.5 % Trunk surface agarwood-inducing technique 2 months Promoting the agarwood formation Chen et al., 2018
41. Psathyrellaceae
64. Coprinopsis A. sinensis 12.5 % --- --- --- Chen et al., 2018
42. Russulaceae
65. Russula A. subintegra 12.5 % --- --- --- Monggoot et al., 2017
Unclassified
66. Mycelia sterilia A. sinensis 12.5 % --- --- --- Gong and Guo, 2009
67. Pleosporales A. sinensis 12.5 % --- --- --- Chen et al., 2018

a. Distribution percentage = host species number of an isolated fungal genus × 100 % / number of all the reported host species (nine species which include A. crassna, A. malaccensis, A. microcarpa, A. sinensis, A. subintegra, G. walla, G. caudata, and G. verstegii).

* The endophytic fungi which could improve the quality and yield of agarwood.

It is worth mentioning that there is a discrepancy in the endophytic fungal diversity pattern in Aquilaria trees based on their growing regions, such as A. sinensis, an agarwood-producing species endemic to China that is naturally distributed in three provinces, including Guangdong, Guangxi, and Hainan. It was proposed that the biodiversity of fungal endophytes in A. sinensis might be due to the various geographical locations containing different levels of the atmosphere, light, soil moisture, and nutrient contents. To date, endophytic fungal studies on A. sinensis are abundant and well-documented. It was revealed that the dominant fungal genus from the population in Hainan was Penicillium (Zhang et al., 2009a), while the endophytic fungal diversity for A. sinensis growing in Guangxi was dominated by Fusarium (Huang et al., 2017). The fungal diversity could also be regionally specific, in which two genera, Chaetomium and Pichia, were only identified in A. sinensis of Hainan, but not from those in Guangdong and Guangxi (Chen et al., 2019). Also, the fungal diversity of agarwood derived from A. sinensis showed regional specificity. Lignosphaeria is the dominant fungal genus in agarwood samples produced from Haikou and Wanning in Hainan province. Perenniporia and Pyrigemmula are the dominant fungal genera in agarwood products from Danzhou and Ledong in Hainan province. Phaeoacremonium is the dominant fungal genus in agarwood products collected from Huazhou and Dongguan in Guangdong province.

Furtherly, the variation in microbiome composition is represented by multiple plant host organs, and tissue types (Cregger et al., 2018; Jia et al., 2016). In general, most of the fungal endophytes reside in the root, stem, and leaf at the same time; yet, the leaf tissue contains more fungal species when compared to the root and stem parts. So far, a total of 16 fungal endophytes were discovered commonly present in all three vegetative parts of A. sinensis, including Botryosphaeria, Cephalosporium, Cladophialophora, Epicoccum, Fusarium, Geotrichum, Glomerularia, Gonytrichum, Guignardia, Monilia, Mortierella, Mycelia sterilia, Ovulariopsis, Penicillium, Pleospora, and Rhinocladiella (Gong and Guo, 2009; Tian et al., 2013). On the other hand, four were reported specific to the leaf tissue of A. sinensis, including Alternaria, Cylindrocladium, Phoma, and Phomopsis (Gong and Guo, 2009; Tian et al., 2013), suggesting that these fungal endophytes are only able to survive under certain habitat, which in this event, the requirement for survival was fulfilled in the leaf tissue, but not in the root and stem parts.

At the stem and branch part, fungal endophytes not only colonize the healthy part (white wood), but also can be found in the resinous part (agarwood). Additionally, the diversity of fungal endophytes in resinous wood is much higher than that in the healthy wood of Aquilaria (Chen et al., 2017a); Liu et al., 2022). Based on the studies on A. malaccensis and A. sinensis, it was deduced that the resinous wood of the trees not only contained some of the fungal endophytes which were recorded to be present in both the healthy and resinous wood of the tree, such as Alternaria sp., Hypocrea sp., Lasidiplodia sp., and Trichoderma sp., but also included some of the fungal endophytes which were enriched in the resinous wood, i.e. Cladosporium sp., Curvularia sp., Fusarium sp., Phaeoacremonium sp., and Preussia sp. (Liu et al., 2022; Mohamed et al., 2010; Tian et al., 2013). Endophytic fungi isolated from resinous parts were proven to be good candidates in developing fungal inoculum that could promote agarwood production; however, only a few were evaluated on their efficacies. To date, 18 fungal genera were reported on their capability to promote the formation of agarwood, including Acremonium sp., Aspergillus sp., Botryodyplodias sp., Botryosphaeria sp., Chaetomium sp., Cladosporium sp., Diplodia sp., Fomitopsis sp., Fusarium sp., Hypocrea sp., Lasiodiplodia sp., Penicillium sp., Pestalotiopsis sp., Phaeoacremonium sp., Rhizopus sp., Rigidoporus sp., Trichoderma sp., and Xylaria sp. (Table 2).

