Early years

I was born in Waipiro Bay, a beautiful, remote bay on the east coast north of Gisborne, the north island of Aotearoa New Zealand. Driving down the narrow, windy gravel road to get to it from Te Puia in later years, was something I remembered fondly when watching the film Mahana, directed by Lee Tamahori.

Dad was the Power Board engineer and like his dad was also raised in Gisborne and on the coast, grandad being a truck driver in the district in the 1920’s and 1930’s.  Posted to Tokomaru Bay in 1957, Dad’s job was liasing with the local communities, farmers and power board gangs to plan and install powerlines and bring electricity (what he called juice), to the coast north of Ruatorea. Mum raised me and my three brothers, grew most of our veges, cooked our kai, did (and still does) some incredible baking, made most of our clothes, and  engaged actively in community affairs. Toko was a small but intimate and vibrant settlement with its own picture theatre, quite a few shops and a wharf, and there was always lots happening, as some of the East Coast pages of the former Gisborne Photo News remind us of.

I return to Tokomaru Bay every year, and always buy a calender, produced by the Tokomaru Bay Heritage Trust as a fundraiser towards restoration of the old wharf. This month’s (March 2024) page has a photo (posted below) of my primary school class soon after I started school. Standing two to the left of her, I remember the pride us little kids felt, when our teacher was crowned Queen of Tokomaru Bay. Life was slower, relationships and communities were strong, and few locked their doors at night.

Like many in the community at the time, Dad loved tramping, and would go away on Search and Rescue trips or take my older brothers and sometimes me into the bush, or up the slopes of Mt Hikurangi. The hill behind our house in Toko, was a decent climb and high enough to be a mountain in many countries. It was also a rich hunting ground for the possoms my brothers trapped and skinned, then nailed the furs to the walls of our garage to cure, before selling them for pocket money.

Mānuka and kānuka were scattered throughout most of the hilly sheep farms at that time, native pioneer species then considered a nuisance by farmers but cut for firewood and an extra income, by motivated locals.

Many areas of te ngahere (the bush) nearby contained a diverse wealth of native trees at all stages of growth, including kahikatea, pukatea, rimu, puriri, totara, matai, tanekaha, karaka and kohekohe. Smaller plants such as koromiko, tutu, kawakawa and ferns were also endemic, and many coastal areas were protected from storms or erosion by native plants including our famous pohutakawa, the one in Te Araroa being the largest in the world.

However, te ngahere back then was only a tiny fraction of what it was when Captain Cook and co landed on Kaiti Beach. Waihirere Domain and Greys Bush near Gisborne are reminders of the pre-European bush landscape that once characterised the region. A weekend trip to Waihirere Domain for a swim and turns on the long slide, followed by a family walk in the mysterious bush, was paradise as a youngster.  It made absolute sense when I learnt that Māori regarded trees as being senior to humans, and respected them for their provision of shelter, food, clothing and medicines, and the connection they provided between humans and their sacred ancestors, Papatūānuku and Ranginui.

A rich growing region

Horticulture was and still is the main type of farming in the Gisborne district. Watties once had a lot of vegetables grown for their canning and freezing operation by the Gisborne wharf, which was the biggest employer in town for many years. Sweetcorn from Gisborne and the east coast is amongst the sweetest and tastiest in the country, and can be eaten five nights a week with butter and a little salt when in season, without taste bud fatigue.

Fruit such as apples, pears, persimmons, citrus and strawberries have also long been grown throughout the entire ‘Poverty Bay flats’, as the district was once misnamed by  Captain Cook. The bay is now the largest citrus growing area in Aotearoa, and a growing provider of avocados, feijoas and kiwifruit.

A German migrant named Fredrich Wohnsiedler, who moved out of town to Ormond after his butchers shop in town was trashed during the first world war, became the first commercial grape grower and winemaker in the district. Since then of course the industry has grown and flourished in the region. Gisborne chardonnay is amongst the best in the world, but unlike Marlborough sauvignon blanc, hasn’t had the same marketing dollars put behind it, to achieve such a global reputation.

LeaderBrand, one of the biggest vegetable and salad growers in the country, was conceived in and grew out of the Gisborne district. It has grown to become a major producer of fresh vegetables for families in Aotearoa, and markets around the world.

The Farmers market in Gisborne every Saturday, is a wealth of offerings of what is one of the richest foodbowls of Aotearoa, and a warm reflection of a close and committed community.

Recent tough times

However, the Tairāwhiti region has also had it hard over the years, due to a combination of adverse economic and climatic events. The demise in traditional animal-based forms of farming, factory closures, unemployment and urbanisation, have exacerbated longstanding cultural and socioeconomic inequities within the region as with many areas of our country, and lead to increasing poverty related problems. The Covid 19 pandemic put a temporary brake on tourism, and the impacts of Cyclones Bola in 1988, and the dual hits of Cyclones Hale and Gabrielle in 2023, were massive.

Health Research Council of New Zealand data has found the level of housing and health deprivation in the Tairāwhiti region is amongst the highest in the country. Māori, who make up 45% of the population, are particularly prone to negative health outcomes, due to a range of factors including poor access to some health services.

Cyclone Gabrielle was a devastating event, when normality took a nosedive for the entire region of around 50,000 people. Flooding, slips, road closures, total destruction of hillsides and homes, forestry waste being deposited on beaches and farmland, and the subsequent loss of jobs, took a huge toll. Climate change and the relatively young geology and soil types in the region contributed to the severity of these impacts, as did an over reliance on an exotic plantation forestry sector. Large scale plantings of Pinus radiata in areas and on hillsides prone to erosion, a monoculture model based upon a single species that can impact negatively on many native plants, was in retrospect a flawed policy decision.

