Immunomodulatory and Anti-Inflammatory Actions of Berberine-Containing Herbs
Abstract
Sustainability of commonly employed medicinal plants is becoming a global concern, heightened by shortages imposed during the current pandemic. Berberine-containing plants are found broadly in nature, present across several families of plants and potentially cultivated almost anywhere in the world. Research in berberine has exploded in recent years, leaving a well-developed body of good quality evidence demonstrating a wide array of important clinical outcomes across a broad spectrum of applications. This review will showcase important roles of berberine from both modern research and traditional herbal systems of medicine. The review will also raise important concepts relating to herbal medicine sustainability and demonstrate that berberine ranks very high when considering environmental stewardship while seeking safe and effective herbal medicines.
Introduction
With the prevalence of chronic disease and inflammation on the rise, we have seen a boom in natural anti-inflammatory treatments. The most renowned anti-inflammatory treatment is Curcuma longa (turmeric), a bright yellow rhizome that is native to India and southeast Asia. Modern research has highlighted curcumin, a constituent in turmeric, as an anti-inflammatory agent and it has been well-studied in multiple inflammatory conditions such as autoimmune diseases and cancer (White et al 2019). Curcuma is in high demand worldwide and is sourced commercially almost exclusively from its native areas (Schippmann et al 2002). Recently (2020- current) we have seen wide scale disruptions in supply chains and the ability to import products such as Curcuma ethically and consistently. Concerns around environmental impacts and sustainability of mono cultivation, as well as quality of large-scale commercially grown crops and a growing interest in bio-regional herbalism have recently come to prominence. This creates a need to identify more anti-inflammatory herbs that are local to practitioners’ areas (Schippmann et al 2002). Turmeric’s traditional use is for digestive conditions such as gallstones, jaundice, colic and flatulence, and blood sugar support. It has also traditionally been used as an anti-inflammatory for arthritis, menstrual pains, and topically for skin issues such as eczema (Khalsa and Tierra 2008, Tierra 1988). In looking for North American herbs with a similar traditional profile to turmeric we find Mahonia aquifolium (Oregon Grape root) and Hydrastis canadensis (Goldenseal).
Mahonia and Hydrastis, native to western and eastern North America respectively, also have bright yellow rhizomes and have very similar traditional uses to Curcuma (see below). The main identified constituent in these two plants is berberine. Berberine is an isoquinoline alkaloid found in many different herbs across multiple continents and plant families. Berberine-containing herbs are commonly known as digestive tonics, bitter stimulants, anti-microbials and immune stimulants (Yarnell 2004). Some of the more commonly known herbs include: the Berberidaceae family – Berberis spp. (Barberry) found in Europe, the Middle East and India and Mahonia in North America; the Annonancea family – Annickia chlorantha (African whitewood) in west Africa; the Papaveraceae family – Argemone mexicana (Prickly Poppy) in Mexico and Chelidonium majus (Celandine poppy) from Europe and western Asia; the Ranunculaceae – Coptis chinensis (Chinese goldthread) from China and Hydrastis in North America; and the Rutacea – Phellodendron spp. (cork tree) in eastern Asia to Japan (Ehteshamfar et al 2020). This widespread cultivation range and diversity of berberine-containing herbs makes them a sustainable and locally sourced choice for herbal treatment worldwide.
Traditional Usage of Berberine-Containing Herbs
Most berberine-containing herbs are traditionally used for liver, gallbladder, and metabolic support, as well as a gastrointestinal and dermatological anti-microbial (Ehteshamfar et al 2020, Wood 2008, Wood 2009).
Multiple plants have specific anti-inflammatory and immune related traditional uses as well, such as:
European herbs Chelidonium for migraines, myalgias and abdominal cancer; and Berberis spp for chronic inflammation, throat and tonsil swelling/inflammation/infection, eczema and psoriasis and acute and chronic infection.
North American herbs Hydrastis for insulin resistance, colitis, cystitis, and multiple inflammatory skin conditions and Mahonia for allergies, Crohn’s disease, psoriasis, and both osteo and rheumatoid arthritis (Wood 2009).
The Chinese herb Coptis for acute and chronic inflammation and infection, gynecological, and urinary inflammation and abscess, boils, and burns (Bown 1995, Buhner 2012).
Indian barberry, Berberis aristata (Tree turmeric) for spleen inflammation, fever, bacterial infections, and gallbladder inflammation (Khalsa and Tierra 2008).