Given that the diversity of endophytic fungi in Aquilaria trees could be varied in different regions, little was reported for other agarwood-producing species, especially those from Gyrinops. While the diversity of endophytic fungi in different Aquilaria host parts might be related to the environmental filtering or biotic interaction at the species level which was similar to Populus trees (Cregger et al., 2018). The fungal endophytes that can be identified in the while wood and resinous wood of Aquilaria and Gyrinops could be varied largely. Therefore, it is suggested that studies on endophytic fungi in other agarwood-producing species need to be hastened to uncover the uncertainties.

4

4 Effects on the host trees of Aquilaria and Gyrinops by endophytes

4.1

4.1 Use of fungal endophytes in the promotion of agarwood

In nature, endophytes could maintain endosymbiotic relationship within plants without any harm. However, after the trees of Aquilaria and Gyrinops were wounded, the micro-ecosystem balance was broken, and some of the fungal endophytes might grow fast and could trigger the self-defense reaction of the tree and thus, stimulate the formation of secondary metabolites that protect the host trees against invasions and diseases (Cui et al., 2013; Faizal et al., 2020; Liu et al., 2022; Xu et al., 2013). Similarly, the inoculating the isolated endophytes with agarwood promoting ability to the holed trees could quickly induce the phosphorylation of the plant immune reaction and promote agarwood accumulation (Liu et al., 2022; Xu et al., 2013). Therefore, the agarwood produced in the tree is recognized as the product of the tree’s defense response (Xu et al., 2013). Since the work to investigate the relationship between fungi and agarwood-producing trees in the process of agarwood formation started off in the early nineteenth century, for the past two decades, a considerable number of studies provided evidence on the crucial roles of fungi in enhancing agarwood formation (Huang et al., 2013; Mega et al., 2016; Zhang et al., 2014). It is believed that endophytes secrete signals that will initiate the defense mechanism of the tree; thus, endophytes promote the formation of agarwood (Chen et al., 2017; Sen et al., 2017). Chemometric analysis revealed that aroma (e.g. dodecane, 4-methyl-, tetracosane) in Fusarium sp. played a direct role in the activation of A. malaccensis tree’s defense and secondary metabolism (Sen et al., 2017). Fungal infection often leads immediately to the increased formation of free fatty acids that trigger oxidative burst and fatty acid oxidation cascades leading to the production of oxylipins such as jasmonates (Sen et al., 2017). And the endophytic strains of Lasiodiplodia theobromae were found to produce jasmonic acid (JA) (Chen et al., 2017). JA is known to be one of the crucial signal transducers that is responsible to induce sesquiterpene and chromone derivative formation in A. sinensis and A. malaccensis (Faizal et al., 2021; Xu et al., 2016). Furthermore, agarwood sesquiterpene accumulation can also be achieved by having Phaeoacremonium rubrigenum to induce phosphorylation of the transcription factors (TFs)-mevalonate (MVA) network in A. sinensis (Liu et al., 2022). Despite studies on the molecular interaction between agarwood-producing trees and fungal endophytes have been constantly reported, the findings are still limited and in-depth research ought to be fostered.

To date, six fungal taxa, i.e. Fusarium sp., Trichoderma sp., Acremonium sp., Curvularia sp., Cunninghamella sp., and Phaeoacremonium sp., were commonly known to be potential agents in promoting agarwood formation in Aquilaria and Gyrinops trees (Blanchette 2003; Hidayat et al., 2021; Liu et al., 2022; Mohamed et al., 2010). For the endophytes, Fusarium was most reported when compared to other fungal taxa; while for the host plant, studies on A. sinensis were most abundant (Table 2). In A. sinensis, it is believed that agarwood formed with the aid of Cladorrhinum bulbillosum, Fusarium solani, Gongronella butleri, Humicola grisea, Lasiodiplodia theobromae, Phaeoacremonium rubrigenum, Rigidoporus vinctus, Saitozyma podzolica, and Tetracladium marchalianum was able to produce high-quality raw material for essential oil production (Chen et al., 2017; Chen et al., 2018; Liu et al., 2022; Ma et al., 2021; Zhang et al., 2014). So far, a total of 12 fungal taxa were identified to induce agarwood formation in A. sinensis, including Botryosphaeria, Cladosporium, Fusarium, Fomitopsis, Hypocrea, Lasiodiplodia, Phaeoacremonium, Pestalotiopsis, Penicillium, Rigidoporus, Trichoderma, and Xylaria (Table 2). Three fungal taxa, Aspergillus sp., Botryosphaeria sp., and Fusarium sp. were also reported useful in promoting agarwood formation in A. crassna (Chi et al., 2016), while a mixture of fungi Phialophora sp. and Fusarium sp. applied to A. crassna could result in higher sesquiterpene content compared to the chemical and mechanical treatments (Thanh et al., 2015). Similar to Aquilaria, endophytes in Gyrinops also play an active role in the agarwood development of trees. In Gyrinops walla, the endemic species of Sri Lanka, Aspergillus niger and Fusarium solani have been described to be contributing to agarwood formation; Aspergillus niger is more effective than Fusarium solani in the tree host tissue discoloration and resin content (Subasinghe et al., 2019). On the other hand, three fungal taxa, including Fusarium sp., Rhizopus sp., and Trichoderma sp., were proven effective in the promotion of agarwood in Gyrinops versteegii, a plantation species that is mass cultivated in the western region of Indonesia (Mega et al., 2020; (Faizal et al., 2020)).