Future opportunities

The Tairāwhiti region’s history as an efficient and rich producer of a diverse range of plant crops and processed foods and beverages, provides insight into future opportunities. However, the peaks and troughs in supply and demand that various industries have incurred over the years, due to climatic or global economic events, changing consumer trends or corporate priorities, are sobering and informative.

A powerful attribute of the region and its population is resilience, something that has got it through many natural disasters and climatic events, and economic shocks, over several generations.  Out of adversity comes opportunity, and out of struggle, comes renewed strength and resolve. These truths are particularly relevant to the Tairāwhiti region in March 2024. While mistakes have been made with how we humans have treated and tried to reap a living from the land and sea, lessons have also been learned, and many new opportunities revealed.

Several local companies continue to make headway, into providing meaningful jobs and livelihoods for people in the region through horticulture based activities.  Apart from Leaderbrand and many vineyards, Riversun is the leading national supplier of grafted grapevines, and a breeder and propagator of premium avocado rootstocks and a range of other plant materials for commercial horticulturalists around the country.  Rua Bioscience operates a plant discovery and breeding programme from a research and cultivation centre in Ruatorea, with a vision to create cannabis-derived medicines that change people’s lives

The wealth of benefits provided both to the land, air and waterways, as well as to humans and other animals from a landscape that is rich in a wide range of native plants, needs little further explanation or justification. The challenge now, is to apply the knowledge gained from past successes and mistakes, and allocate resource and mahi to return many unstable terrains to native forests, and to foster a greater biodiversity within the ecosystem. Identifying and leveraging existing and new ways to obtaining some form of commercial return in the process, will catalyse and incentivise these much needed changes in our approach to land care.

Several opportunities also exist for crop trials or land use diversification, for landowners and iwi within the region. I’ve learnt from my personal experience that plants such as calendula, echinacea and withania all love the east coast soils and climate. There are many, many more, where commercial scale operations involving non-native as well as native medicinal plants could become profitable, through a sustained and collaborative approach.

Te Taiao

In Māori culture, Te Taiao is the natural world that contains and surrounds us, and acknowledges the interconnection of people and nature. It is underpinned by three guiding principles: 

• Our land, water, air and biological life must be able to thrive without over-use.
• Any use is a privilege, not a right, and
• If something is not healthy or well, we must fix it.

For Aotearoa New Zealand, many factors are emerging which are likely to lead to increasingly difficult challenges to the current format and operational models of our farming sector. We have become over-dependent on agrichemicals and farming animals, and need to invest more in new crop and companion crop research, and give greater respect to Te Taiao and the need to nurture our natural heritage.

With rapidly changing geopolitical and climatic landscapes, supply chain disruptions and an increasing need for healthcare to revert to more natural and selfcare based approaches, phytomedicines will make a greater contribution to our country’s future.

As I reflect on the Toko Bay March 2024 calender page, I feel very grateful to have been raised in this part of Aotearoa, and conditioned by such a culturally and naturally rich environment and community.  These reflections and experiences also reinforce my long held belief, that Tairāwhiti is one of the most suitable regions for establishment of an industry based upon medicinal plants, and that this would have enormous benefits for both its people and environment.

Access to plant (phyto) medicines to prevent or treat illnesses or health conditions both acute and chronic, is an ethical obligation. Many factors impact on this, including their costs and affordability, their quality and availability in efficacious dosage forms, and how they are regulated

Termed Complementary Medicines in Australia, Herbal Medicinal Products in Europe, Botanical Drugs in the U.S.A, and Natural Health Products (NHP’s) in Aotearoa New Zealand and Canada, the products themselves are all used in some way to support human and animal health. How the population of each country regards and uses them, and what checks and balances governments decide to put on their safety and accessibility, is influenced by relevant legislation.

Plant medicines are however, a complex and diverse group of products. In practice, many countries have more than one regulatory agency (generally that responsible for foods, plus that responsible for medicines), involved in overseeing their compliance to what is often a rather confusing legislative framework.

NHP Regulations In Aotearoa New Zealand

In Aotearoa New Zealand, successive governments have struggled for more than 25 years to develop suitable new legislation to replace the hopelessly outdated 1981 Medicines Act, and bring regulations of medicines and NHP’s into the 21^st century⁽¹⁾.  

The Australia New Zealand Therapeutic Products Agency (ANZTPA) was an attempt initiated by the New Zealand and Australian governments in 1996 to develop a joint trans-Tasman scheme for regulating therapeutic products. Government officials and industry representatives worked for eleven years on the detail of this new agency until 2007, when the New Zealand government postponed further legislation.

The next attempt was the Natural Health and Supplementary Products (NHSP) Bill, on which the government worked from 2011 until dropping it at the end of 2017.

The Therapeutic Products Bill was the third attempt to regulate all medicines and medical devices as well as NHP’s, and was introduced by the current government in November 2022. In July of this year it passed its third reading in the House, and subsequently became the Therapeutic Products Act (2023). Regulations as provided for in the Act are now being developed, and need to be in place by September 2026⁽²⁾.

Regulatory Challenges

The huge plethora and diversity of brands and product types, digital marketing, ongoing incorporation of new technologies and supply chain disruptions, are driving constant changes in the availability of products in the marketplace.

The important issue of sustainability of some medicinal plants used as raw materials, is largely left to companies themselves to commit to, and voluntarily opt into secondary regulatory agencies such as the Union for Ethical Biotrade, EcoCert, Rainforest Alliance, FairWild and B-Corp.

Many medicinal plants are also foods, and well known culinary foods and spices such as beetroot, garlic, ginger and turmeric are incorporated into capsule and tablet dosage forms. Whether something is in fact a food or ‘dietary supplement’, or is actually ‘medicinal’, is a 6 million dollar question which extracts different answers depending on who is asked.

