Introduction:
Inflammatory bowel disease is a term used to designate two chronic inflammatory gastrointestinal disorders, Crohn’s disease and ulcerative colitis.
Possible Causes:
The reasons why a chronic inflammatory intestinal disease arises are unclear. Crohn’s disease, for example, is attributed to immunological factors, genetic factors such as polygenic transmission, nutritinal factors such as for example the frequent consumption of candy, and also infectious factors such as rotaviruses, non-capsulated myco-bacterial and pseudomanads.
Lack of Short chain fatty acids (SCFA):
SCFAs are normal products of anaerobic bacterial fermentation of carbohydrates in the colon and are the major energy source for the colonic epithelium. Approximately 90% of the total SCFA content in the colon is composed of acetic, propionic, and n-butyric acids. It has been suggested that a lack of luminal SCFAs leads to mucosal atrophy in the short term and nutritional colitis after prolonged periods. This is particularly evident in diversion colitis which develops after diversion of the fecal stream and resolves with restoration of colorectal continuity. SCFA enemas have been shown to be effective in the treatment of diversion colitis: (Wu, US 5,569,680)
Butyrate enemas have been used to reduce inflammation in patients with distal ulcerative colitis. In two studies, butyrate enemas were shown to result in a significant clinical response in patients whose disease did not respond to traditional forms of treatment including use of corticosteroids and 5-amino sali-cylic acid. The potential clinical utility of butyric acid, however, is limited by the apparent difficulty of achieving effective concentrations.
Diagnosis:
The definitive diagnosis of a IDD can frequently succeed only through the chronic course.
Treatment:
Since a causal therapy is not yet possible, the treatment of IIDs like Crohn’s disease and ulcerative colitis is prinicipally aimed at alleviation of the symptoms. The established therapies for IIDs at present are based on unspecific, inflammation inhibiting substances such as glucocorticoids and aminosalicylates.
Remicade (Centocor) is an approved antibody for treating Crohn’s diease.
Specific Diseases:
I. Inflammatory bowel disease (IBD):
Inflammatory bowel disease (IBD) refers to active ulcerative colitis (UC) and active Crohn’s disease (CD). IBD is characterized by excessive and chronic inflammation at various sites in the gastro-intestinal tract. Ulcertaitve colitis and Crohn’s disease are chronic inflammatory disorders of the bowel that fall under the category of IBD.
IB is a collective term used to describe three gastrointestinal disorders of unknown etiology. Cronhn’s disease (CD), ulcerative colitis (UC and indeterminate colitis (IC). (Singh, US Patent Application 16/536,777, published as US 2020/0088749); see also US 10422807)
Despite greater than fifty years of clinical experience with Crohn’s disease and ulcerative olitis, the precise eitology of these diseases remains unknown and the mobidity high (Mannick, US 2004/0077020A1).
A. Types of IBDs
1. Colitis ulcerosa (ulcerative colitis): Ulcerative colitis is a chronic inflammation of the large intestine. This IDD is chacaracterized by ulcerations with mucosal islands remaining between them. The disease encroaches on the small intestine only in rare cases. In ulcerative colitis, only the mucosa is affected, while in Crohn’s disease affects all wall layers and fistulas often form. Most CD patients experience characteristic period of remission and flare-ups of the disease, often requiring long term medication and/or hospitalization and surgery. The symptoms differ depending on what part of the intestinal tract is inflamed. Symptoms include chronic diarrhea, abdominal pain, cramping, anorexia, and weight loss. Systemic features include fatigue, tachycardia and pyrexia. Chronic or acute blood loss in the bowel may result in anemia and even shock. The most common complication of CD is the presence of obstructions of the inestine due to swelling and formation of scar tissue. Another complication involves sores or ulcers within the intestinal tract. Pateitns with CD are also at increased risk of cancer of both the small and alrge intestine (US 2009/0081658).
There is no single definitive test for the diagnosis of CD. Physicians will evaluate a combination of information from the history and physcial examination of a patient and from results of endoscopic, radiologic and histologic (blood and tissue) tests.
–Treatment:
Because there is no cure for DC, the goal of medical treatment is to suppress the inflammatory response and alleviate the symptoms. The FDA advises that a physican reported endoscopic and histological assessmetn and a pateint reported assessment of signs and symptoms should be included as ideal efficacy endpoints for treatment sutides. The agency has advised against use of Mayo Score and Ulcerative Colitis Disease Activity Index measurements when seeking approval. (“Ulerative Colitis: Clinical Trial Endpoints Guidance for Industry, Draft Budiance). Non-surgical treatment for active disease involves the use of anti-inflammatory (aminosalicylates and corticosteroids), antimicrobial, and immunomodulatory agents. The biologic therapies are targeted towards specific disease mechanisms and have the potential to provide more effective and safe treatment.