4.2

4.2 Endophytes improve the ecological adaptability of Aquilaria and Gyrinops

Another function of fungal endophytes of Aquilaria and Gyrinops is improving the ecological adaptability of hosts. Different types of fungi strains could induce the different compounds of Aquilaria and Gyrinops (Monggoot et al., 2017; Mega et al., 2020), which could explain the diversity of agarwood components to increase the resistance to environmental stresses. Similarly, either Aquilaria or Gyrinops grows in certain places with different geographic and climate conditions with certain kinds of fungi, which could promote the ecological adaptability of the host. Consistent with the roles of fungi in the plant defense system, they may be a contributory role in increasing antimicrobial activity, because the resinous site of agarwood tree has a less fungal abundance. When A. malaccensis was infected by Lasiodiplodia theobromae, Cunninghamella bainieri, and Fusarium solani, the abundance of fungi decreased after wounding and the number of target DNA molecules also declined, especially at 6–12 months of post-injury (Mohamed et al., 2014). The lower level of fungal species may be due to the high level of terpenes which are the major components of agarwood and can prevent or control pathogen attacks (Tamuli et al., 2005; Naef, 2011; Zulak and Bohlmann, 2010). Similarly, the agarwood derived from the infected A. sinensis and decayed Gyrinops spp. could show antifungal activity against Candida albicans, Fusarium oxysporum, Fusarium solani, and Lasiodiplodia theobromae (Hidayat et al., 2021; Zhang et al. 2014). So it is believed that the fungi can trigger the plant defense system to protect plants from invasions. And the metabolites produced by fungi also can provide protection for the host, which gives plants the ability to be resistant to abiotic and biotic stresses (Chowdhary et al., 2012; Jong 2012; Kharwar et al., 2011; Kumar and Kaushik, 2013; Suryannaryanan et al., 2009). And agarwood endophytes can also produce chemical compositions such as 2-phenylethyl-1H-indol-3-yl-acetate, (2R)-(3-indolyl)-propionic acid, and 9,11-dehyroergosterol peroxide, which displayed phytotoxic activity, cytotoxic activity, and anti-fungi and anti-bacterial activities, resulting in the enhancement of plant ecological adaptability. However, there are also a plenty of compounds, such as benzylacetone, benzaldehyde, palustrol, anisylacetone and chromone derivatives, the ecological functions of which have not been explored. It is possible that the fungal endophyte is one of the factors to resist the invasion of exogenous pathogens and to keep the plant growing well. Thus, we summarized the effects of fungal endophytes on the host trees of Aquilaria and Gyrinops on two sides: inducing the plant defense system and improving their ecological adaptability (Fig. 1).

Effects of endophytes on their agarwood host trees, Aquilaria and Gyrinops.
Fig. 1
Effects of endophytes on their agarwood host trees, Aquilaria and Gyrinops.

5

5 Pharmacological effects of metabolites produced by fungal endophytes derived from Aquilaria and Gyrinops

Endophytic fungi can be one of the best-known sources of natural products, while the endophytic fungi present in Aquilaria and Gyrinops tree, in the process of agarwood formation, were also recognized as the new sources of secondary metabolites, which hold pharmaceutical and ecological significance. A total of 92 compounds were recorded from the endophytes of Aquilaria and Gyrinops trees, including terpenoids (40.22 %: containing monoterpenes, sesquiterpenes, and steroids), aromatics (26.09 %), alkaloids (5.44 %), chromones (2.17 %), and others (Fig. 2, Table 3). Interestingly, some endophytes of Aquilaria and Gyrinops could produce sesquiterpenes which were the important compounds of agarwood (Fig. 3, Table 3). Acremonium sp., Arthrinium sp., Collectotrichum sp., Diaporthe sp., Fimetariella rabenhorstii, Nemania sp., Nigrospora oryzae, and Nodulisporium sp. are responsible for the production of sesquiterpenes (Li et al., 2014; Monggoot et al., 2017; Tao et al., 2011a; Tibpromma et al., 2021; Wu et al., 2010; Zhang et al., 2009b). Thus, those fungal stains were considered to be the potential materials for fermenting agarwood compounds.