Many companies in the industry have leveraged this situation to their advantage, and the terms ‘dietary supplement’ or ‘food supplement’ are widely used as descriptive terms when selling products. Most plant-based NHP’s are safe and fulfill a nutritive or functional dietary need when taken in small doses as a supplement to the diet. Food regulations, while having some obligations on manufacturers and sponsors, also tend to have a lower regulatory bar and thus cost, than those for medicines.

Language however, and the terminology used to describe something can greatly influence one’s perception. By referring to most NHP’s as supplements rather than as pharmacologically active medicines, their perceived ability in the eyes of many to produce tangible health improvements, is somewhat compromised. In many ways it fosters an impression that NHP’s are pawns, rather than knights or rooks, kings or queens. As such their status or ‘mana’ (a Māori word that signifies the presence or intrinsic influence or power of something), is lessened.

Personally, since training in medical herbalism after several years working as a pharmacist, I’ve always regarded well manufactured and properly used plant extracts as medicines. The name of the company I founded 25 years ago, and the title of this blog, extols this principle.

Taking the right approach is a minefield for regulators though, and it is impossible to please everyone. Many parameters require consideration when trying to distinguish between a food or dietary supplement and a medicine. They include the product potency, therapeutic claims made for it, the medical condition(s) or intended application, the presence or absence of a qualified practitioner’s oversight, and the manufacturing standards and pharmacovigilance systems in place.

In practice, a more tiered and evolved approach to classification of NHP’s, to include categories apart from dietary supplements and medicines alone, would have much merit.

While alcohol is alcohol regardless of the form it is presented in, low alcohol beer and gin are poles apart, in terms of their alcohol content. Their accessibility, packaging, effects on the user and thus safety, therefore also vary significantly. The same enormous diversity exists in strength, efficacy and safety of many NHP’s being produced and sold today.  Logically therefore, as with drug-based medicines, it is appropriate that certain products should only be able to be prescribed, by suitably trained and registered practitioners⁽³⁾.

Appraising traditional preparations versus modern pharmaceutical manufacturing methods for their relative risks, and ensuring evidence is sufficient to support therapeutic claims, are other challenging areas. For this and other regulatory tasks, adequate knowledge and training in NHP’s is an important capability need for the regulator. A well resourced regulator in budgetary and human expertise terms, and one built upon principles of good science, public safety, consultation and accountability, is therefore essential.

Prevention better than a cure

A more preventative and self help approach to personal health is critical to reduce the dual burden on governments and future taxpayers of aging populations and increasing resource needs of mainstream healthcare systems. Evidence suggests a vast number of plants can either enhance our resistance to and reduce our risks of a wide range of illnesses, or reduce our dependence on drug and hospital treatments. However, to utilise them as prophylactic and safe selfcare interventions, research, education, and a regulatory environment that facilitates this, needs to continue.

Additionally though, there is in fact a growing recognition of the ability of plant derived medicines to provide efficacious treatments for a whole host of serious illnesses and diseases for which conventional medicine is struggling to make more headway.  

Treatment of serious conditions

The incorporation of medicinal plants into mainstream healthcare including for serious conditions such as sepsis, post-stroke and kidney failure, has been a part of Chinese medicine for a long time^(4-6). Also in Japan, Germany and other countries, parenteral products are manufactured from plant extracts and licenced with regulatory authorities for the treatment of specific conditions.

Results from a recent clinical trial in China have put the potential role of phytotherapy for the treatment of sepsis into the spotlight, with a significant reduction in mortality being reported following administration of a polyherbal parenteral preparation⁽⁷⁾.  Sepsis is a seriously dysregulated host response to infection, and more than 19 million cases of severe sepsis occur globally each year, leading to at least 5 million deaths⁽⁸⁾.

The study was a multicentre, randomized double-blind, placebo-controlled trial conducted in intensive care units at 45 sites in China. It included 1817 randomized patients aged 18 to 75 years with sepsis present for less than 48 hours, nearly half of whom had septic shock. Patients received either an intravenous infusion of the herbal preparation at a dose of 100 mL or volume-matched saline placebo every twelve hours for five days, alongside usual hospital care in either an ICU or medical ward. The primary outcome was 28-day all-cause mortality.

Of the 1760 patients who completed the trial, the 28-day mortality rate was significantly lower in the treatment than in the control group. Within the herbal and conventionally treated group, 165 of 878 patients (18.8%) had died, whereas in the control group who received conventional treatment alone, 230 of 882 patients (26.1%) had died after 28 days. The incidence of adverse events was very similar in both groups^{(7, 9)}.

With plant extracts containing multiple phytochemicals including some which may impede absorption, achieving adequate bioavailability from their oral administration can sometimes be a challenge, just as it is for some drugs.  Parenteral dosage forms are often life-saving in modern medicine, as intravenous or intramuscular injections can achieve much higher plasma and tissue levels, and thus enable better, faster and a more protracted efficacy to be achieved.

However, as every pharmacist knows, parenteral medicines need to be manufactured using a high level of Good Manufacturing Practice (GMP) standards, far greater than those in place for dietary or food supplements, to avoid serious adverse events or treatment failure that may result in death.

Leveraging the potential of phytotherapy

Studies such as this one, highlight the potential contribution of medicinal plants to modern healthcare, as being a whole lot more than that of ‘dietary supplements’ alone.

It is encouraging to see that in some countries of the world, companies, clinicians, governments and regulators have for some time now been actively embracing and researching new potential applications for their traditional plant medicines, including their parenteral (injectable) use for serious or difficult to treat conditions.

Incorporating these and other medicinal plants into current treatment protocols for serious and expensive to treat conditions such as acute infections, sepsis, diabetes, cancer and mental unwellness, is an ambitious aspiration, but an essential one. Additionally for most of these applications, adequate regulatory oversight and adherence to medicine-manufacturing standards, will also be required.

