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These evidence-based botanical medicines proven to induce or maintain remission in the debilitating inflammatory bowel disease known as Crohn’s offer hope to those resigned to a fate of life-altering immunosuppressive drugs or surgery.
Inflammatory bowel disease (IBD), which is subdivided into ulcerative colitis and Crohn’s disease, afflicts 1.4 million Americans and typically first appears between the ages of 15 and 30 (1). Whereas ulcerative colitis is more distal, affecting the rectum and spreading upwards toward the descending and transverse colon in an uninterrupted fashion, Crohn’s disease typically involves the ileum and colon and can affect any part of the digestive tract, often in a discontinuous pattern characterized by skip lesions (2).
In ulcerative colitis, inflammation is generally circumscribed to the mucosa, whereas inflammation can navigate down intestinal crypts, becoming transmural or penetrating the entire depth of the intestinal wall in Crohn’s disease (2). Due to this disparity, Crohn’s disease can ulcerate through the layers of the bowel into the mesentery, leading to complications such fibrosis or scarring of tissue that leads to strictures or perforations, as well as intestinal granulomas and fistulas (2). Fever, diarrhea, abdominal pain, rectal bleeding, and weight loss are hallmark symptoms.
Although risk is multifactorial, there is a prominent genetic predisposition, with first-degree relatives having a 12 to 15 times elevated risk of developing Crohn’s disease (3). Cesarean section delivery, smoking, early life antibiotic use, low fiber intake, and use of oral contraceptives and non-steroidal anti-inflammatory drugs (NSAIDS) are all correlated with risk of Crohn’s disease (4, 5, 6, 7, 8). Ultraviolet sun exposure is protective, as exhibited by marked a latitudinal gradient for IBD-related hospitalizations whereby northern states have significantly more admissions (9, 10).
Not only is microbial dysbiosis fundamental to IBD, but “Accumulating evidence suggests that inflammatory bowel disease results from an inappropriate inflammatory response to intestinal microbes in a genetically susceptible host” (2, p. 2006). Viruses from the herpes family, including Epstein Barr Virus (EBV), cytomegalovirus (CMV), and human herpes virus 6 (HHV) likewise occur at a higher prevalence in IBD and may play a role in its pathogenesis (11).
Crohn’s and colitis have different clinical features, but both exhibit a relapsing and remitting course, and both represent autoimmune pathologies of the gut. Because the disease etiology is autoimmune in nature, people with IBD are at increased risk for other autoimmune disorders including psoriasis, ankylosing spondylitis, and primary sclerosing cholangitis (12). Although standards of care, such as corticosteroids, antibiotics, biologics, and immunosuppressive pharmaceutical drugs are fraught with life-threatening side effects, there are evidence-based natural substances that can be used as adjunctive therapies alongside a holistic regimen that includes an anti-inflammatory diet, stress management, social support, physical activity, and sleep hygiene. This review will emphasize selected therapies with empirical evidence in Crohn’s disease, with a focus on human trials.
Although glutamine is not an herb, its prolific evidence-base renders it worthy of inclusion. In Crohn’s disease, the main objective of treatment is healing the mucosal lining of the gut, which is associated with reduced disease activity, elongated duration of remission, and decreased requirement for surgical resection of the bowel (13). Reversing the pathologic paracellular intestinal permeability, colloquially known as leaky gut syndrome, will not only arrest Crohn’s disease processes, but it will also mitigate risk of future autoimmune diagnoses since gut barrier integrity precludes the ability of immunogenic material and foreign antigens to translocate into systemic circulation and incite self-directed autoimmune responses (14).
According to researchers, “Glutamine is presently the best known compound for reducing intestinal permeability (IP)” (15). Glutamine is considered a conditionally essential amino acid in the critically ill, meaning that, during periods of severe metabolic stress, the ability to synthesize sufficient quantities of glutamine is exceeded by the body’s requirements for glutamine (16). Glutamine speeds healing of damaged enterocytes (intestinal cells) and improves mucosal barrier integrity, as it is the preferred respiratory fuel over glucose for rapidly dividing cells (17). Not only does it enhance the rate of cellular renewal or turnover, but it also prevents cell death, or apoptosis, associated with cellular stress (17).
Glutamine has been shown to reduce infection frequency following abdominal surgery, shorten hospital stay, enhance long-term survival, and improve intestinal barrier function in malnourished children, critically ill patients with multi-trauma or multi-organ failure, premature neonates, disorders of ischemia/reperfusion, bone marrow transplantation, and experimental biliary obstruction (18, 19, 20, 21, 22, 23). Moreover, glutamine supplementation protects the gut during recovery from high-intensity exercise, which has been demonstrated to induce transient leaky gut (24).