—-Anti-inflammatory cytokines (recombinant IL-10 and IL-11):
–—Cytokine inhibitors:
——TNF inhibitors such as AbbVie’s Humira. infliximab (Remicade®) is a chimeric monoclona antibody against TNFalpha, and the first biologic therapy that was approved for CD. IL-12/23 inhibitors such as J&Js antibody Stelara. TREMFYA (Guselkumab -J&J): is a monoclonal antibody against interleukin-23 used for the treatment of plaque psoriasis, psoriatic arthritis, and ulcerative colitis.
—-antisense therapies (ICAM-1) are also being evaluated.
—-integrin therapy such as Takeda’s Entyvio
–—sphingosine-1-phosphate receptor inhibitors: Zeposia by Bristol Myers contains an active substance, ozanimod, which blocks the action of sphingosine-1-phosphate receptors on lymphocytes (cells of the immune system that can attack the body’s own tissues in diseases such as multiple sclerosis or ulcerative colitis). By attaching to these receptors, ozanimod stops lymphocytes from travelling from the lymph nodes towards the brain, spinal cord or intestine, thus limiting the damage they cause in multiple sclerosis and ulcerative colitis.
A number of complementary therapies have been shown beneficial for UC. Curcumin, the probiotic VSL#3 and ale ver have all been shown to at least induce a response in ctrolled traisl in pateints with mild UC who are already using mesalmine. (Moss, “Residual inflmmation and ulcerative colitis in remission” Gastroenterology and Hepatology, 10(3), 2014).
II. irritable bowel syndrome (IBS): IBS is a chronic condition that mostly affects people under the age of 50. It does not cause cancer or hurt the gastrointestinal tract, but it can interfere with work, school, social events and daily life. irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD) are not the same. While both can cause digestive issues, IBS is a functional disorder characterized by gastrointestinal symptoms without physical damage to the digestive tract, while IBD is a disease of chronic inflammation that can damage the digestive tract.
IBS is a common condition. Approximately 10% to 15% of the United States population has IBS. The majority of people develop IBS in early adulthood, prior to age 35. Women have been shown to be twice as prone to the disorder than men. IBS is also thought to affect approximately 5% of children between ages 4 and 18. Common symptoms of IBS include abdominal pain, cramping, diarrhea, and constipation. Symptoms of IBS may mimic those of other digestive diseases, like inflammatory bowel disease, celiac disease, or even bowel cancers. Because of this, it’s important to seek the advice of a physician if you are experiencing a change in bowel habits.
The exact cause of IBS is still unknown, but a number of factors may influence why some people are more prone to the condition than others. Physiological factors, genetics, mental health, and food triggers are all thought to potentially play a role.
IBS is not curable, but different treatment options can help manage symptoms. Medical treatment, mental health support, and lifestyle changes are all options that may be explored. Gaining a better understanding of what may be contributing to your symptoms can help you and your health care provider develop a personalized treatment plan. If your symptoms appear to be linked with food triggers, making certain dietary changes may be recommended. If stress is a contributing factor, implementing stress reduction techniques may be your primary focus.
The importance of gut microbiota dysbiosis in IBS is highlighted by the fact that triggers for IBS such as infections, poor sleep, antibiotic use, diet, and stress can affect intestinal microbiota composition. Using machine learning, investigators recently identified a potential microbial signature for severe IBS. Likewise, analyses of fecal metabolomes and microbiomes distinguished IBS from healthy controls suggesting that a microbial signature at the strain level may be present for IBS. In addition, transplantation of fecal microbiota from IBS-D individuals to germ-free mice resulted in alteration in gut function, immune activation and behavior in mice similar to that seen in IBS-D. A number of strategies to modulate gut microbiota in IBS have been proposed, including prebiotics, probiotics, dietary modifications, antibiotics, and recently fecal microbiota transplantation (FMT). See Lembo
III. Crohn’s disease:
Crohn’s is an unspecific granulomatous inflammation which can affect all sections of the digestive tract from the esophagus to the anus, but is mainly present in the region of the lower ileum and the colon. In about 40% of all cases the terminal ileum is exclusively affected, rarely the esophagus and stomach. Crohn’s disease is an inflammatory bowel disease (IBD) in which inflammation extends beyond the inner gut lining and penetrates deeper layers of the intestinal wall of any part of the digestive system (esophagus, stomach, small intestine, large intestine, and/or anus). It is a chronic, lifelong disease which can cuase painful, often life altering symptoms including diarrhea, cramping and rectal bleeding. It occurs most frequently in the industrialized world and the typical age of onset falls into 2 distinct ranges, 15-30 and 60-80 years of age. The highest mortality is during the first years of disease, and in cases wehre the disease symptoms are long lasting, an increased risk of colon cancer is observed. Crohn’s disease account for about 2/3 of IBD-related physician visits and hospitalization, and 50-80% of Crohn’s disease patients eventually require surgical treatment. Development of Crohn’s disease is influenced by environmental and host specific factors, together with exogenous biological factors such as constituents of the intestinal flora. It is believed that in genetically predisposed individuals, exogenous factors such as infectious agents combine with specific environmental factors to cause a chronic state of improperly regulated immune system function. In this model, microorganisms trigger an immune response in the intestine, and in susceptible people, this response is not turned off (US 2010/0081129).