The current evidence base has broad support for berberine use in certain conditions. Berberine has been well studied for its metabolic effects and is commonly used in treatment of diabetes, hyperlipidemia, and other metabolic conditions (Ye et al 2021). Additional research has been done on its effect on metabolic and inflammatory pathways in patients with polycystic ovarian syndrome (PCOS) (Kuang et al 2020). Its antimicrobial actions have been seen with a plethora of different microbes from streptococcus spp to Treponema pallidum (syphilis) to Giardiasis and other amoebas and parasites (Buhner 2012, Kane 2017, Wood 2009).
Inflammatory Outline
Chronic inflammation can arise through multiple pathways. The main causes of chronic inflammation include persistent pathogens, auto immune reactions, and foreign bodies (Beg et al 2011). Chronic inflammation can also be initiated by an unresolved episode of acute inflammation (Hall 2011). Acute inflammation is the response to cellular or vascular injury from trauma or invasion of pathogens. Acute inflammation includes many different cell types including endothelial cells, macrophages, and signaling and stimulating factors. Most notable of these factors are the pro-inflammatory cytokines Interluekin-1 (IL-1), tumor necrosis factor (TNF), and IL-6 (Chapel et al 2008). Chronic inflammation can also arise from persistent infections, hypersensitivity reactions, allergens, and exposure to toxic agents (Kumar et al 2015). The body’s attempts to resolve or remove the insulting factor leads to continuous signaling of the inflammatory cascade and increased immune reaction intensity. This over-abundance of the immune response can then lead to significant tissue damage. Macrophages are key cells in chronic inflammation, releasing products such as reactive oxygen species (ROS) and transforming growth factor beta (TGF-β). Activated macrophages release TNF, IL-1, and other cytokines, drawing more cells to the affected area. T cells are stimulated by the macrophage response and the produced cytokines, in particular IL-12. Activated T cells release TNF, IL-17, and other cytokines to recruit macrophages and interferon gamma (IFN-γ) which activates them. In many conditions, especially auto immune conditions, different subsets of T cells are known to be highly inflammatory and correlate to disease expression. These include T helper type 1 (Th1) and Th17 in particular with T regulatory cells (Tregs) helping to modulate inflammation (Ehteshamfar et al 2020, Shen et al 2020). While this author recognizes there are multiple other chemical and hormonal factors that can influence inflammatory states, they are outside the scope of this review. This review will focus on a selection of commonly studied and measured cytokines and immune cells mentioned above.
Metabolic Inflammation
As a metabolic therapeutic, berberine improved dyslipidemia and insulin resistance in multiple human trials (Lan et al 2015, Ye et al 2021). Much of berberine’s effect on glucose uptake is through adenosine monophosphate-activated protein kinase (AMPK). AMPK has antioxidant effects which in turn decrease inflammation (Cicero and Baggioni 2016). IL-6, TNF-α and COX-2 additionally play a large role in diabetes and atherosclerotic pathology (Chang et al 2015, Rui et al 2021). Berberine has been shown to protect endothelial cells by lowering IL-6 and TNF-α and attenuating NF-κB signaling (Rui et al 2021). Berberine has also been shown to inhibit cycoloxygenase-2 (COX-2) activity and prostaglandin E2 (PGE2) activity (Liu et al 2015). Modulation of these inflammatory pathways is additionally enhanced by berberine’s ability to influence monocyte mobility and macrophage activity (Rui et al 2021).
Polycystic Ovary Syndrome (PCOS)
Most berberine and PCOS studies focus on the metabolic markers of PCOS (Rondanelli et al 2020, Xie et al 2019). Berberine alone as a treatment can improve ovulation and menstrual patterns in PCOS patients (Li et al 2015B). A systemic review showed berberine to be superior to metformin treatment for metabolic markers as well as hormone modulation (Xie et al 2019). The pathophysiology of PCOS is far more complex though then just insulin resistance and metabolic changes (Zhang et al 2021). Inflammation in PCOS patients is considered to be chronic and low-grade (Kuang et al 2020). Chronic low-grade inflammation is a pattern seen in multiple forms of chronic disease including obesity, asthma, chronic fatigue, inflammatory bowel disease, and more (Zhong and Shi 2019). The PCOS inflammatory picture is characterized by high levels of leukocytes, IL-6, and increased activation of Th-17 cells (Rudnicka et al 2021, Yang et al 2021). A murine model of PCOS showed widespread anti-inflammatory actions with berberine treatment. Significant decreases in expression of multiple inflammatory markers including TLR4, NF-kB, TNF-α, IL-1, and IL-6 were seen (Shen et al 2021). Not all people with PCOS have global or central adiposity, though those who do have increased inflammatory production from adipose tissues as well (Wawrzkiewicz-Jalowiecka et al 2020). Changes in body composition and visceral fat have been seen which have an anti-inflammatory effect (Wawrzkiewicz-Jalowiecka et al 2020, Wei et al 2012). Treatment with berberine decreased hs-CRP in a small PCOS clinical trial (Cicero et al 2014).