The categories of 92 compounds produced by the endophytes of Aquilaria and Gyrinops.
Fig. 2
The categories of 92 compounds produced by the endophytes of Aquilaria and Gyrinops.
Table 3 Metabolites produced by endophytes of Aquilaria and Gyrinops and their pharmacological values.
No. Compounds Molecular Formula Pharmacological Values Fungal Endophytes Host Plant References
Monoterpenes
1 γ-Terpinene C10H16 Trypanocidal effect
Acaricidal activity		 Acremonium sp. A. sinensis Tibpromma et al., 2021;Zhang et al., 2009b
2 Terpinen-4-ol C10H18O --- Arthrinium sp.
Collectotrichum sp.		 A. subintegra Monggoot et al., 2017
3 1,8-Cineole C10H18O Antibacterial activity Acremonium sp. A. sinensis Wang et al., 2007;Zhang et al., 2009b
4 Bicyclo[3.1.1]hept-3-ene-2-acetaldehyde, 4,6,6-trimethyl, C12H18O --- Nemania aquilariae A. sinensis Tibpromma et al., 2021
Sesquiterpenes
5 β-Agarofuran C15H24O --- Collectotrichum sp.
Diaporthe sp.		 A. subintegra Monggoot et al., 2017
6 Alloaromadendrene C15H24 Anti-oxidant activity
Cytotoxic activity
Anti-feedant activity
Anti-proliferative activity		 Nemania aquilariae A. sinensis Baldissera et al.,2016Jesionek et al, 2018Sawant et al., 2007Yu et al.,2014
7 1,2,3,4,4α,5,6,7-Octahydro-4α,8-dimethyl-2-(1-methylethenyl)-naphthalene C15H24 --- Nemania aquilariae A. sinensis Baldissera et al., 2016
8 Z-Eudesma-6,11-diene C15H24 --- Arthrinium sp.
Diaporthe sp.		 A. subintegra Capello et al., 2015Monggoot et al., 2017
9 α-Selinene C15H24 Anti-cancer activity
Repellent activity		 Nemania aquilariae A. sinensis Alakanse et al., 2019Baldissera et al., 2016Mauti et al.,2019
10 α-Agarofuran C15H24O Antianxiety activity Arthrinium sp.
Collectotrichum sp.
Diaporthe sp.		 A. subintegra Monggoot et al., 2017Peeraphong et al., 2021Zhang et al., 2004
11 Oxo-agarospirol C15H24O2 Antioxidant activity Arthrinium sp.
Collectotrichum sp.
Diaporthe sp.		 A. subintegra Capello et al., 2015Monggoot et al., 2017
12 Ar-Curcumene C15H22 Mosquito larvicides
Anti-inflammatory activity
Anti-ulcer activity		 Acremonium sp. A. sinensis Duarte et al., 2007Podlogar et al., 2012Yamahara et al.,1992Zhang et al., 2009b
13 Zingiberene C15H24 Anti-inflammatory activity
Anti-apoptotic effect
Anti-oxidant activity
Anti-cancer activity
Cytotoxicity, Genotoxicity		 Acremonium sp. A. sinensis Duarte et al., 2007Li et al., 2021Togar et al., 2015Türkez et al., 2014Zhang et al., 2009b
14 10-epi-γ-Eudesmol C15H26O Prevention of mosquito-related disease Collectotrichum sp.
Diaporthe sp.		 A. subintegra Capello et al., 2015(Kracht et al., 2019)
15 cis-Dihydroagarofuran C15H26O Antimicrobial activity Diaporthe sp. A. subintegra Capello et al., 2015Sadgrove et al., 2015
16 β-Dihydroagarofuran C15H26O --- Arthrinium sp.
Collectotrichum sp.
Diaporthe sp.		 A. subintegra Capello et al., 2015Monggoot et al., 2017
17 Valencen C15H24 --- Nemania aquilariae A. sinensis Baldissera et al., 2016
18 Z-Caryophyllene C15H24 --- Arthrinium sp.
Collectotrichum sp.
Diaporthe sp.		 A. subintegra Capello et al., 2015Monggoot et al., 2017
19 β-Elemene C15H24 High cytotoxic activity Diaporthe sp. A. subintegra Capello et al., 2015Monggoot et al., 2017
