Inflammatory bowel disease (IBD), including both ulcerative colitis (UC) and Crohn’s disease (CD), emerged and dramatically increased for about a century. Despite extensive research, its cause remains regarded as unknown. About a decade ago, a series of findings made me suspect that saccharin may be a key causative factor for IBD, through its inhibition on gut bacteria and the resultant impaired inactivation of digestive proteases and over digestion of the mucus layer and gut barrier (the Bacteria-Protease-Mucus-Barrier hypothesis). It explained many puzzles in IBD such as its emergence and temporal changes in last century. Recently I further found evidence suggesting sucralose may be also linked to IBD through a similar mechanism as saccharin and have contributed to the recent worldwide increase of IBD. This new hypothesis suggests that UC and CD are just two symptoms of the same morbidity, rather than two different diseases. They are both caused by a weakening in gut barrier and only differ in that UC is mainly due to increased infiltration of gut bacteria and the resultant recruitment of neutrophils and formation of crypt abscess, while CD is mainly due to increased infiltration of antigens and particles from gut lumen and the resultant recruitment of macrophages and formation of granulomas. It explained the delayed appearance but accelerated increase of CD over UC and many other phenomena. This paper aims to provide a detailed description of a unified hypothesis regarding the etiology of IBD, including the cause and mechanism of IBD, as well as the relationship between UC and CD.
As we know, inflammatory bowel disease (IBD) refers to ulcerative colitis (UC) and Crohn’s disease (CD), two highly related debilitating diseases of the digestive tract with similar clinical, pathological, and epidemiological features[1,2]. Although some descriptions in ancient books had been suspected as symptoms of IBD, clustered cases only started to emerge around the end of the 19th century. Right now, IBD has become one of the most common chronic inflammatory conditions only after rheumatoid arthritis, with millions of patients all over the world. It is most prevalent in young adults and remains regarded as incurable, with the patients usually requiring lifelong heavy medication and multiple devastating surgeries like bowel resection, proctocolectomy, ileostomy, and ileal pouch-anal anastomosis, etc.[2,4]. As stated by Dr. Kirsner, “ulcerative colitis and Crohn’s disease today represent two of the more challenging diseases in all of medicine”.
Since its appearance, people had been puzzled by the constant changes of manifestations of IBD in age, gender, ethnic, temporal and geographical distributions[3,5,6]. Great efforts have been taken to find out its cause. Many factors had been suspected, including bacteria such as Bacillus coli, Bacillus proteus,Bacillus pyocyaneus, Bacillus lactis aerogenes, diplostreptococci, dysentery bacillus, Spherophorus necrophorus, Bacillus morgagni, Escherichia coli, spirochetes, Mycobacteria (Mycobacteria tuberculosis, Mycobacteria paratuberculosis and Mycobacteria kansasii), Pseudomonas maltophilia,Bacillus vulgatus, Aerobacter aerogenes, Aerobacter coprococcus, Aerobacter bifidobacteria,Campylobacter fetus ssp. jejuni, Yersinia enterocolitica, and Chlamydia trachomatis, Aeromonas hydrophila, Plesiomonas shigelloides, Edwardsiella tarda, Blastocystis hominis, Bacteroides necrophorum, Bacteroides fragilis, Pseudomonas maltophilia, Helicobacter hepaticus or pylori species[1,7,8]; fungi like Histoplasma and Monilia; virus such as lymphopathia venereum, Behcet’s virus, cytomegalovirus, Echo A, B adenovirus, Epstein-Barr, rotavirus, Norwalk virus, influenza, mumps, measles, herpes, Coxsackie A and B, Reovirus, Polio virus, Paramyxovirus[1,7,8]; protozoa and parasites like Escherichia histolytica; vaccines such as the trivalent measles, mumps and rubella and Bacillus Calmette-Guérin[9,10]; microparticles of aluminum, titanium , silicon oxides, calcium phosphate from the diet, tooth paste, dust or soil[8,10–12]; drugs like oral contraceptives and non-steroid anti-inflammatory drugs (NSAIDs)[10,13]; dietary components like protein, fat, sugar, fruits and vegetables, margarine, dairy products, coffee, coca cola, fast food, or glycoalkaloids in potato, and carrageenan in seaweeds; smoking; and other factors like refrigeration (cold chain)[8,10,16]. Despite that, the cause of IBD remains virtually unknown, as none of them can well explain the dynamically changed profiles of IBD. For instance, smoking is currently regarded as the most determined environmental factor for IBD: it reduces the risk of UC, while exacerbates CD. Despite that, the low prevalence of CD in heavily smoking countries like China and high prevalence of CD in the low smoking countries like Canada suggest the contribution of smoking in the general population being negligible and other factors in the environment would have played the predominant role. Another example would be the Mycobacterium avium subspecies paratuberculosis (MAP), a bacteria that causes Johne’s disease in cattle, that had been suspected the causative factor for CD as early as 1913. Despite a century long research and debate, a causal relationship between MAP and CD still cannot be established[18,19]. MAP hypothesis also failed to explain the cause of UC, which has been the main form of IBD in most circumstances.
About a decade ago, I found that digestive proteases like trypsin and chymotrypsin can be inactivated by free (unconjugated or deconjugated) bilirubin but not conjugated bilirubin or biliverdin. Further pursuit in the literature led me to suspect that impairment in this process due to inhibition of gut bacteria (thus the major source of β-glucuronidase that is needed for deconjugation of the mostly conjugated biliary bilirubin) by dietary chemicals like saccharin may have played an important causative role in IBD, as the result of damage of the protective mucus layer and the underlying gut tissue by the poorly-inactivated digestive proteases. Recently, I further found that sucralose, the new generation of artificial sweetener, may exert an even potent impact on gut bacteria than saccharin and have probably contributed to the record high incidence of IBD seen recently in many countries. Based on the evidences gathered and thoughts evolved and developed in the last decade, this paper aims to provide a detailed description of a unified hypothesis regarding the etiology of IBD, including the cause and mechanism of IBD, as well as the relationship between UC and CD.
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