The current New Zealand government has now passed legislation to replace our hopelessly outdated 1981 Medicines Act, which was no easy task. However, many challenges exist with preparation of the subsequent regulations. These include providing a regulatory model that continues to allow self-selected NHP’s both as a safe self-help intervention, but also recognizes and fosters greater research into their potential applications for the prophylaxis or treatment of more serious conditions, and extends the clinical reach of our many highly trained NHP practitioners.

References:

1. Rasmussen PL, NZ Politicians continue to let the Natural Health Products Industry and Practitioners Down. www.herbblurb.com Jun 19, 2020.
2. https://www.health.govt.nz/our-work/regulation-health-and-disability-system/therapeutic-products-regulatory-regime
3. Rasmussen PL, Statutory regulation of medical herbalists and naturopaths: an essential step towards a more cost and outcome beneficial future healthcare system. www.herbblurb.com 26 April, 2019.
4. Cheng C, Yu X. Research Progress in Chinese Herbal Medicines for Treatment of Sepsis: Pharmacological Action, Phytochemistry, and Pharmacokinetics. Int J Mol Sci. 2021;22(20):11078. 
5. Zhang L, Yang L, Shergis J, et al. Chinese herbal medicine for diabetic kidney disease: a systematic review and meta-analysis of randomised placebo-controlled trials. BMJ Open. 2019;9(4):e025653.
6. Wei M, Wang D, Kang D, et al. Overview of Cochrane reviews on Chinese herbal medicine for stroke. Integr Med Res. 2020;9(1):5-9.
7. Liu S, Yao C, Xie J, et al. Effect of an Herbal-Based Injection on 28-Day Mortality in Patients With Sepsis: The EXIT-SEP Randomized Clinical Trial. JAMA Intern Med. 2023;183(7):647-655.
8. Fleischmann C, Scherag A, Adhikari NK, et al. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med. 2016;193(3):259-272
9. Rasmussen PL, Chinese parenteral phytomedicine reduces mortality from sepsis. Pharmacy Today, October 2023. ISSN 1170-1927

Introduction

Many of our native plant medicines have the ability to help in the management of conditions affecting the gastrointestinal tract⁽¹⁾. While these have diverse actions and undoubtedly act on many levels concomitantly to prevent and treat such conditions, their direct effects on the gut microbiome, are likely to be contributory.

The gut microbiome is an intricate and dynamic ecosystem of microbes that is strongly influenced by our environment, diet and genes, and altering it can significantly influence our predisposition to and outcomes from many illnesses. While these extend way beyond gastrointestinal conditions alone^(2,3), the association between modulation of the gut microbiome and digestive health, is of particular interest.

Furthermore, it is these intestinal microbiota that play an important role in both the activation and metabolism of medicinal plant phytochemicals themselves, just as they break down proteins, carbohydrates and fats in foods, to simpler and bioavailable molecules. A diverse and healthy microbiome is thus conducive to ensuring optimal processing and bioavailability of medicinally active phytochemicals, and thus achieving favourable clinical outcomes in phytotherapy.

Probiotics (live microorganisms that when administered in adequate amounts confer a health benefit) are now highly regarded, but we’re also increasingly learning about the important role of prebiotics, in feeding and selectively promoting probiotic growth and human health. These include plant foods such as psyllium, onion, asparagus, garlic, kumara, chicory, Jerusalem artichoke, bananas, beetroot and oats, which provide complex carbohydrates such as inulin and other beneficial fibres to support a healthy gut microbiota and immune system.  Additionally, there seem to be positive contributions made by other specific primary or secondary components of many plants and mushrooms, to the microbiome community and subsequently to health outcomes.

Native plants and the microbiome

Regular ingestion of various herbal teas including green, kuding and baical skullcap teas can exert beneficial effects on the gut microbiota, including an increased number of unique bacterial genera, and changes in the relative abundances of particular species^(4-6). Catechins and insoluble fibre contribute to these benefits, and exert a prebiotic-like effect on gut microbiota⁽⁷⁾. Supplementation with certain tannins has also been found to increase the diversity and abundance of butyrate-producing and probiotic bacteria and metabolism of amino acids⁽⁸⁾. In fact the antioxidant and disease preventative properties of many polyphenolic rich plants, may correlate to some extent with their effects on gut bacterial species⁽⁹⁾.

While research is required, many native plants from Aotearoa New Zealand are very rich in a diverse range of polyphenolic compounds and are likely to also produce similar benefits. While tannins and other larger ones of these have poor oral bioavailability, they can nevertheless facilitate significant changes in the abundance of bacterial species associated with a wide range of health outcomes. The hydrolysis of tannins and flavonoids by gut microbiota is also being increasingly recognised as producing smaller, bioavailable and bioactive metabolites, with many health benefits^{(10, 11)}.

Controlling infections

Antibiotics are widely used to eradicate unwanted bacteria, yet they are generally not very selective, and often produce serious negative impacts on beneficial bacteria and the gut microbiome⁽¹²⁾. Plants with a narrower spectrum of antimicrobial activity and when carefully combined, have the ability to provide a more targeted action, and thus reduced adverse events⁽¹³⁾.   They should therefore be used more as first line treatments for many types of infection, and more research into this as well as their combined use with antibiotics, is urgently needed.

The microbiota is also involved in reducing and preventing colonization by enteric pathogens through the process of competitive exclusion and the production of antimicrobial substances. Plants that enhance this production of bacteriostatic and bactericidal substances by the microbiota, are therefore potential interventions to deal with some pathological infections⁽¹⁴⁾.

