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Impaired inactivation of digestive proteases by deconjugated bilirubin: The possible mechanism for inflammatory bowel disease
Abstract
Inflammatory bowel disease refers to ulcerative colitis and Crohn's disease, two gut diseases with unknown causes. The dramatic increase in the last half century and the big difference in incidence for people with the same ethnic background but living in different areas strongly suggested that environmental factors played the dominant role for these diseases. The similarity in many aspects for these two diseases suggested a common causative factor. Here I suggest the impaired inactivation of digestive proteases by deconjugated bilirubin, as the result of the inhibition of bilirubin deconjugation enzyme, beta-glucuronidase, originated from the luminal bacteria and mucosa of the gut, to be a possible mechanism for both ulcerative colitis and Crohn's diseases. I also provide evidence to suggest that saccharin could be the causative or one of the most important risk factors for inflammatory bowel disease as for its inhibition on beta-glucuronidase in the intestine.
... As carbohydrates are slowly absorbed and fermented by the microbiota, hydrogen and methane concentrations in colon increase, leading to worsening of intestinal gas and other typical IBD symptoms such as abdominal pain, distension, diarrhea and flatulence. This can easily explain why these restrictive diets cause an important improvement of the symptoms [51,52]. ...
... In patients with IBD the changes in NOD2 reduce the enteric tolerance to bacteria, and consequently produce inflammation. The latter together with a diet rich in polyols has shown an increase of intestinal dysbiosis as well as mucosa inflammation and deterioration of intestinal permeability [50][51][52][53]. Sorbitol, mannitol and xylitol are susceptible to fermentation with secondary production of hydrogen, methane, carbon dioxide and SCFAs; recognized as potential regulators of the inflammatory process and of intestinal permeability in patients with IBD [54]. ...
... Qin XF in a paper suggest that a decade ago, several discoveries made hypothesized that saccharin (the first and more ancient AS since the late 1880s), could have importance in the IBD through the inhibition of intestinal bacteria and affection to the digestive proteases, as well as excessive damage to the mucin layer and the underlying intestinal tissue [52]. In other paper suggested that in Canada the incidence of IBD is directly associated with the use of NNS in cereals, beverages, desserts, chewing gum, candy and other products; also, these products are used indiscriminately by the food industry in pediatric population from 1983 to 2005 [55,56]. ...
Non-caloric sweeteners (NCS) are natural or chemical additives, found in food products and beverages as a measure to reduce their energy content. Several studies report possible effects on the gastrointestinal tract, especially in patients with predisposition such as Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD). The aim of this review is to describe the association between NCS consumption and changes in bowel habits.
... The evidences demonstrated above provided a simple explanation for many puzzles of IBD such as the emergence and temporal changes of IBD in last century. It suggests saccharin might be the key causative factor for IBD, by primarily its inhibition on gut bacteria [20] . This notion is supported by the recent large-scare studies showing antibiotics greatly increased the risk of IBD [103,104] . ...
... Then these poorly inactivated proteases work synergistically with the glycosides from the remaining bacteria to cause an accelerated degradation of the mucus layer, resulting in damage of the gut barrier (the Bacteria-Protease-Mucus-Barrier hypothesis). This will further result in infiltration of bacteria and their components (mainly in the large intestine) and recruitment of neutrophils leading to the formation of crypt abscess [20] , the characteristic change of UC [134] ; while at places or situations being relative sterile, the increased infiltration of antigens and particles from gut lumen would result in accumulation of macrophages and formation of inflammatory granulomas [20] , the hallmark of CD [134] (Figure 5). This would further induce enhanced immune response of the body, leading to further damage of the gut as well as extra-intestinal manifestations in the joints, skin, eyes and mouth, etc. [135,136] . ...