20 δ-Elemene C15H24 --- Collectotrichum sp.
Diaporthe sp.		 A. subintegra Capello et al., 2015Monggoot et al., 2017
21 Agarospirol C15H26O Anti-nociceptive activitiy
Anti-oxidant activity		 Collectotrichum sp.
Diaporthe sp.		 A. subintegra Capello et al., 2015Monggoot et al., 2017Okugawa et al., 1996
22 rel-(1S,4S,5R,7R,10R)-10-Desmethyl-1-methyl-11-eudesmene C15H26O Cytotoxic activity Nodulisporium sp. A. sinensis Li et al., 2011
23 Capitulatin B C15H26O2 --- Nigrospora oryzae A. sinensis Zhang et al., 2004
24 6α-Hydroxycyclonerolidol C15H26O2 Cytotoxic activity Nodulisporium sp. A. sinensis Li et al., 2011
25 Frabenol C15H26O2 --- Fimetariella rabenhorstii A. sinensis Tao et al., 2011a
26 6-Methyl-2-(5-methyl-5-vinyltetrahydrofuran-2-yl) hept-5-en-2-ol C15H26O2 --- Nodulisporium sp. A. sinensis Li et al., 2011
27 11-Hydroxycapitulation B C15H26O3 --- Nigrospora oryzae A. sinensis Zhang et al., 2004
28 δ-Eudesmol C15H28O Prevention of mosquito-related disease Arthrinium sp.
Diaporthe sp.		 A. subintegra Capello et al., 2015(Kracht et al., 2019)
29 (3R,6E,10S)-2,6,10-Trimethyl-3-hydroxydodeca-6,11-diene- C15H28O3 --- Colletotrichum gloeosporioides A. sinensis Liu et al., 2018
Chromones
30 2,3-Dihydro-5-hydroxy-2-methylchromen-4-one C10H10O3 Cytotoxic activity Nodulisporium sp. A. sinensis Wu et al., 2010
31 Mellein C10H10O3 Antibacterial activity Aspergillus sp. A. sinensis Peng et al., 2011
Anthraquinones
32 1,7-Dihydroxy-3-methoxyanthraquinone C15H10O5 Anti-bacterial activity Unknown fungal strain AL-2 A. malaccensis Blakeney et al., 2019Shoeb et al., 2010
Steroids
33 Ergosterol C28H44O Anti-inflammatory activity Nodulisporium sp. A. sinensis Kobori et al., 2007Li et al., 2011
34 Ergosterol peroxide C28H44O3 Induced apoptosis of cells
Anti-inflammatory activity
Cytotoxic activity
Anti-oxidant activities
Anti-complementary activity
Trypanocidal activity
Antibacterial activity
Anti-proliferative activity		 Nodulisporium sp. A. sinensis Li et al., 2011Takei et al.,2005Kobori et al., 2007Nam et al., 2001Kim et al., 1999Kim et al., 1997Ramos-Ligonio et al., 2012Duarte et al., 2007Nowak et al., 2016
35 5α,8α-Epidioxy-(22E,24R)-ergosta-6,22-dien-3β-ol C28H44O3 Anti-tumor activity Fimetariella rabenhorstii A. sinensis Li, 2016Plotnikov et al., 2021Tanapichatsakul et al., 2020Nam et al., 2001Kim et al., 1999
36 3β,5α,9α-Trihydroxy-(22E,24R)-ergosta-7,22-dien-6-one C28H44O3 Anti-tumor activity Fimetariella rabenhorstii A. sinensis Li, 2016Plotnikov et al., 2021Takei et al., 2005
37 Cerevisterol C28H46O3 Anti-microbial activity
Resistance modifying activity		 Nodulisporium sp. A. sinensis Li et al., 2011Appiah et al., 2020
38 (3β,5α,6β,22E)-Ergosta-7,22-diene-3,5,6-triol C28H46O3 --- Phaeoacremonium rubrigenum A. sinensis Ribeiro et al., 2007
39 3β,6β,7α-Trihydroxy-(24R)-ergosta-8(14),22-diene C28H46O3 --- Fimetariella rabenhorstii A. sinensis Li, 2016Plotnikov et al., 2021
40 3β,5α,6β-Trihydroxy-(22E,24R)-ergosta-7,22-diene C28H46O3 Anti-tumor activity Fimetariella rabenhorstii A. sinensis Li, 2016Plotnikov et al., 2021Kobori et al., 2007Kim et al.,1997
Aromatics
41 Methylphenol C7H8O Antibacterial activity Fimetariella rabenhorstii