Crohn’s disease is a subacute and chronic inflammation that extends through the intestinal mucosa resulting in the formation of fistulas, fissures and abscesses. Granu lomas occur in 50% of the cases. As the disease advances, the intestinal lumen narrows, causing obstruction. Ulcer ative colitis, a chronic inflammatory disease of the superficial mucosa of the colon affects approximately 500,000 individuals in the United States alone. This disease is characterized by multiple ulcerations and friability of the colonic mucosa associated with diffuse inflammations.
B. Treatment Strategies:
Treatment for patients with IBD includes immunosuppressive and immunomodulating agents such as azathioprine/-mcercaptopurine, methotrexate, tacrolims, and cyclosporine A (CsA). Infliximab which is a chimeric monoclonal antibody targeting tumor necrosis factor alpha has also shown benefit in inducing remission in active CD (Digestive Diseases and Sciences, 47(6), 2002, pp.1362-1368).
–Butyrate & its prodrug Tributyrin:
Tributyrin was initially synthesized during the 1920’s. It is commercially available through a number of chemical distributors including Sigma Chemical Company, St. Louis, Mo. and Aldrich Chemical Company Inc., Milwaukee, Wis. Butyrate enemas have been found to be an effective treatment for ulcerative colitis unresponsive to conventional treatment. However, the utility of these enemas is severely limited due to their intensely unpleasant odor which leads to patients refusing to use the treatment.
Tributyrin is an ester of butyrate, a short chain fatty acid. Short chain fatty acids are normal products of anaerobic bacterial fermentation of carbohydrates in the colon.
(Wu, US 5,569,680) discloses that tributyrin, a prodrug of butyrate which does not have an unpleasant odor, is an even more potent inhibitor of epithelial inflammatory response than sodium butyrate. Wu discloses that tributyrin is a more effective and better tolerated anti-inflammatory agent in the treatment of chronic inflammatory bowel disease. Tributyrin, an apolar and hydrophobic compound, can also penetrate colonic epithelial cells at least as effectively as sodium butyrate, resulting in a 3-fold increase in effect. Wu disloses a method is provided for treating inflammatory bowel disease in a patient which includes administering to a patient an effective amount of tibutyrin.
–alpha4beta7 integrain-neutralizing antibodies:
—-Vedolizumab: is a gut specific, alpha4beta7 integrin neutralizing monoclonal antibodywhich does not affect peripheral blood cell counts and appears to clack systemic effects. Vedloizumab is an anti-inflammatory treatment for the management of therapy refractory patients. (Singh, US Patent Application 16/536,777, published as US 2020/0088749); see also US 10422807)
–IL12p40 nuetralizing antibodies:
—-Ustekimumab (Stelara) is a IL-12p40 monoclonal antibody which is used to treat IBD. Ustekinumab is specific for IL-12 and IL-23 via theri common p40 subunit and blocks inflammation through these pathways. (Singh, US Patent Application 16/536,777, published as US 2020/0088749); see also US 10422807),
Ustekimuab is approved to treat Crohn’s disease in the US and EP, and ulcerative colitis in the US and in the EU to people who have not responded to more traditional treatment. It was not found effective to treat multiple sclerosis. It has also been used to treat psoriasis. It is adminsitered with by intravenous infusion or subcutaneous injection.
–IVIG:
Barstow (US20030099635) discloses treating neurodegenerative diseases by oral administration of immunoglobulin.
Reipert (US2009/0148463) teaches that IVIG have been shown to be effective in the treatmnet of MS.
Tjellstrom (US2002/0114802) discloses a method of treating inflammatory bowel disease (IBD) by orally adminsitering an effective amount of a pooled human polyclonal immunoglboulin preparation.