... Then these poorly inactivated proteases work synergistically with the glycosides from the remaining bacteria to cause an accelerated degradation of the mucus layer, resulting in damage of the gut barrier (the Bacteria-Protease-Mucus-Barrier hypothesis). This will further result in infiltration of bacteria and their components (mainly in the large intestine) and recruitment of neutrophils leading to the formation of crypt abscess [20] , the characteristic change of UC [134] ; while at places or situations being relative sterile, the increased infiltration of antigens and particles from gut lumen would result in accumulation of macrophages and formation of inflammatory granulomas [20] , the hallmark of CD [134] (Figure 5). This would further induce enhanced immune response of the body, leading to further damage of the gut as well as extra-intestinal manifestations in the joints, skin, eyes and mouth, etc. [135,136] . ...
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.
... Further pursuit led me to suspect that dietary chemicals such as the widely used artificial sweeteners saccharin and sucralose may have played an important causative role in IBD through a mechanism such as the inhibition of gut bacteria and resultant impaired inactivation of digestive proteases mediated by deconjugated bilirubin. 3,4 This work proposed a unified hypothesis for the etiology of IBD, including the cause and mechanism of IBD and the relationship between ulcerative colitis and Crohn disease. ...
... In my perception, the primary cause of IBD may be the general, nonspecific decrease of gut bacteria, and the root mechanism of IBD may be impaired inactivation of digestive proteases mediated by deconjugated bilirubin as the result of a decrease in gut bacteria. 3,4 Thus, the most important contributing factor for the dramatic increase in IBD prevalence may be the improved hygiene conditions and practices in modern society, whereas agents such as saccharin, sucralose, cyclamate, and antibiotics may have contributed to many of the unexplained irregular temporal and geographical changes. More epidemiological research is suggested to find out the cause of IBD, which is essential for the ultimate goal of effective treatment and prevention of IBD. ...
... More than a decade ago at about the same time when the first risk gene, NOD2/CARD15/IBD1, of IBD was found [89,90], I found evidence suggesting impairment in the inactivation of digestive proteases, which is likely mediated by the deconjugated bilirubin, as the result of inhibition of gut bacteria by dietary chemicals such as saccharin may have played critical role in the pathogenesis of IBD [91]. It provided simple explanations for many puzzles in IBD such as the emerging of clustered cases of IBD around the beginning of last century, the dramatic increase of IBD in the western countries since 1950s, and the leveling off or decrease of IBD as observed in multiple studies during later 1970s and early 1980s at the time when saccharin was found capable of causing cancer in animals. ...
... To my perception, CD is more likely similar to IBD in dogs and cats rather than Johne'sdisease in cattle [107]. I proposed that the reduction in commensal microbiota in modern society and the resultant impairment in inactivation of pancreatic digestive protease in the lower gut rather than any specific pathogens may have played the primary causative role for both CD and UC, with the main difference being the relative sterility at the location of the damaged gut and the correspondent predominant reaction either by macrophage or neutrophils [91,94]. ...
... [1], as its fi nding that patients with Crohn's disease (CD) have more pronounced reduction and dysbiosis in gut bacteria than ulcerative colitis (UC) is just as what I have predicted during the last fi fteen years [2,3]. However, in contrast to the notion of the authors of the Gut paper that the more pronounced reduction in gut bacteria in CD suggests CD and UC are two different diseases, my prediction came from the perception of the profound intimate connections between UC and CD. ...
... I read with great interest a paper published recently in Gut [1], as its fi nding that patients with Crohn's disease (CD) have more pronounced reduction and dysbiosis in gut bacteria than ulcerative colitis (UC) is just as what I have predicted during the last fi fteen years [2,3]. However, in contrast to the notion of the authors of the Gut paper that the more pronounced reduction in gut bacteria in CD suggests CD and UC are two different diseases, my prediction came from the perception of the profound intimate connections between UC and CD. ...
... More than a decade ago at about the same time when the first risk gene, NOD2/CARD15/IBD1, of IBD was found [89,90], I found evidence suggesting impairment in the inactivation of digestive proteases, which is likely mediated by the deconjugated bilirubin, as the result of inhibition of gut bacteria by dietary chemicals such as saccharin may have played critical role in the pathogenesis of IBD [91]. It provided simple explanations for many puzzles in IBD such as the emerging of clustered cases of IBD around the beginning of last century, the dramatic increase of IBD in the western countries since 1950s, and the leveling off or decrease of IBD as observed in multiple studies during later 1970s and early 1980s at the time when saccharin was found capable of causing cancer in animals. ...