Glutamine likewise maintains transepithelial resistance, or the electrical voltage across epithelial cell barriers required for proper cell communication, and reduces permeability in cell culture in vitro studies of intestinal cells (25). In a randomized clinical trial of Crohn’s subjects in remission, L-glutamine administered at 0.5 grams per kilogram of ideal body weight per day for two months normalized intestinal permeability in 57% of subjects, and also significantly improved the intestinal villous-crypt ratio, a marker of intestinal architecture which is blunted in Crohn’s (26).
An evergreen shrub native to the Mediterranean called Pistacia lentiscus var. Chia (Anacardiaceae), also known as Chios mastic gum, has been revered for its therapeutic effects in the liver, stomach, and intestines since ancient Greek and Roman times (27). Oleanolic acid, a triterpene within mastic gum, exerts anti-inflammatory and anti-cancer effects and prevents chemical-induced hepatotoxicity in animal models (28). Mastic gum additionally possesses antiatherogenic, antioxidant, antibacterial, and anti-ulcer effects (29, 30, 31).
In a four week pilot study of patients with mild to moderately active Crohn’s disease, patients received six capsules a day of mastic gum, with each capsule containing 0.37 grams (27). Compared to baseline, Crohn’s Disease Activity Index (CDAI) was significantly decreased post-treatment alongside significant increases in total antioxidant potential (TAP), presumably due to the triterpene and phenolic compounds contained in mastic gum (29). Increases in TAP result in improved capacity to neutralize the oxidative stress and inflammation that promote Crohn’s disease pathogenesis (27).
Likewise, post-treatment, patients exhibited significant decreases in interleukin-6 (IL-6), a pro-inflammatory intercellular signaling molecule that recruits other immune cells, and plays “a pivotal role in induction and amplification of the inflammatory cascade” (27, p. 748). IL-6 similarly incites production of inflammatory acute phase reactants from the liver, and promotes differentiation and proliferation of T cells and B cells, lymphocytes which perpetuate the disease process (32, 33).
C-reactive protein (CRP), an acute phase reactant that is a surrogate marker for systemic inflammation, was also significantly decreased after mastic gum treatment (27). A trend towards decreases in monocyte chemotactic protein 1 (MCP-1), a chemical messenger which incites macrophages, a subset of immune cells, to migrate to the site of inflammation and infiltrate tissue, was also observed in Crohn’s patients after the trial (27, 34). Lastly, there was a pattern towards improvement in the Nutritional Risk Index (NRI) in Crohn’s patients after the mastic gum intervention, mainly due to body weight gain (27). Researchers attribute this to a decrease in liquid stool frequency due to mastic gum supplementation, which resulted in better nutrient absorption (27).
Boswellia serrata, known in India as salai guggal, is a staple of Ayurvedic medicine that is referenced in texts such as the Charaka Samhita from the first to second century AD and the Astangahrdaya Samhita from the seventh century AD (35). Extracts of its oleo gum resin contain active constituents called boswellic acids, such as 11-keto-β-boswellic acid (KBA) and acetyl-11-keto-β-boswellic acid (AKBA), which are classified as pentacyclic triterpenes (36).
Boswellic acids down-regulate the expression of pro-inflammatory signaling molecules such as interleukin (IL)-1 IL-2, IL-4, IL-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α (35). They likewise inhibit activation of nuclear factor kappa beta (NFκB), a transcription factor that leads to downstream inflammatory cascades (35). Boswellic acids additionally inhibit the formation of reactive oxygen species (ROS), and proteases such as elastase, which play a destructive role in autoimmune disease (35). Thus, boswellia has shown promise in chronic inflammatory disorders, including osteoarthritis, bronchial asthma, rheumatoid arthritis, and inflammatory bowel disease (35).
One randomized, double-blind, placebo-controlled trial of patents with active Crohn’s disease compared 3.6 grams per day of Boswellia serrata extract H15 to mesalazine (37). Both interventions elicited significant decreases in Crohn’s Disease Activity Index (CDAI) and statistical analyses concluded that boswellia had equivalent efficacy to mesalazine (37). Because boswellia was better tolerated, the researchers concluded, “Considering both safety and efficacy of Boswellia serrata extract H15 it appears to be superior over mesalazine in terms of a benefit-risk-evaluation” (37, p. 11).