Phaeoacremonium rubrigenum 		A. sinensis Li, 2016Wei et al., 2011
42 p-Hydroxybenzaldehyde C7H6O2 Anti-oxidative activity
Blood-brain barrier
Toxicity		 Phaeoacremonium rubrigenum A. sinensis Ribeiro et al., 2007Kinjo et al., 2020Borneman et al., 1986Wei et al., 2011
43 Phenylethyl alcohol C8H10O Antibacterial
Sedative effects
Antifungal activity		 Acremonium sp. A. sinensis Duarte et al.,2007Lilley and Brewer, 1953Oshima and Ito, 2021Boukaew and Prasertsan, 2018Zhang et al., 2009b
44 4-Hydroxyphenyl ethyl alcohol
(Tyrosol; 4-Hydroxy-benzeneethanol)		 C8H10O2 Nematicide
Antioxidant activity
Anti-inflammatory activity		 Fimetariella rabenhorstii
Acremonium sp.
Nodulisporium sp.		 A. sinensis Tao et al., 2011bDuarte et al.,2007Li et al.,2018Zhang et al., 2009bLi et al., 2011Wei and Liu, 2007Tao et al., 2011b
45 6-Methoxy-7-O-(p-methoxyphenyl)-coumarin C17H14O5 --- Unkonw fungal strain AL-2 A. malaccensis Blakeney et al., 2019
46 3,4-Dihydroxybenzoic acid C7H6O4 Antibacterial activity Phaeoacremonium rubrigenum A. sinensis Ribeiro et al., 2007
47 Phthalic acid diisobutyl ester C16H22O4 Phytotoxicity
Testicular atrophy		 Colletotrichum gloeosporioides A. sinensis Appiah et al., 2020Huang et al.,2021Oishi et al.,1980
48 Decyl butyl phthalate C22H34O4 --- Acremonium sp. A. sinensis Duarte et al., 2007
49 1-(2,6-Dihydroxyphenyl) ethanone C8H8O3 Cytotoxic activity Nodulisporium sp. A. sinensis Wu et al., 2010
50 8-Methoxynaphthalen-1-ol C11H10O2 Antifungal activity Nodulisporium sp. A. sinensis Li et al, 2011;Takei et al., 2005
51 p-Hydroxyphenethyl alcohol C8H10O2 Antibacterial activity Phaeoacremonium rubrigenum A. sinensis Wei et al., 2011
52 Ethyl benzoate C9H10O2 --- Arthrinium sp.
Collectotrichum sp.
Diaporthe sp.		 A. subintegra Monggoot et al., 2017
53 Phenyl butanone C10H12O --- Collectotrichum sp.
Diaporthe sp.		 A. subintegra Monggoot et al., 2017
54 1-(2,6-Dihydroxyphenyl) butan-1-one C10H12O3 Cytotoxic activity Nodulisporium sp. A. sinensis Wu et al., 2010
55 1-(2,6-Dihydroxyphenyl)-3-hydroxybutan-1-one C10H12O4 Cytotoxic activity Nodulisporium sp. A. sinensis Wu et al., 2010
56 Benzeneacetic acid C8H8O2 --- Acremonium sp. A. sinensis Duarte et al., 2007
57 (2R*,4R*)-3,4-Dihydro-4-methoxy-2-methyl-2H-1-benzopyran-5-ol C11H14O3 Cytotoxic activity Nodulisporium sp. A. sinensis Wu et al., 2010
58 Phenethyl 2-hydroxypropanoate C11H14O3 --- Colletotrichum gloeosporioides A. sinensis Liu et al., 2018
59 Benzyl benzoate C14H12O2 Treatment of scabies Arthrinium sp.
Diaporthe sp.		 A. subintegra Monggoot et al., 2017;Li et al., 2011
60 1,8-Dimethoxynaphthalene C12H12O2 --- Nodulisporium sp. A. sinensis Li et al., 2011
61 (7R*,8S*)-3,6,7,8-Tetrahydro-4,7,8-trihydroxynaphtho [2,3- C12H12O5 Cytotoxic activity Nodulisporium sp. A. sinensis Wu et al, 2010
62 Propyl p-methoxy phenyl ether C10H14O2 --- Unkonw fungal strain AL-2 A. malaccensis Shoeb et al., 2010
63 p-Hydroxyphenylacetic acid C8H8O3 --- Phaeoacremonium rubrigenum A. sinensis Ribeiro et al., 2007
64 4-Pentylbenzoic acid C12H16O2 --- Acremonium sp. A. sinensis Duarte et al., 2007
Alkaloids
