“Big fleas have little fleas upon their backs to bite ‘em.
And little fleas have lesser fleas, and so, ad infinitum.
And the great fleas, themselves, have greater fleas to go on,
While these again have greater still, and greater still, and so on…”
– Jonathan Swift
Originally published in Plant Healer Quarterly
Many of us think of ourselves and other beings as individuals: Jane, Joe, Rex the dog, Tiger the cat. In reality, life is more similar to a fractal, or perhaps to a set of Russian nesting dolls. We’re each a hodge-podge of many smaller individuals — a collection of our own cells as well as fungal and bacterial cells that are about as numerous as our own. These bacteria and fungi do more than just tag along, they influence how we are. (Don’t get me started on the the viruses that infect our resident bacteria and influence how they are.) Beyond that, our chromosomes contain many segments of viral DNA. So the various microbial bits we carry with us may even influence who we are. Not to forget the other end of the spectrum, in which we as humans are but one component of the larger organism of the planet. “Individuals”, indeed.
Plants are no exception to this nesting doll reality. When herbalists make plant extracts, we are in fact making plant, fungal, and bacterial extracts. Popular medicinal plants such as Chamomile, Saint John’s Wort, Rosemary, Ginkgo, Sweet Annie, and Echinacea have been studied for their fungal and bacterial tag-alongs (1, 2). These microbes are called endophytes, meaning “inside plants”. All plant species tested to date contain endophytes, critters who hang around inside plant tissues without causing disease. Wash the plant all you want before extracting and you don’t get rid of the endophytes. And, really, you may not want to get rid of them.
“So what?”, you may ask. Well, endophytes may be a key determinant of the quality of our plant medicine. As research is uncovering just how much human health is impacted by the state of our resident microbes, the same is becoming clear for plants. The growth, reproduction, stress resistance, and chemical make up of plants is heavily influenced by endophytes. In addition to that, endophytes are pretty cool. Have you heard of hypericin, a constituent of St. John’s Wort? An endophyte can make it. Diosgenin, a constituent of Wild Yam that’s used in the commercial synthesis of progesterone? Ditto. Taxol from the Pacific Yew? Yup. You get the idea…
More on “plant” medicine momentarily. First, let’s get in to the how, what and why of endophytes.
Endophytes, you say?
If you’re a plant geek, you’ve likely heard of microbes that grow in association with roots. These microbes facilitate water and nutrient uptake by the roots and mediate plant-to-plant communication as well. Those microbes that are encompassed by the roots are, technically speaking, endophytes. But endophytes are also found inside of seeds, leaves, stems, flowers, fruit, buds and bark (3). Most endophytes identified so far are filamentous fungi, though some are bacteria (4).
Endophytes are tough to study due to their location and to how easy it is for contaminating microbes to confound experimental results. Most of the researchers studying endophytes are those in the pharmaceutical industry who are interested in the metabolites they produce. For the studies, scientists have to surface sterilize a plant then grind it up to release the endophytes, which they’ll attempt to cultivate on various growth media. But not all endophytes are willing to be grown in a dish. Just how many different endophytes are out there? One study reported successful culturing of 181 bacterial endophytes from 13 medicinal herb species (1). This total, of course, didn’t include those that can’t be cultured, nor did the study look for fungal endophytes. In any event, the answer to how many endophytes are out there is “a whole lot”.
So, what do plants get out of this intimate arrangement? In some cases, the endophyte grants the plant increased resistance to parasites or to grazing insects and animals. Or a better likelihood of surviving changing environmental conditions. Or more robust growth. And the endophyte? Many survive in the soil for a long time without a plant home. But, when inside the plant, the endophyte gets necessary nutrients or completing its life cycle (3). This living arrangement is not all roses. Sometimes the relationship is antagonistic (Married with Children?) or parasitic (The Hunger?) rather than mutualistic (3).
When and how did endophytes get there initially? Have they been tagging along since plants were plants? Or, did plants become colonized later down the line? Plants are thought to have first set foot (er, root) on land by about 700 million years ago. Fossil evidence points to a plant-endophyte relationship starting at least 400 million years ago (5). So it’s certainly not a new partnership.