Medicinal, sociocultural, and psychospiritual use of marijuana, which dates as far back as 2737 BCE by the Chinese, has been intimately woven into the fabric of human ritual (38). Δ9-tetrahydrocannabinol (THC), the best studied psychoactive cannabinoid within cannabis, induces euphoria, relaxation, and modified sensory perception, whereas cannabidiol (CBD) acts peripherally, exerting antipsychotic, analgesic, anti-seizure, anti-anxiety, and anti-inflammatory effects (39). Activation of cannabinoid receptors, which are distributed throughout the nervous system, immune system, and hematopoietic system, are closely tied to diverse functions including memory, cognition, appetite, stress, motivation, and reward, which accounts for their far-reaching therapeutic effects (40, 41). In addition to its applications in cachexia, muscle spasticity, and chronic pain, autoimmune disorders such as Crohn’s disease represent another
promising arena for use of cannabis (38).
Initial evidence of the efficacy of marijuana in IBD comes from animal studies. Mouse models have demonstrated that activation of cannabinoid receptors in the colon ameliorates symptoms and histological damage in IBD, and that prolonging the half-life of endogenous cannabinoids confers significant protection against 2,4-dinitrobenzene sulfonic acid (DNBS)-induced Crohn’s (42, 43, 44).
Impressively, in a randomized, double-blind, placebo-controlled clinical trial of Crohn’s patients whose symptoms were resistant to steroids, immunomodulators, and anti-tumor necrosis factor-alpha agents, THC-rich cannabis induced complete remission in 45% of subjects compared to 10% who received placebo (45). Further, a significant decrease in the Crohn's Disease Activity Index (CDAI) was witnessed in 90% of those in the cannabis group versus 40% of controls (45). In addition to improvements in sleep and appetite, three patients in the THC group were able to taper off of steroid therapy (45). Although this study used marijuana cigarettes containing 115mg of Δ9-tetrahydrocannabinol (THC), cannabis-containing baked goods, tinctures, sprays, teas, oils, and lozenges would circumvent exposure to combustion byproducts and prevent any smoking-associated deleterious health outcomes.
The large-leafed herb Curcuma longa is known as the culinary spice turmeric or Indian saffron (46). Belonging to the ginger family, turmeric is revered in the cuisines of China, India, Iran, Malaysia, Polynesia, and Thailand, but has also been used in traditional Chinese and Ayurvedic medicine for stress, mood disorders, dermatologic diseases, and infection (Kocaadam & Sanlier, 2017). Curcumin is a natural lipophilic polyphenol that is the primary pigment and active constituent within turmeric, acquired from the rhizome of the herb. Research has discovered numerous beneficial effects of curcumin, including antimicrobial, antioxidant, anti-inflammatory, cholesterol-lowering, anticancer, pro-apoptotic, and antiplatelet properties (46). Given its expansive therapeutic profile, curcumin has proven applications in diabetes as well as autoimmune, cardiovascular, and neurological disorders (47).
In an open label study, curcumin was administered to five patients with Crohn’s disease and five patients with proctitis, a mild form of ulcerative colitis (48). Crohn’s patients received 360 milligrams of curcumin three times a day for one month, followed by the same dosage administered four times a day for two months (48). The dosing schedule for proctitis patients was 550 mg of curcumin twice daily for one month, followed by 550 mg three times daily for another month (48).
In 80% of subjects in both groups, curcumin reduced the inflammatory response (48). Improvements were observed in all proctitis patients, with two terminating their 5-aminosalicylic acid (5-ASA) medications, two reducing medication dosages, and one eliminating their prednisone therapy (48). Indices of inflammation, including erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), reverted to the normal range after the study (48). In Crohn’s patients, the Crohn's Disease Activity Index (CDAI) fell by an average of 55 points, and reductions in ESR and CRP were also observed (48).
Another double-blind, placebo-controlled, randomized study of patients with mild-to-moderate ulcerative colitis that was uncontrolled despite full-dose mesalamine therapy revealed that 3 grams of curcumin per day reduced mucosal inflammation and induced clinical remission in 53.8% of patients relative to 0% of controls (49). A six month study of quiescent colitis similarly showed that 1 gram of curcumin twice daily plus sulfasalazine (SZ) or mesalamine was superior to these drugs alone in maintaining remission (50).
The therapeutic efficacy of curcumin in IBD is reinforced by animal colitis models, where curcumin inhibits development of colitis induced by chemical agents such as trinitrobenzene sulfuric acid or dinitrobenzene sulfuric acid (DNB) (51, 52). Curcumin may attenuate IBD by suppressing stimulation of NFκB, a transcription factor integral to the production of pro-inflammatory signals such as chemokines and cytokines (Sahl et al., 2003). Likewise, curcumin may mediate immunosuppressive effects by inhibiting activation and infiltration of lymphocytes, or white blood cells, into tissue (48).