65 Nicotinic acid C6H5NO2 Prevention of atherosclerosis and reduce the risk of cardiovascular events Fimetariella rabenhorstii A. sinensis Okugawa et al., 1996(Gille et al., 2008)
66 Thymidine C10H14N2O5 Anti-cancer activity
Anti-metabolites activity		 Phaeoacremonium rubrigenum A. sinensis Ribeiro et al., 2007Stokes and Lacey, 1978Martin et al., 1980O'Dwyer et al, 1987
67 N-Phenylacetamide C8H9NO Cytotoxic activity Fimetariella rabenhorstii A. sinensis Okugawa et al.,1996
68 N-(6-Hydroxyhexyl)-acetamide C8H17O2N Antibacterial activity Phaeoacremonium rubrigenum A. sinensis Ribeiro et al., 2007
69 2-Anilino-1,4-naphthoquinone C16H11NO2 Anti-fungal activity Fimetariella rabenhorstii A. sinensis Okugawa et al.,1996(Leyva et al., 2017)
Thiazoles
70 Colletotricole A C9H13NO3S --- Colletotrichum gloeosporioides A. sinensis Appiah et al., 2020
71 2-(4-Methylthiazol-5-yl)ethyl 2-hydroxypropanoate C9H13O3NS --- Colletotrichum gloeosporioides A. sinensis Appiah et al., 2020
Others
72 Colletotricone A C14H20O4 Anti-tumour activity
Cytotoxic activity		 Colletotrichum gloeosporioides A. sinensis Appiah et al., 2020Kim et al., 2019Liu et al., 2018
73 Colletotricone B C14H20O4 --- Colletotrichum gloeosporioides A. sinensis Liu et al., 2018
74 Nigrosporanene A C14H20O4 Cytotoxicity
Radical scavenging activity		 Colletotrichum gloeosporioides A. sinensis Appiah et al., 2020Liu et al., 2018Ma and Qi, 2019
75 Nigrosporanene B C14H22O4 Radical scavenging activity Colletotrichum gloeosporioides A. sinensis Appiah et al., 2020Liu et al., 2018Ma and Qi, 2019
76 d-Galacitol C6H14O6 --- Fimetariella rabenhorstii A. sinensis Tao et al., 2011b
77 2,3-Dihydroxybutane C4H8O3 --- Acremonium sp. A. sinensis Zhang et al., 2009b
78 5-Hydroxymethylfurfural C6H6O3 Antibacterial activity Phaeoacremonium rubrigenum A. sinensis Wei et al., 2011
79 Cyclohexanone C6H10O --- Acremonium sp. A. sinensis Zhang et al., 2009b
80 4-Hydroxy-4-methyl-2-phentanone C6H12O2 --- Acremonium sp. A. sinensis Zhang et al., 2009b
81 3,5-Dimethyl cyclopentenolone C7H11O2 --- Acremonium sp. A. sinensis Zhang et al., 2009b
82 5-Methyl-2-vinyltetrahydrofuran-3-ol C7H12O2 --- Nodulisporium sp. A. sinensis Li et al., 2011
83 Octanoic acid C8H16O2 Toxicity
Reducing the magnitude of tremor
Anti-tumor activity		 Acremonium sp. A. sinensis Duarte et al., 2007Viegas et al., 1995Lowell et al., 2019Altinoz et al., 2020
84 (Z)-9,17-Octadecadienal C18H32O --- Acremonium sp. A. sinensis Duarte et al., 2007
85 Sorbic acid C6H8O2 Anti-fungal activity
Anti-microbial activity		 Acremonium sp. A. sinensis Duarte et al., 2007Razavi‐Rohani and Griffiths, 1999Eklund et al., 1983
86 Linoleic acid C18H32O2 Pro-inflammatory activity
Anti-cancer activity
Cholesterol and blood pressure lowering effects
Epidermal permeability barrier
Anaerobic degradability
Inhibitory effects		 Acremonium sp. A. sinensis Duarte et al., 2007Young et al., 1998Burns et al., 2018Lalman et al., 2000Elias et al., 1980
87 Acetic acid C2H4O2 --- Acremonium sp. A. sinensis Duarte et al., 2007
88 Oleic acid C18H34O2 Anti-tumor
Anti-inflammatory
Anti-bactericidal
Vasculoprotective effects
Pro-inflammatory		 Acremonium sp. A. sinensis Duarte et al., 2007(Carrillo Pérez et al., 2012)