As to the how, it’s known that some endophytes are transmitted vertically, meaning that they’re passed from parent to progeny via seed. These are “obligate” endophytes that can’t exist outside of the plant (3). Other endophytes are transmitted horizontally, meaning that they’re spread from plant to plant by endophyte spores (6). These are “facultative” endophytes, capable of hanging out in some form elsewhere but living inside of the plant for a good chunk of their lifecycle (3). So maybe at some point way back when, a spore made its way into a plant. After all, fungi were already present on land long before plants showed up. Some plants need their endophytes in order to grow from seed to maturity (4), or to survive in a stressful environment (7). So maybe endophytes were there influencing plant evolution from the very beginning.
Back to medicinal plants
The existence of endophytes has been known for over a hundred years (4), yet I can’t claim to have though about them and their contribution to the tinctures on my shelf until recently. Herbal medicine is a “thing” because many of the metabolites that plants contain benefit us as as well as them. Such metabolites — and hence, what’s in the tincture bottles — are influenced in multiple ways by a plant’s endophytes. Certain metabolites may not be present in a plant if not for the endophytes. For instance, an endophytic species may stimulate the plant to make something it wouldn’t otherwise produce. Resveratrol production in Doug Fir is an example of this (4). Alternatively, an endophyte might synthesize stuff that the plant itself doesn’t make. An anti-tumor metabolite found in Ginkgo is an example of this (8). Endophytes may stimulate increased production of a metabolite already present in the plant. Echinacea’s immune modulating alkamides are an example of this (9).
Sometimes both the plant and the endophyte produce the same metabolite, as is the case with the cancer drug, taxol (2). In these instances it may be that the plant and endophyte have shared a gene for the metabolite via gene transfer from one organism to the other. Or, the plant and the endophyte may have co-evolved the ability to make a particular metabolite, as seems to be the case in some Artemesia species (2). All of these mechanisms point to a significant role of endophytes in plant medicine.
Endophytes themselves make a veritable cornucopia (yes, I went there) of medicinal compounds. There’s a handy table included at the end of the article that was compiled for you “tabley” types. It lists some metabolite categories produced by endophytes, along with examples of specific metabolites and their bioactivities. Anyone familiar with plant chemistry will immediately recognize that endophytes make a whole passel of metabolites that we typically think of as plant medicine.
Multiple questions remain regarding endophytes and herbal medicine from a practical standpoint. These include:
- In terms of the effect of growth conditions on the quality of an herbal medicine, how much of the influence is related to the plant and how much to the endophytes? Location, soil, and climate are all considered determinants of how good our plant medicine will be. This has been attributed to the effects on the plant itself, but may also be related to the impact on the plant’s endophytes (10).
- Can endophytes from a plant with desired medicinal qualities be transferred to another plant to promote those qualities? In other words, if the Mugwort you grow in San Francisco is stronger than that grown by your second cousin in Poughkeepsie, would sharing the endophytes from your plants with her improve her crop?
- Is there a potential problem in trying endophyte transfers such as in the above hypothetical situation? A chance, for instance, of transmitting a disease-causing microbe? One idea that is appealing in this age of environmental degradation and over-harvesting is the idea of an endophyte library being created to help in the propagation of endangered medicinal plants (10). A characterized library would also reduce the chance of transferring unwanted critters cross country.
These meanderings may be a bit more technical than the level at which many of us work day-to-day, but they’re relevant to plant medicine and are something to chew on until next time, when we delve deeper into the critter chemical factories within some of our best known and loved medicinal plants.