Use of Artemisia absinthium, or wormwood, dates back to the Ebers Papyrus, the oldest preserved medical document which is theorized to be a reproduction of the Thoth from 3500 BC (53). Wormwood is referenced several times in the bible and in the opus Historia Naturalis by Roman scholar Pliny the Elder (53). Wormwood was used as an antihelmintic by the ancient Egyptians, and by the ancient Greek physician Hippocrates for rheumatism and menstrual pain (53). Researchers note, “In the Middle Ages, wormwood was used as a purge and vermifuge, and it developed towards a “general remedy for all diseases” and was referred to as “a herb of Mars” for its overarching medical powers” (53). Contemporary studies have also elucidated neuroprotective and heptatoprotective actions of wormwood (54, 55).
In a double-blind, randomized, placebo-controlled trial of patients with active Crohn’s disease, patients in the intervention arm received 500 mg of wormwood three times a day (Omer et al., 2007). In addition to taking medications such as 5-ASA, methotrexate, or azathioprine, all Crohn’s subjects were on a stable dose of prednisone when the study commenced, and underwent a defined tapering schedule two weeks into the trial such that all patient patients were steroid-free after ten weeks (11).
In the wormwood group, 90% of subjects exhibited steady improvement despite the continuous steroid taper, as indicated by their scores on the Crohn's Disease Activity Index (CDAI) questionnaire, an Inflammatory Bowel Disease Questionnaire (IBDQ), and an 8-item Visual Analogue Scale (VA-Scale) (11). In addition, wormwood improved scores on the 21-item Hamilton Depression Scale (HAMD), indicating that it elicited benefits in the domains of mood and quality of life (11). 65% of patients in the wormwood group achieved near complete resolution of symptoms by the eighth week, which remained throughout the entirety of the observation period up to week twenty without any need for steroids (11). In contrast, none of the placebo group achieved remission, and the condition of controls progressively deteriorated with the omission of steroids, prompting steroids to be re-introduced in 80% of cases after week ten (11).
In another open label trial of patients with active Crohn’s disease receiving conventional medications, patients were randomly allocated to receive 750 milligrams of dried wormwood powder three times a day or placebo for six weeks (56). Average CDAI scores fell by an average of 100 points, and 80% of patients in the wormwood group entered clinical remission compared to only 20% of controls (56). Wormwood also led to significant improvements in the HAD and IBDQ scales (56).
Likewise, significant reductions in levels of tumor necrosis factor (TNF)-α, an inflammatory cytokine that is elevated in active Crohn’s disease, occurred in the wormwood group (56, 57). TNF-α is considered to be intrinsic to the inflammatory response in Crohn’s, so much so that newer generation monoclonal antibody drugs such as infliximab (Remicade) and adalimumab (Humira) specifically block its effects (58). However, TNF inhibitors are associated with significant side effects, including enhanced susceptibility to infections, cancers, and rare neurologic complications (59). Therefore, wormwood may represent a safe alternative and an interim strategy to attenuate inflammation while embarking upon a root-cause resolution approach to treating Crohn’s disease (56).
Acquiring high quality wormwood is imperative, with a standardization of at least 0.2% absinthin (56). Thujone, thujyl alcohol, and other terpene-derivatives which are particularly concentrated in the essential oil of wormwood pose risk of neurotoxicity and seizures at high doses, so researchers recommend that α- and β-thujones should not exceed five parts per million to be safe for human consumption (56).
Because natural and botanical agents are not patentable, they do not represent profitable commodities and the incentive to conduct elaborate clinical trials is absent. There is little fiscal incentive for pharmaceutical industries, who are beholden to shareholder interests, to invest resources in investigating natural substances for which market exclusivity cannot be granted.
However, given the litany of adverse side effects inherent to conventional pharmacotherapy, using these natural agents alongside other holistic strategies represents a viable alternative to maintain or even induce remission in some cases. More research is needed to elucidate optimal dosing regimens, delivery mechanisms, and efficacy alongside other complementary approaches. But, it is undeniable that herbs have multiple advantages over the toxic xenobiotic cocktails of the biomedical paradigm. In addition to eliciting side benefits rather than the side effects observed with synthetic medications, botanical agents have the benefit of synergistic phytochemical constituents, a proven track record spanning thousands of years of history of use, and quintessentially, biocompatibility with human physiology.
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