Mānuka (Leptospermum scoparium), Kānuka (Kunzea ericoides), Harakeke (Phormium tenax), Horopito (Pseudowintera colorata), Tanekaha (Phyllocladus trichomanoides), Rewarewa (Knightia excelsa) Totara (Podocarpus totara, Rimu (Dacrydium cupressinum) and Pukatea (Laurelia novae-zelandiae), all exhibit good activity against specific pathogens. 

Animal studies are increasingly showing the microbiome to have a positive impact not only on gut physiology, but also the immune system of the host. Part of the mechanism of Echinacea purpurea’s immunomodulatory effects may involve its influences on the gut microbiota, as shown by improvement in immunosuppressed ducks in conjunction with increased abundance of beneficial intestinal bacteria⁽¹⁵⁾.

Antibacterial and antifungal actions are prominent activities of many native plants, and traditional uses for gastrointestinal tract infections, were once common. Tannin rich native species such as Mānuka can treat dysentery and diarrhoea, and most tannins also have intrinsic antibacterial properties. The powerful astringent and antimicrobial effects produced by infusions and hydroethanolic liquid extracts of Mānuka’s leaves and stems, make it a useful component of a treatment for gastrointestinal infections.

In its living state, Mānuka itself has around 200 different bacteria within its leaves, stems and roots, that make up a rich community of endophytes (microorganisms that live within and near plants, in a symbiotic relationship). Several of these bacteria themselves produce antifungal or antibacterial compounds as part of their competitive survival⁽¹⁶⁾. Ingestion of preparations made from its leaves and stems will deliver a range of phytochemicals with the potential to modulate the gut microbiome, and thus provide digestive system benefits. The often symbiotic relationships between endophytes and plants, and those between microbes and humans, appear to have much in common.

Koromiko (Hebe stricta) is another effective remedy used for diarrhoea and dysentery among Māori and European settlers, including by New Zealand soldiers during the Second World War. Rebalancing of different microbial species within the gut, is probably involved in its antidiarrhoeal and anti-inflammatory properties.

Intestinal mucosa tonics

Damage to the integrity of the intestinal biofilm can result in alteration in intestinal permeability, a condition widely described asleaky gut. When this occurs, the immune system can become weak or dysregulated, making conditions such as irritable bowel syndrome or inflammatory bowel disease more likely⁽¹⁷⁾. Ulcerative colitis, Crohns and irritable bowel syndrome are all associated with enhanced secretion of proinflammatory cytokines, poor maintenance of the epithelial barrier, and gut dysbiosis^{(18, 19)}.

Kawakawa (Piper excelsum) is a plant widely used for gastrointestinal inflammation and has many pronounced digestive system benefits^{(20, 21)}. As with other Piperaceae species, influences on gastrointestinal absorption and gut permeability, and vascular barrier protective effects have been shown for Kawakawa and some of its amide constituents, including pellitorine, piperine and piperdardine^{(22, 23)}.  Lignans are also prominent constituents, and given other lignans are known to interact with gut microbiota, microbiomal modulations through these phytochemicals within Kawakawa, may also take place.

Other plants with broad-ranging effects on the digestive system, are Horopito (Pseudowintera colorata) and Akeake (Dodonaea viscosa). Both plants exhibit astringent, anti-inflammatory and some antimicrobial properties which probably impact population levels of some microbiome species in a negative manner, and others in a potentially facilitatory manner. An Indian variety of Dodonaea viscosa has been shown to be gastroprotective in animal studies⁽²⁴⁾, suggesting a potentially useful role in the management of peptic ulcers⁽²⁵⁾.

Polysaccharides

These are another type of secondary metabolite whose oral bioavailability is limited, but are increasingly being recognized for the complex interactions they have with microbes within the gut. These include modulation of the gut microbiota composition itself, metabolism of polysaccharides to short chain fatty acids, and polysaccharide-induced modulation of the production of gut microbiota metabolites such as trimethylamine, tryptophan and lipopolysaccharides⁽²⁶⁾. The widely used Psyllium husk (Plantago ovata), increases faecal water content and improves constipation while increasing populations of butyrate-producing microbiota⁽²⁷⁾. Amelioration of antibiotic-associated diarrhoea has been associated with  a prebiotic effect of polysaccharides from the medicinal fungus Hoelen (Poria cocos)⁽²⁸⁾.

Hoheria (Hoheria populnea), is a native tree whose various different organs are all rich in polysaccharides.  Like Slippery Elm and other polysaccharide hydrocolloid rich plants, Hoheria can help reduce symptoms of dyspepsia or gastritis when taken either as an infusion or hydroethanolic liquid extract. As with many other polysaccharide-rich plants or medicinal fungi, beneficial effects on the gut microbiome, also seem likely.

Bitters

Medical herbalists are generally taught that it is the stimulatory effects of bitter-tasting plants on every component of the gastrointestinal system, which accounts for their many beneficial and tonic like actions on digestive processes and thus overall health. We now also know that activation of bitter receptors is involved in the regulation of appetite, insulin sensitivity, airway innate immunity, and other physiological processes. The ability of bitter tasting plants and their inclusion in the diet or regular herbal tonics to positively influence the gut microbiome community, is being increasingly revealed^(29-31).

Native plants such as Kohekohe (Dysoxylum spectabile) and Tanekaha make excellent bitter substitutes to classical European bitters such as Gentian and Wormwood.  These are also likely to have complex but beneficial actions on the gut microbiome.

Summary

Humans have a wide variation in the makeup of their gut microbiome.  This potentially results in variations in microbial metabolism of many phytochemicals, and thus the resulting therapeutic activities of medicinal plants. The relationships between plants and microbes works in both directions though, and there are a multitude of ways in which the ingestion of many plants can produce health benefits through influencing the functions of these bacteria found without our gastrointestinal tract.