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References & further reading
1. Goryluk-Salmonowicz, A, et al (2016) Endophytic detection in selected European herbal plants. Pol J Micro. 65(3):369-75. http://www.pjmonline.org/endophytic-detection-in-selected-european-herbal-plants/
2. Huang, WY, et al (2007) Methods for the study of endophytic microorganisms from traditional Chinese medicine plants. Econom Bot. 61(1): 14-30. https://www.jstor.org/stable/4257167?read-now=1&loggedin=true&seq=1#page_scan_tab_contents
3. Gouda, S, et al (2016) Endophytes: A treasure house of bioactive compounds of medicinal importance. Frontiers in Microbiology. 7:1583. https://www.frontiersin.org/articles/10.3389/fmicb.2016.01538/full REVIEW
4. Owen, NL & N Hundley (2004) Endophytes — The chemical synthesizers inside plants. Science Progress. 87(2):79-99. https://www.jstor.org/stable/43423175?seq=1#page_scan_tab_contents REVIEW
5. Krings, M, et al (2007) Fungal endophytes in a 400-million-yr-old land plant: infection pathways, spatial distribution, and host responses. New Phytol. 174(3):648-57. https://www.researchgate.net/publication/6380784_Krings_M_Taylor_TN_Hass_H_Kerp_H_Dotzler_N_Hermsen_EJ_Fungal_endophytes_in_a_400-million-yr-old_land_plant_infection_pathways_spatial_distribution_and_host_responses_New_Phytol_174_648-657
6. Kaul, S, et al (2012) Endophytic fungi from medicinal plants: a treasure hunt for bioactive molecules. Phytochem Rev. 11(4):487-505. https://www.academia.edu/17123332/Endophytic_fungi_from_medicinal_plants_a_treasure_hunt_for_bioactive_metabolites REVIEW
7. Rodriguez, R & R Redman (2008) More than 400 million years of evolution and some plants still can’t make it on their own: plant stress tolerance via fungal symbiosis. J Exp Biol. 59(5):1109-14. https://academic.oup.com/jxb/article/59/5/1109/538568
8. Li, H, et al (2014) Chaetoglobosins from Chaetomium globosum, an endophytic fungus in Ginkgo biloba, and their phytotoxic and cytotoxic activities. J Agric Food Chem. 62(17):3734-41. https://www.researchgate.net/publication/261441769_Chaetoglobosins_from_Chaetomium_globosum_an_Endophytic_Fungus_in_Ginkgo_biloba_and_Their_Phytotoxic_and_Cytotoxic_Activities
9. Maggini, V, et al (2017) Plant-endophytes interaction influences the secondary metabolism in Echinacea purpurea (L.) Moench: an in vitro model. Sci Rep. 7: 16924. https://www.nature.com/articles/s41598-017-17110-w
10. Jia, M, et al (2016) A friendly relationship between endophytic fungi and medicinal plants: A systemic review. Front. Microbiol. 7:906. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899461/ REVIEW
11. Yu, H, et al (2010) Recent developments and future prospects of antimicrobial metabolites produced by endophytes. Microbiol. Res. 165(6):437-449. https://www.sciencedirect.com/science/article/pii/S0944501309001128 REVIEW
12. Gunatilaka, AAL (2012) Natural products from plant-associated microorganisms: Distribution, structural diversity, bioactivity and implications of their occurrence. J Nat Prod. 69(3):509-26. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362121/ REVIEW
13 Golinska, P, et al (2015) Endophytic actinobacteria of medicinal plants: diversity and bioactivity. Antonie van Leeuwenhoek. 108:267–289. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491368/ REVIEW
14. Venieraki, A, et al (2017) Endophytic fungi residing in medicinal plants have the ability to produce the same or similar pharmacologically active secondary metabolites as their hosts. Hellenic Plant Prot J. 10:51-66. https://www.researchgate.net/publication/318656074_Endophytic_fungi_residing_in_medicinal_plants_have_the_ability_to_produce_the_same_or_similar_pharmacologically_active_secondary_metabolites_as_their_hosts REVIEW
15. Kual, S, et al (2013) Prospecting endophytic fungal assemblage of Digitalis lanata Ehrh. (foxglove) as a novel source of digoxin: a cardiac glycoside. 3 Biotech. 3(4): 335-40. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3723867/
16. Kuar, A, et al (2017) Secondary metabolites from fungal endophytes of Echinacea purpurea suppress cytokine secretion by macrophage-type cells. Nat Prod Commun. 11(8):1143-6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414731/
17. Nicoletti R & A Fiorentino (2015) Plant bioactive metabolites and drugs produced by endophytic fungi of spermatophyta. Agriculture. 5:918-970. http://www.mdpi.com/2077-0472/5/4/918/htm
18. Zin Z, et al (2017) Antimicrobial activity of saponins produced by two novel endophytic fungi from Panax notoginseng. 31(22):2700-03. https://www.tandfonline.com/doi/abs/10.1080/14786419.2017.1292265
19. Lu, H et al (2000) New bioactive metabolites produced by Colletotrichum sp., an endophytic fungus in Artemesia annua. Plant Sci. 151(1):67-73. http://www.paper.edu.cn/scholar/showpdf/NUz2MN2INTz0kxeQh