Autoimmune Actions
Berberine has displayed the ability to modulate Th17/Treg responses in multiple autoimmune conditions including rheumatoid arthritis (RA) and experimental colitis, type 1 diabetes, and myocarditis (Shen et al 2020). Berberine’s effects on autoimmune conditions are directed through Th1/Th17 modulation and indirectly through regulation of Tregs, macrophages, and dendritic cells (Ehteshamfar et al 2020). Modulation of Th1 and Th17 responses has been linked to clinical progression and severity of auto immune disease. Decreases in Th1 and Th17 cells reduced levels of pro-inflammatory cytokines and thus decreased autoimmune responses (Ehteshamfar et al 2020). Reduction of these cells in experimental autoimmune myocarditis and colitis showed improvements in respective organ function and decreases in pathophysiology (Li et al 2015A, Liu et al 2016).
Murine models repeatedly show decreases in multiple cytokine pathways and direct decreases in Th1 and Th17 cells with berberine administration (Marinova et al 2000, Yue et al 2017). In rheumatoid arthritis models, berberine extract has demonstrated the ability to decrease the inflammatory cytokines IFN γ, IL-17, and IL-2, suggesting actions on both the humoral and cell mediated immune pathways (Hu et al 2011). Multiple additional immunomodulating actions of berberine in relation to RA have been found including apoptosis, inhibition of NF-κB and dendritic cells, and modulation of macrophages and Th17/Treg cell responses (Shen et al 2020). Berberine has also been shown to suppress TNF-α, IL-6 and MCP-1, decrease levels of PGE2, down regulation of cyclooxygenase-2 (cox-2) and inhibit mitogen-activated protein kinase signaling (Ehteshamfar et al 2020).
For a detailed table of berberine actions on specific tissues see Ehteshamfar et al 2020.
Cancer
A 2022 review by He et al gives a very thorough review of the multiple cancer pathways Coptis and berberine extracts work on across multiple different cancer types (He et al 2022). Some of these actions include reduction of tumor weight in breast, lung and gastric cancer in animal and cell studies (Xu et al 2019). Dose dependent responses were seen in many of the reviewed cancer studies. Cytotoxic effects of Mahonia extracts were seen on breast, pharyngeal, and tongue cancer cells (Petruczynik et al 2019). Berberine is seen to work on multiple molecular pathways in cancer studies, with the key anti-inflammatory pathways seen in breast cancer being decreasing cytokines IL-1β, IL-6, TNF-α, and NF-kB (Karnam et al 2017). Small clinical studies show protection of lung damage from radiation as well as decreases in radiation induced intestinal side effects with berberine administration (Li et al 2010, Liu et al 2008). A study on multiple extracts of Mahonia from different parts of the plant showed many significant results. The root extract, the more traditionally used part of the plant, showed significant modulation of CD8+ T cells and IL-10. Interestingly the extract from green fruits of Mahonia showed a greater effect on TNF-α modulation as well as monocytes and β cells than the traditional root extract (Andreicut et al 2019).
Dermatological Conditions
Berberine shows antimicrobial effects against multiple skin bacteria including Propionibacterium acnes and Staphylococcus spp. (Clark et al 2017). Psoriasis immunopathology includes Th17 lymphocytes and their associated cytokines IL-17a, IL-17F, and IL-22 as well as TNF-α. A topical cream with 10% Mahonia extract has shown significant benefit in multiple clinical trials for psoriasis (Bernstein et al 2006, Janeczek et al 2018). The same topical preparation was significantly beneficial in one study on atopic dermatitis as well. Atopic dermatitis has a Th2 dominant immune profile with IL-4, IL-5, and IL-13 cytokines. (Janeczek et al 2018). This shows a wide breadth of immunomodulation capacity from topical applications.
Return to Traditional Usages – Gastrointestinal Actions and Microbiome Manipulation as Key Immunomodulatory Pathways
We can see that there is a growing evidence base of the multiple immunomodulatory actions of berberine. When we think of the role of herbal medicines in integrative treatment, we must consider their traditional uses in conjunction with the research base. In the case of berberine-containing herbs, this leads us to the digestive tract.