While we are only just starting to understand elements of the complex human gut microbiome, it seems certain to provide innovative targets for the incorporation of plants native to Aotearoa New Zealand, to help prevent and treat several gastrointestinal conditions.

References:

1. Rasmussen PL. Treating digestive conditions using New Zealand native plants. Phytomed seminar, October 2009.
2. Miyauchi E, Shimokawa C, Steimle A, Desai MS, Ohno H. The impact of the gut microbiome on extra-intestinal autoimmune diseases. Nat Rev Immunol. 2023;23(1):9-23
3. Sasso JM, Ammar RM, Tenchov R, et al. Gut Microbiome-Brain Alliance: A Landscape View into Mental and Gastrointestinal Health and Disorders. ACS Chem Neurosci. 2023;14(10):1717-1763.
4. Morishima, S., Kawada, Y., Fukushima, Y., Takagi, T., Naito, Y., & Inoue, R. (2023). A randomized, double-blinded study evaluating effect of matcha green tea on human fecal microbiota. Journal of clinical biochemistry and nutrition, 72(2), 165–170.
5. Vamanu E, Dinu LD, Pelinescu DR, Gatea F. Therapeutic Properties of Edible Mushrooms and Herbal Teas in Gut Microbiota Modulation. Microorganisms. 2021;9(6):1262. 
6. Shen J, Li P , Liu S , et al. The chemopreventive effects of Huangqin-tea against AOM-induced preneoplastic colonic aberrant crypt foci in rats and omics analysis [published correction appears in Food Funct. 2021 Mar 15;12(5):2336-2337.
7. Thumann, T. A., Pferschy-Wenzig, E. M., Aziz-Kalbhenn, H., Ammar, R. M., Rabini, S., Moissl-Eichinger, C., & Bauer, R. (2020). Application of an in vitro digestion model to study the metabolic profile changes of an herbal extract combination by UHPLC-HRMS. Phytomedicine : international journal of phytotherapy and phytopharmacology, 71, 153221.
8. Correa PS, Mendes LW, Lemos LN, et al. Tannin supplementation modulates the composition and function of ruminal microbiome in lambs infected with gastrointestinal nematodes. FEMS Microbiol Ecol. 2020;96(3):fiaa024.
9. Morisette A, Kropp C, Songpadith JP, et al. Blueberry proanthocyanidins and anthocyanins improve metabolic health through a gut microbiota-dependent mechanism in diet-induced obese mice. Am J Physiol Endocrinol Metab. 2020;318(6):E965-E980.
10. Sallam IE, Abdelwareth A, Attia H, et al. Effect of Gut Microbiota Biotransformation on Dietary Tannins and Human Health Implications. Microorganisms. 2021;9(5):965.
11. Marín L, Miguélez EM, Villar CJ, Lombó F. Bioavailability of dietary polyphenols and gut microbiota metabolism: antimicrobial properties. Biomed Res Int. 2015;2015:905215.
12. Patangia DV, Anthony Ryan C, Dempsey E, Paul Ross R, Stanton C. Impact of antibiotics on the human microbiome and consequences for host health. Microbiologyopen. 2022;11(1):e1260.
13. Chou, S., Zhang, S., Guo, H., Chang, Y. F., Zhao, W., & Mou, X. (2022). Targeted Antimicrobial Agents as Potential Tools for Modulating the Gut Microbiome. Frontiers in microbiology, 13, 879207.
14. Clavijo, V., & Flórez, M. J. V. (2018). The gastrointestinal microbiome and its association with the control of pathogens in broiler chicken production: A review. Poultry science, 97(3), 1006–1021.
15. Lin R, Zhi C, Su Y, et al. Effect of Echinacea on gut microbiota of immunosuppressed ducks. Front Microbiol. 2023;13:1091116
16. Wicaksono WA, Jones EE, Monk J, Ridgway HJ. The Bacterial Signature of Leptospermum scoparium (Mānuka) Reveals Core and Accessory Communities with Bioactive Properties. PLoS One. 2016;11(9):e0163717.
17. Fukui H. Increased Intestinal Permeability and Decreased Barrier Function: Does It Really Influence the Risk of Inflammation?. Inflamm Intest Dis. 2016;1(3):135-145.
18. Wu X, Chen H, Gao X, Gao H, He Q, Li G, Yao J, Liu Z. Natural Herbal Remedy Wumei Decoction Ameliorates Intestinal Mucosal Inflammation by Inhibiting Th1/Th17 Cell Differentiation and Maintaining Microbial Homeostasis. Inflamm Bowel Dis. 2022 Jul 1;28(7):1061-1071.
19. Aldars-García L, Chaparro M, Gisbert JP. Systematic Review: The Gut Microbiome and Its Potential Clinical Application in Inflammatory Bowel Disease. Microorganisms. 2021;9(5):977.
20. Rasmussen, P.L., Kawakawa: a monograph. Phytonews, published by Phytomed Medicinal Herbs Ltd, 7, 1-7, Sept 2000. ISSN 1175-0251
21. Rasmussen, P.L., Kawakawa: a promising New Zealand native plant. Pharmacy Today, August 2021. ISSN 1170-1927
22. Lee W, Ku SK, Min BW, et al. Vascular barrier protective effects of pellitorine in LPS-induced inflammation in vitro and in vivo. Fitoterapia. 2014;92:177-187.
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24. Arun M, Asha VV. Gastroprotective effect of Dodonaea viscosa on various experimental ulcer models. J Ethnopharmacol. 2008;118(3):460-465.
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Plants are incredibly clever organisms in having evolved over millions of years and survived predatory pressures, severe climatic events and ecological stressors, largely through their ability to produce and utilise chemicals. These compounds, known as phytochemicals or secondary metabolites, are the essence of phytopharmacology, the medicinal actions of plants.

