Endophytes: Think you’re making HERBAL medicine? Think again….

by | Jan 4, 2021

Originally published in Plant Healer Quarterly

“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 

Many of us think of ourselves and other beings as an “individuals”…Jane, Joe, Rex the dog, Tiger the cat.  In reality, life is more similar to a fractal, or perhaps a set of Russian nesting dolls.  We’re each a hodge podge of many smaller individuals; a collection of our cells as well as fungi and bacteria that do more than just tag along…they influence how we are. Don’t even get me started on the the viruses that infect our resident bacteria and fungi and influence how they are.  Even “our own” cells contain viral genetic sequences integral to our DNA. So microbial tag alongs may even influence who we are.  Not to forget the other end of the spectrum, in which we’re but one component of the larger organism of the planet.  “Individuals”, indeed. 

Plants are no exception to this nesting doll reality. When we make plant extracts, we are in fact making plant, fungal and bacterial extracts. Medicinals such as Chamomile, Mints, Saint John’s Wort, Skullcap, Rosemary, Geranium, Fennel, Artemesia and many others have been studied for their fungal and bacterial tag-alongs, called “endophytes” (1, 2), meaning “inside plants”.  In fact, all plant species tested to date contain endophytes, critters who hang around inside living tissue without causing disease. Wash the plant all you want before extracting and you don’t get rid of them. Endophytes exist either inside of or squeezed in between the plant cells. 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 more and more research is pointing to just how much our health and emotional state are impacted by the health of our microbiome, it’s becoming clear that the growth, stress resistance and chemical make up of plants is dependent upon their resident microbiome, the endophytes. And, well, endophytes are pretty cool.  Have you heard of hypericin?  An endophyte can make it.  Diosgenin? Ditto.  Artemisin?  Yup. Taxol? 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 a plant geek, you’ve heard of mycorrhizal microbes that grow associated with plant roots. These bugs facilitate water and nutrient uptake by the roots and mediate plant-to-plant communication as well. Those that actually penetrate into the roots are 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 many are bacteria (4), and they’re tough little bastards to study.  Most of the research looking at endophytes are folks interested in “drugifying” the metabolites that they make.  To study them scientists have to surface sterilize a plant then grind it up to release the endophytes, which they’ll attempt to culture on various growth media. But not all endophytes are willing to cooperate with this arrangement and refuse to be cultured.  Just how many different endophytes are out there?  One study alone cultivated 181 bacterial endophytes from 13 medicinal herb species (1). This, of course, doesn’t include those that can’t be grown in culture and the study didn’t look for fungal endophytes. Thus, the answer to how many endophytes are out there is “a shitload”.  

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).  Though this relationship 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???  Who the hell knows…  Have they been tagging along since the beginning?  Or, did plants become colonized somewhere 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 being in place by about 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 mama to baby plants via seed. These are thought to be “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 thought to be “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 it’s way into a plant. After all, fungi were already hanging around on land long before plants showed up. Or, given that some plants need their endophytes in order to grow to maturity from seed (4) or to survive in a stressful environment (7), maybe endophytes were there from the very beginning and were pivotal to successful plant evolution. 

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 medicine sitting in jars on my shelf until recently.  Plants obviously provide great medicine. Herbal medicine works because many of the secondary metabolites that aid the plants also benefit us. What’s become clear is that endophytes also make secondary metabolites, many that we typically associate with plants.

Endophytes may be influencing our plant medicine in multiple ways.  Clearly there are more plant chemicals by sheer mass than endophyte chemicals in that jar of macerating Peppermint in the cabinet.  But it’s evident that endophytes have an impact on that medicine. For example, there may be chemicals in those jars that likely wouldn’t be there if not for endophytes (8). In some cases, this is because the endophytes are synthesizing stuff that the plant doesn’t make itself. Alternatively, the endophyte may be stimulating the plant to make something it wouldn’t without the endophyte’s influence; resveratrol in Doug Fir is an example (4, 8).  Endophytes may also influence levels of metabolites the plant already makes on its own.  Echinacea’s immune modulating alkamides are an example of this (9).

Echinacea purpurea

Sometimes both the plant and the endophyte produce the same metabolite(s). In this case, the plant and endophyte may be sharing genes via gene transfer from one organism to the other, or they may have co-evolved the ability to make a particular metabolite, as seems to be the case in some Artemesia species (2). 

It’s theoretically possible that endophytes may be responsible for the primary medicinal actions of a plant in some cases. Either by directly producing strong medicinal metabolites that you don’t need a whole lot of for effects, or by influencing the plant’s production of medicinal stuff.  Endophytes themselves make a veritable cornucopia (yes, I went there) of medicinal compounds. There’s a handy table included here that was compiled for you tabley types. It lists many of the categories of secondary metabolites that endophytes produce, along with some specific examples. Anyone familiar with plant chemistry will immediately recognize that endophytes make a whole pile of metabolites that we typically think of as plant medicine.  

As mentioned, the majority of the research being carried out on endophytes is towards the discovery of novel new drugs. The relevance of endophytes is perhaps different for us herbalists…more on this monetarily. It’s known that fungal endophytes produce a larger array of secondary metabolites than bacterial do.  And, endophytes in desert and tropical plants make a wider variety of compounds than endophytes in temperate climes (4).  In any case, it’s interesting for us medicine making herbalists to know that the origin of our plant medicine is more complex than it seems at first glance.  

At this point, there are more questions than answers. For example…

  • How much is the quality of our herbal medicine determined by the influence of growth conditions on the plant itself versus on the plant’s endophytes?   It seems likely that the answer is that both are important.  Many of us consider role of growing location and conditions as key determinants of how good our plant medicine will be. Studies to date show that these factors also impact who is living inside our medicinal plants (10), which is likely influencing our medicine.  
  • Along those lines, how much do endophytes contribute to how good your Mugwort medicine is compared to the Mugwort grown in your second cousin’s garden on the other side of the country? If hers is a stronger dream herb, would it work to expose your soil and plants to her ground up Mugwort?   Research shows that environmental conditions do influence the endophytes present (10), so I wonder how such a transfer experiment would work if you live in Sedona, Arizona and your second cousin lives in Presque Isle, Maine.  I bet some endophytes will “take”.  
  • Is there a potential problem in trying endophyte transfers such as these?  A chance, for instance, of transmitting an unwanted infection by a disease-causing organism? 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 propagate endangered medicinal plants (10).   This 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 our 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.

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. Huang, L-H, et al (2018) Endophytic fungi specifically introduce novel metabolites into grape flesh cells in vitro. PLOS One. 13(5): e0196996.   https://doi.org/10.1371/journal.pone.0196996

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

Written By Anna-Marija Helt

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