The impact of the gut on the immune system has become widely known in both medicine and the public in recent years. The balance of microorganisms in the gut stimulates or prevents inflammation through multiple pathways. The microbiota of the intestinal tract contains over 1014 microorganisms including bacteria, viruses, fungi, archaea, and protozoans (Lazar et al 2018). Gut microbiota influences the differentiation of T cells into Th1, Th2, Th17, and Treg cells. Secretory immunoglobulin A (IgA) is the first line of immune defense in the gut and its production is stimulated by commensal bacteria. In instances of dysbiosis, the gut’s natural anti-inflammatory and protective immune actions become less effective. This creates room for further pathogenic colonization and opportunistic infections which further imbalance the gut immune system and contribute to inflammation (Beg et al 2011, Lazar et al 2018).
Organisms that increase the permeability of the intestines can create inflammatory conditions. Increased bacterial metabolites being passed through the gut immune cells leads to local and systemic inflammation. Disruption of lipopolysaccharides on gram-negative bacteria, through diet or other organisms, can also increase permeability and thus an increase in immune components like cytokines and macrophages (Al Bander et al 2020).
Berberine has specific action against multiple pathogens including Escherichia coli and enterococci bacteria, and increases beneficial Lactobacilli and Bifidobacteria (Habtemariam 2016). It also remediates intestinal health by acting as an antimicrobial and by repairing the intestinal mucosa (Li et al 2020). Indeed, part of the success of Hydrastis’s action on clearing infectious agents has been attributed to its ability to speed up healing of the affected tissue and restore host cell immune functions (Wood 2009). A 2020 study showed berberine’s ability to up-regulate tight junctions in the intestinal mucosa and suppressed fibrosis and cell infiltration in colon tissues (Li et al 2020).
Short-chain fatty acids (SCFAs), in particular butyrate, have been noted as an anti-inflammatory component in the gut. Well-balanced gut bacteria help break down complex carbohydrates into SCFAs and administration of butyrate improves symptoms in inflammatory GI diseases such as Crohn’s (Al Bander et al 2020). SCFA production from certain bacteria, such as proprionate from Phascolarctobacterium, has been associated with NF-κB and with decreased levels of the acute phase reactant and inflammatory marker C-Reactive protein (Al Bander et al 2020). Oral administration of berberine in rat models has resulted in an increase in butyrate-producing bacteria (Yue et al 2019). This modulation of the intestinal microbial environment helps stabilize physiologic hypoxia in the intestines (Yue et al 2019). A human trial in diabetics showed berberine to change the population of 78 different species of gut microbiota and had improvements in clinical outcomes. In this study probiotics had minimal additional effect on microbiota changes compared to berberine (Zhang et al 2020). Along with the varied actions above, prevention of inflammatory cytokines in colitis with berberine has been well documented in murine models (Kawashima et al 2004, Lee et al 2010, Yan et al 2012, Zhang et al 2011, Zhou and Mineshita 2000). In a murine model of autoimmune uveitis, berberine-induced regulation of T-reg/Th17 cells was associated with changes in microbiota (Du et al 2020). This finding has been repeated in colitis models, with T reg/Th17 modulation being associated with changes in the bacterial balance (Cui et al 2018).
Environmental Considerations
With the current evidence base for berberine and berberine-containing herbs we are seeing it become a more commonly used therapy. Many of the ecological and supply issues of Curcuma can be applied to berberine-containing herbs. Using sustainably grown and wild crafted plants should always be considered when administering herbal medicines. Certain berberine-containing plants have specific ecological considerations.
Coptis is a challenging and low-yield plant to cultivate and is already in high demand. Its agriculture, as with most large-scale monocultures, is having detrimental effects on natural ecology. In the wild most Coptis spp are considered endangered or vulnerable and thus not recommended for wild crafting (Qin 2010).
Wild Hydrastis is a threatened plant in Canada and the United States. The cost of the cultivated plant has increased dramatically in recent years due to its more difficult cultivation and yield as well as demand (UPS 2022). Because of the many varieties of berberine-containing plants, choosing a locally sourced and affordable herb is still manageable. Wild Mahonia for example is very prolific in many parts of western North America and the rhizome can easily be sustainably harvested. With Chelidonium every part of the plant is used which often increases yield and facilities cultivation.
Conclusion
Berberine-containing herbs are found across the globe and have a multitude of actions. Through a combination of modern research and traditional usage we can see that berberine has multiple beneficial immune and inflammatory actions. Its ability to work on multiple pathways and immune cells can be applied to many different health conditions. One of the strongest actions of berberine is in the digestive tract, where it acts directly and in-directly on inflammation. Usage of berberine-containing herbs can improve inflammatory status through specific application to the conditions mentioned above and improve overall health through digestive and metabolic support. Because berberine-containing herbs can be found all over the world and in many different plant families and growing environments, they can be an effective and sustainable medicine choice.
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