We as humans are fortunate in being able to also benefit from this foresight by plants, as many of these secondary metabolites help to protect against and treat disease and ill health in humans, as well as slow down our aging processes.

Many drugs or single chemical entities with pharmacological activities have been developed from plants, and we know that individual phytochemicals such as morphine, atropine and digoxin are very potent medicines.  Also how these and most if not all other ‘active’ phytochemicals initiate their actions through modulating receptors and numerous physiological processes throughout our bodies.

However, for the majority of plants used medicinally, there exists little scientific knowledge about their phytochemistry, and what so-called ‘active constituents’, contribute to their therapeutic properties. There are exceptions to this, particularly those plants which have achieved high levels of usage or attracted significant research interest. For some of these, we now have an understanding from traditional knowledge as well as science, that most and probably all phytomedicines contain more than one or even numerous active constituents present. Also that within each individual plant some form of natural synergy between phytochemicals takes place in relation to bioactivity, pharmacokinetic and/or safety profiles.

Purification of many plant constituents often leads to a reduced intestinal absorption after oral administration. The presence of co-existing constituents including primary (carbohydrates, lipids, amino acids etc) and other secondary metabolites can often promote gastrointestinal absorption of pharmacologically active constituents by improving solubility, modulating the gut microbiome, increasing enterocyte membrane permeability, inhibiting liver metabolism, or promoting the formation of active metabolites⁽¹⁾.  

Drug discovery and bioprospecting is often about trying to separate a plant’s phytochemistry in to pieces, in an attempt to unmask a single ‘active constituent’, and subsequently purify and synthesise it or a chemically related potent derivative. In fact the published and undoubtedly much unpublished research field is littered with instances in which despite scientists doing their utmost to split medicinal plant extracts into different fractions, and from there work hard to further narrow down and finally identify the ‘active constituent’, it remains as elusive as the Holy Grail.

A recent study into the cytotoxicity and antimicrobial activities of Echinacea purpurea for example, which attempted to identify key active compounds, found the highest antimicrobial activity was shown by dichloromethane, ethyl acetate, and acetone extracts of the herb, whereas dichloromethane and n-hexane extracts showed the highest cytotoxic activity⁽²⁾. These extracts were therefore fractionated, and the obtained fractions also assessed for potency as cytotoxics. However, and to the perplexity of the researchers, when the cytotoxicity and bioactivity of these purified fractions was compared to those of the original ‘crude’ extracts, the original extracts were still superior, and showed greater bioactivity. This indicated the existence of a possible synergistic effect of different compounds in the whole extracts⁽²⁾.

Such findings are in fact commonplace in phytomedicine research. Of note is that despite what surely must have been billions of dollars of expenditure by pharmaceutical company researchers to date into identifying the active antidepressant constituent within the highly acclaimed plant St Johns Wort (Hypericum perforatum), it has yet to be revealed. 

Standardised extracts:

There are therefore many potential pitfalls with placing too much emphasis on individual phytochemicals when appraising the therapeutic properties of plant medicines, and the boundary between what is a natural or ‘whole extract’ rather than single chemical entity-based medicine, is often a shifting one. Risks include the usually unknown efficacy consequences of not having other types of secondary metabolites or facilitatory ‘team players’ present as occurs in nature, possible safety concerns, and erring excessively down a slippery slope towards the product becoming more like a drug rather than a herbal medicine.  As with other forms of medicine, there are also instances where commercial interests or poor science has highlighed specific phytochemicals as being essential for good clinical outcomes, with little evidence provided.

Despite these cautionary comments, it is often the relative richness or content of particular phytochemicals in a batch of herbal medicine, that largely determines whether the treatment is effective or not, and it can therefore be an important indicator of quality.

Echinacea

Traditional use of both Echinacea purpurea and Echinacea angustifolia is based upon the root, yet when products based upon these north American native plants (and in particular E. purpurea) began to be commercialized, the principle plant part utilized by some companies, became the whole plant or flowering aerial parts.

Alkylamides (alkamides) on the other hand, are now regarded as the major bioavailable and active components in oral forms of Echinacea(^3,4,5), and highest levels of these are found in the traditionally used root, and not the cheaper flowering tops^(6,7,8). Alkylamide-enriched extracts also show the strongest anti-inflammatory activity^(9,10) and have the ability to both dampen down an over-activated immune system in certain situations, as well as enhance its infection prophylactic ability, in others ^{(11, 12)}.

For many years and still today with some companies, measurements of ‘total phenolics’ in echinacea have been used as an apparent indicator of quality, and by implication therefore, of the immunomodulatory and anti-inflammatory actions for which Echinacea is best known. Given that the assay for total phenolics incorporates a wide range of phytochemicals with a simple or polyphenolic structure, including flavonoids, tannins, cichoric and caftaric acid, and that many of these exhibit poor oral bioavailability and have not been strongly associated with Echinacea’s principle actions, this analytical method appears to have little relevance to the relative quality or potency, of most Echinacea extracts.

The immunomodulatory and anti-inflammatory effects of alkylamides, have been shown to be dose-related in many studies. This fact, combined with traditional use involving doses of up to 30 grams of root in some cases, reinforces the importance of taking adequate amounts of these key tongue-tingling compounds and thus using products that have a guaranteed alkylamide content, wherever possible.

Echinacea extracts have also been shown to modulate endogenous cannabinoid receptors, and alkylamides have again been strongly associated with these effects^(13-14). As with research into the anti-inflammatory properties of Echinacea, recent studies support potential applications for peripheral inflammatory pain such as arthritis and burns, again reflecting the traditional uses of these plants by indigenous north Americans. Other investigations have found Echinacea purpurea root extracts to improve insulin resistance, enhance glucose uptake in adipocytes and activate peroxisome proliferator-activated receptor γ, with alkylamides being contributory^{(15, 16)}.

