CBD and inflammatory bowel disease: not just a gut feeling
IcBD has developed a CBD formulation which could be the answer to inflammatory bowel disease.
In recent years, few topics have been as hot and yet remain as inconclusive as the therapeutic effects of cannabis and its derivatives on a range of conditions. In particular, cannabidiol (CBD) and its effects on many diseases have been the subject of far too many articles. But all we know for certain is that it is not always effective; nor is it always safe. One of the conditions where we believe CBD could be the answer is Inflammatory Bowel Disease (IBD).
Based on promising findings in our initial research efforts, we founded IcBD, with the belief that for millions of patients around the world with colon-related problems, it is time to find out what really does and doesn’t work.
IcBD is led by the senior team that founded Talent Biotechs (acquired by Kalytera Therapeutics), Stero, CannaLean, and CannaMore. David Bassa, CEO, a successful serial entrepreneur, twice recipient of the President of Israel’s Excellence Award; Dr Sari Prutchi Sagiv (yours truly), PhD, CSO with vast experience in biotech and cannabis companies and Director of Tech Transfer at MOR RESEARCH Ltd, the tech transfer arm of Clalit Health Services, the world’s second largest HMO, boasting more than five million patients, 9,000 physicians, and 14 hospitals. MOR manages the process of finding new indications and commercialising the ideas and inventions conceived at Clalit, benefiting researchers, industry partners, and the public at large. The team is completed by Dr Timna Naftali, PI and Senior Medical Advisor, a Specialist in Gastroenterology, Senior Physician at Meir Medical Center, as well as a pioneer and key opinion leader in the field of cannabis as treatment for IBD, who has conducted and published many preclinical and clinical studies in the field.
We have taken a novel, multi-pronged, topical route. Applied locally in combination with a number of other compounds, CBD could be the definitive answer to IBD issues ranging from serious discomfort, impairments to leading an active life; and in extreme cases, even death.
In our new CBD topical patent protected enema formulation, CBD acts synergistically with various additional compounds for several indications where reducing inflammation, restoring the colon epithelial barrier function, controlling diarrhoea and improving microbiome stability are crucial.
There is no lack of literature about CBD potentially treating colon dysfunctions, but there is very little methodical scientific research and conclusive proof, as we examine below.
Inflammatory bowel diseases include Crohn’s disease (CD) and ulcerative colitis (UC). Both are chronic, often disabling and occasionally life threatening. They require constant care and sometimes surgery.
Three interdependent elements determine IBD pathophysiology: intestinal microbiome; barrier function; and immune system. Dysfunction in any one of them (dysbiosis, leaky gut, and inflammation, respectively) can bring on or exacerbate IBD.
What is new in our proposition, in comparison to previous work in this area, is that we believe CBD alone is not as potent as other cannabinoids or as CBD could be in combination with other compounds, working in tandem to regulate and re-stabilise all three axes. We have therefore initiated preclinical and clinical trials to evaluate the safety and efficacy of a new, multi-directional approach, hoping to make significant inroads into helping these patients.
Our efforts are currently focused on ulcerative colitis, a condition that causes mucosal inflammation in the colon.
A close look at the IBD trio
The immunological reactions, epithelial mucus barrier and microbiome that keep the colon healthy work together, maintaining a delicate balance in the gastrointestinal tract. When one or more of these functions is disrupted and the body cannot regulate them on its own, disease sets in: the intestinal microbiome is altered for a long time or permanently (dysbiosis); the barrier function is damaged (leaky gut); and the immune system is activated (inflammation). The three are mutually dependent.
Many genetic and environmental factors determine the health of the mucosal barrier, epithelial cells and tight junctions which separate the microbiome from the immune system. When this barrier breaks down, gastrointestinal organisms translocate and trigger the immune system, resulting in inflammation. This in turn causes further damage to the mucosal barrier.
Most current IBD therapies target only one of these phenomena: inflammation. But many IBD patients do not respond to immuno-modulating therapies, which has led us to explore new approaches targeting the microbiome and the barrier function simultaneously.
The basics of UC
Ulcerative colitis, a chronic relapsing-remitting IBD of the colon, involves a superficial mucosal inflammation extending from the rectum to the more proximal colon, to varying degrees. Patients may exhibit symptoms such as bloody diarrhoea (with or without mucus), rectal urgency, frequent evacuation, and abdominal pain. Some patients may also have constipation. Many patients also experience serious involuntary weight loss or anaemia. Random attacks come and go with increasing frequency, some leading even to hospitalisation. Proper diagnosis requires endoscopy and biopsy. Although the debate on what causes UC is still raging, increasing evidence suggests it may be an autoimmune condition.
Incidence and prevalence of IBD are higher in developed countries, in colder climates and in urban regions. Internationally, UC incidence ranges from 0.1 to 16 cases per 100,000 persons per year. Prevalence rates are around 249 per 100,000 persons in North America and 505 per 100,000 persons in Europe, with no significant gender differences. Racial differences observed can be mostly attributed to environmental influences, food habits and lifestyle rather than genetics. Age-wise, UC peaks in the second and third decades of life; and peaks again between the ages of 50 and 80.
The gut microbiome is a vast, microscopic ecosystem made up of trillions of microorganisms. These little creatures are essential to keeping us healthy: their multiple roles include helping us metabolise foods and drugs, develop our intestinal epithelium, and develop and modulate our immune system. They even protect us from infections. If we are lucky enough to have a healthy microbiota from an early age, many environmental factors will need to act together in order to create long term clinical issues. Surprisingly, besides IBD, irritable bowel syndrome, and enteric infections, many other seemingly unrelated conditions are associated with changes in the microbiome, including neuropsychiatric and atopic diseases, asthma, obesity and colorectal cancer.
In patients with UC, the mucus layers become thinner or disappear, while the goblet cells which should protect them are depleted. Some of the microbiota involved in IBD use mucus as an energy source, regulating its production, so that changes in mucus may be the cause and the result of dysbiosis. Microbes translocating beyond the mucosal surface can also be responsible for stimulating the immune system (endotoxemia).
The barrier function of the epithelium
The intestinal mucosal barrier separates the microbiota, food, and other contents inside the intestine from the immune system. The network of proteins called tight junctions connecting epithelial cells, show increased permeability in IBD, which can trigger further inflammation.
The immune system plays a critical role in the development of IBD and it is likely that invading microorganisms trigger inflammation by stimulating various components of the immune system, by releasing inflammatory cytokines and recruiting phagocytic cells, among others.
In order to treat IBD, both immune-based and – to a lesser extent and with varying results – microbiota-based therapies have been tried and used. Other therapies have used antibiotics, probiotics, or faecal microbiota transplantation, all yielding mixed results. Special diets and/or dietary supplements have shown positive results in some cases.
Barrier function-based therapies to restore the integrity of the mucosal barrier seem promising, and this is partially achieved also through immune-based and microbiome-based alternatives. Treatments with natural products such as turmeric are used by natural practitioners in treating IBD; and could possibly also influence tight junctions.
All these directions have been tried and are still being investigated, as we begin to develop an understanding of what influences the three factors and how they influence each other.
Read full CBD and inflammatory bowel disease: not just a gut feeling by Dr Sari Prutchi Sagiv PhD.