Sales-Campos et al., 2013Speert et al., 1979Massaro et al., 2002Young et al., 1998
89 Isovaleric acid C5H10O2 Reduces Na+, K+-ATPase activity
Causes colonic smooth muscle relaxation		 Acremonium sp. A. sinensis Duarte et al., 2007Ribeiro et al., 2007Blakeney et al., 2019
90 Methyl jasmonate C12H18O3 Against pathogens
Salt stress
Drought stress
Low temperature
Heavy metal stress and toxicities of other elements		 Lasiodiplodia theobromae A. sinensis Han et al., 2014Yu et al., 2018
91 Octadecanoic acid C18H36O2 --- Acremonium sp. A. sinensis Duarte et al., 2007
92 Butanoic acid C10H22O2Si --- Acremonium sp. A. sinensis Duarte et al., 2007

Bioactivity: the effects of the fungal endophytes; Pharmacological values: the functions of the compounds produced by the fungi.

The structures of 92 compounds produced by the endophytes of Aquilaria and Gyrinops.
Fig. 3
The structures of 92 compounds produced by the endophytes of Aquilaria and Gyrinops.

Endophytic fungi in agarwood-producing trees can also be a rich source of medicinal agents with various pharmacological properties (Chhipa et al., 2017). The majority of endophytes derived from Aquilaria showed both antimicrobial and antitumor activities simultaneously, including Cladosporium tenuissimum, Coniothyrium nitidae, Epicoccum nigrum, Fusarium equiseti, Fusarium oxysporum, Fusarium solani, Hypocrea lixii, Lasiodiplodia theobromae, Leptosphaerulina chartarum, Paraconiothyrium variabile, Phaeoacremonium rubrigenum, Rhizomucor variabilis, and Xylaria mali (Cui et al., 2011). However, few of them were reported to display only antimicrobial activities, i.e. Phoma herbarum, Geotrichum candium, and Fusarium verticillioides (Chi et al., 2016; Cui et al., 2011). The endophytic fungi, Diaporthe sp. and Colletotrichum sp., which were believed to be responsible for the production of sesquiterpene compounds in Aquilaria trees, were claimed to have antioxidant properties; while the latter taxa also came with anti-inflammatory activities (Monggoot et al., 2017; Wang et al., 2016). Although a total of 92 compounds produced by fungal endophytes in Aquilaria were identified so far (Fig. 3), only 52 of them were proven to come with their related biological properties; in general, most of the identified compounds contained anti-inflammatory, anti-bacterial, and anti-cancer properties (Table 3). Compounds produced by all the isolated endophytes from Aquilaria and Gyrinops and their pharmacological values have been shown in Table 3.

6

6 Conclusion

Endophytes could maintain endosymbiotic relationship within plants at least in one stage of their life cycle (Turjaman et al., 2016). Compared with physical and chemical methods, the use of endophytic fungi has been recognized as a safe method to promote agarwood production for the environment and human health (Tan et al., 2019). Additionally, the endophyte inducing method could be seemed as a prioritized approach to enhance agarwood formation due to its ability to produce the signals associated with continuous agarwood formation and compounds with bioactivity. And the advantages of induced agarwood by endophytes are more pharmaceutical values, higher environmental adaptability, and faster speed of agarwood formation.

To our knowledge, 14 species of Aquilaria and eight of Gyrinops were known to produce agarwood, and different fungal species and abundances were detected because of different planting regions and various species. Fusarium sp. accounted for the largest proportion of Aquilaria and Gyrinops, followed by Colletotrichum sp., Diaporthe sp., and Trichoderma sp. The endophytic fungi spread over various host species with high biodiversity, however, the biodiversity of fungal endophytes distributed in various planting areas is seldom reported, which needs more detailed research. Furtherly, the variation in microbiome composition is represented by multiple A. sinensis tree host organs, and tissue types. The high diversity of fungal endophytes in resinous wood could give some good candidates for developing fungal inoculum that could promote agarwood production.

Various endophytic fungi have been reported to produce metabolites containing sesquiterpenoids and aromatic groups, which are a rich source of medicinal agents to improve the quality and quantity of agarwood. Most of the endophytes from Aquilaria and Gyrinops showed antimicrobial and antitumor activities, and a few fungi that have special abilities, such as the antioxidant activity of Diaporthe sp., and anti-inflammatory activities of Colletotrichum sp. Besides that, some of the secondary metabolites are formed when the fungal endophytes trigger the self-defense reaction of Aquilaria and Gyrinops. In this way, the agarwood fungal endophytes not only protect host trees from microbe invasions and diseases but also activate the accumulation of agarwood. And these compounds produced by the fungal strains are various due to the different species or strains, which might enhance the resistance abilities to various environmental stresses. Conversely, both Aquilaria and Gyrinops trees grow in different places with various geographic and climate conditions and need different sorts of fungi, which could promote the host’s ecological adaptability. In summary, the fungal endophytes on the host trees of Aquilaria and Gyrinops are responsible for activating the plant defense system, strengthening the hosts’ ecological adaptability, and enhancing agarwood production, which may be the reasons why agarwood artificial induction by endophytes has become popular. The mechanism of aroma accumulation and the crucial role of endophytes in the agarwood host trees need to be furtherly explored in the future.

Acknowledgments

This work was supported by the Fundamental Research Funds for the Central Public Welfare Research Institutes (grant no. ZZ13-YQ-093-C1, ZZXT202112), and the CACMS Innovation Fund (Grant No. CI2021A04101).

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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