The complex interactions of bacteria and fungi (endophytes) living symbiotically with Echinacea in its natural state, and their possible modulation of the gut microbiome, is another new area of investigation^{(17, 18)}.

Receptor binding studies involving both crude plant extracts and phytochemically-rich fractions or individual phytochemicals, will continue to reveal more about mechanism(s) of action of our medicinal plants in the future, as well as inform us about ‘new’ (but often simply forgotten), potential applications in clinical practice.

References

1. Zhao, Q., Luan, X., Zheng, M., Tian, X. H., Zhao, J., Zhang, W. D., & Ma, B. L. Synergistic Mechanisms of Constituents in Herbal Extracts during Intestinal Absorption: Focus on Natural Occurring Nanoparticles. Pharmaceutics, 2020;12(2), 128.
2. Coelho, J., Barros, L., Dias, M. I., Finimundy, T. C., Amaral, J. S., Alves, M. J., Calhelha, R. C., Santos, P. F., & Ferreira, I. C. F. R. (2020). Echinacea purpurea (L.) Moench: Chemical Characterization and Bioactivity of Its Extracts and Fractions. Pharmaceuticals (Basel, Switzerland), 13(6), 125.
3. Dietz B, Heilmann J, Bauer R. Absorption of dodeca-2E,4E,8Z,10E/Z-tetraenoic acid isobutylamides after oral application of Echinacea purpurea tincture. Planta Med. 2001;67(9):863-864. 
4. Goel V, Chang C, Slama JV, et al. Alkylamides of Echinacea purpurea stimulate alveolar macrophage function in normal rats. Int Immunopharmacol. 2002;2(2-3):381-38.
5. Jager H, Meinel L, Dietz B, et al. Transport of alkamides from Echinacea species through Caco-2 monolayers. Planta Med. 2002;68(5):469-471.
6. Stevenson LM, Matthias A, Banbury L, et al. Modulation of macrophage immune responses by Echinacea. Molecules. 2005;10(10):1279-1285. 
7. Bauer R, Remiger P. TLC and HPLC Analysis of Alkamides in Echinacea Drugs1,2. Planta Med. 1989;55(4):367-371.Qu L, Chen Y, Wang X, Scalzo R, Davis JM. Patterns of Variation in Alkamides and Cichoric Acid in Roots and Aboveground Parts of Echinacea purpurea (L.) Moench. HortScience. 2005;40(5):1239-1242.
8. Woelkart K, Koidl C, Grisold A, et al. Bioavailability and pharmacokinetics of alkamides from the roots of Echinacea angustifolia in humans. J Clin Pharmacol. 2005;45(6):683-689.
9. Gulledge TV, Collette NM, Mackey E, et al. Mast cell degranulation and calcium influx are inhibited by an Echinacea purpurea extract and the alkylamide dodeca-2E,4E-dienoic acid isobutylamide. J Ethnopharmacol. 2018;212:166-174. 
10. LaLone CA, Rizshsky L, Hammer KD, et al. Endogenous levels of Echinacea alkylamides and ketones are important contributors to the inhibition of prostaglandin E2 and nitric oxide production in cultured macrophages. J Agric Food Chem. 2009;57(19):8820-8830.
11. Vieira SF, Gonçalves VMF, Llaguno CP, et al. On the Bioactivity of Echinacea purpurea Extracts to Modulate the Production of Inflammatory Mediators. Int J Mol Sci. 2022;23(21):13616.
12. Rasmussen PL, Effects of Echinacea on virus induced Cytokines. Phytonews 24, 2006,Feb. Published by Phytomed Medicinal Herbs Ltd, Auckland, New Zealand. ISSN 1175-0251.
13. Liu R, Caram-Salas NL, Li W, Wang L, Arnason JT, Harris CS. Interactions of Echinacea spp. Root Extracts and Alkylamides With the Endocannabinoid System and Peripheral Inflammatory Pain. Front Pharmacol. 2021;12:651292.
14. Gholami M, Amri J, Pazhoohan S, Sadegh M. Anticonvulsive and anti-epileptogenesis effects of Echinacea purpurea root extract, an involvement of CB2 receptor. J Complement Integr Med. 2021;19(4):879-886.
15. Kotowska, D., El-Houri, R. B., Borkowski, K., Petersen, R. K., Fretté, X. C., Wolber, G., Grevsen, K., Christensen, K. B., Christensen, L. P., & Kristiansen, K. (2014). Isomeric C12-alkamides from the roots of Echinacea purpurea improve basal and insulin-dependent glucose uptake in 3T3-L1 adipocytes. Planta medica, 80(18), 1712–1720.
16. Choi, K. M., Kim, W., Hong, J. T., & Yoo, H. S. (2017). Dodeca-2(E),4(E)-dienoic acid isobutylamide enhances glucose uptake in 3T3-L1 cells via activation of Akt signaling. Molecular and cellular biochemistry, 426(1-2), 9–15. 
17. Todd DA, Gulledge TV, Britton ER, et al. Ethanolic Echinacea purpurea Extracts Contain a Mixture of Cytokine-Suppressive and Cytokine-Inducing Compounds, Including Some That Originate from Endophytic Bacteria. PLoS One. 2015;10(5):e0124276. 
18. Maggini, V., Bettini, P. P., Fani, R., Firenzuoli, F., & Bogani, P. (2023). Echinacea purpurea microbiota: bacterial-fungal interactions and the interplay with host and non-host plant species in vitro dual culture. Plant biology (Stuttgart, Germany), 25(2), 246–256.Gerstmeier J, Seegers J, Witt F, et al. Ginkgolic Acid is a Multi-Target Inhibitor of Key Enzymes in Pro-Inflammatory Lipid Mediator Biosynthesis. Front Pharmacol. 2019;10:797.