... To my perception, CD is more likely similar to IBD in dogs and cats rather than Johne'sdisease in cattle [107]. I proposed that the reduction in commensal microbiota in modern society and the resultant impairment in inactivation of pancreatic digestive protease in the lower gut rather than any specific pathogens may have played the primary causative role for both CD and UC, with the main difference being the relative sterility at the location of the damaged gut and the correspondent predominant reaction either by macrophage or neutrophils [91,94]. ...
The role of Mycobacterium avium subspecies paratuberculosis (MAP) in Crohn's disease (CD) has been debated for more than a century. Up to date, it remains a highly controversy issue as there are a large amounts of " solid " scientific evidence on both sides. However, I feel many of these conflicts are superficial and the core issue is just the extreme scarcity of MAP in CD and thus the still unresolved conflict between sensitivity and specificity. Along with in-depth analyses of the likely intimate nature of CD, MAP, and the so-called cell-wall deficient spheroplasts, as well as weighted assessment of findings from treatment and epidemiology, here I suggested that the evidences against a critical role of MAP in CD greatly overweigh those support it. Here I also shared a unified hypothesis I developed during the last 15 years regarding the etiology of inflammatory bowel disease (IBD), including the cause and mechanism of IBD as well as the relationship between CD and ulcerative colitis (UC). I proposed that reduction in commensal microbiota in modern society and the resultant impairment in inactivation of pancreatic digestive protease in the lower gut rather than any specific pathogens may have played the primary causative role in both CD and UC.
... Proteolytic enzyme/protease Deconjugated bilirubin-mediated inflammation, damaged gut barrier, and impaired inactivation of digesting protease (97,98) 3. ...
Artificial sweeteners, prominently exemplified by sucralose, have become pervasive in contemporary diets, prompting intriguing questions about their impact on metabolism and their potential role in the unfolding trends of obesity. Covering topics from its discovery to analytical methods for detection and determination in food samples, the manuscript scrutinizes the metabolic effects of sucralose. Notably, the association between sucralose intake and obesity is examined, challenging the conventional belief of its role in weight management. The document comprehensively examines in vivo studies, revealing sucralose's implications on insulin resistance, gut microbiota, and metabolic syndrome, providing a nuanced comprehension of its impact on human health. Additionally, it explores sucralose's effects on glucose and lipid metabolism, blood pressure, and cardiovascular health, underscoring its possible involvement in malignancy development. The review concludes with a call for increased public awareness, education, and updated dietary guidelines to help individuals make informed choices about sweetener consumption. The future perspectives section highlights the need for longitudinal studies, exploring alternative sweeteners, and refining acceptable daily intake limits to ensure public health recommendations align with evolving regulatory guidelines. Overall, the manuscript provides a comprehensive overview of sucralose's multifaceted impact on health, urging further research and a balanced perspective on sweetener consumption.
... Increasing evidence showed that artificial sweeteners affect inflammation pathways and may be an aetiologic factor associated with IBD onset. 6 Qin suggested that artificial sweeteners such as saccharin and sucralose may be more closely related to IBD than other sweeteners such as syrup and fructose, 7,8 indicating different roles that artificial sweeteners played. Reduction of intestinal bacteria and impaired inactivation of digestive proteases may have played essential roles in this process. ...
LINKED CONTENT
This article is linked to Fu et al papers. To view these articles, visit https://doi.org/10.1111/apt.17149 and https://doi.org/10.1111/apt.17178
... IBD damages tight junction (TJ) proteins, resulting in altered intestinal permeability and impaired epithelial barrier function, and increased immune response due to changes in intestinal flora (Lee, 2015). Alterations in the gut microbiota are responsible for influencing various diseases such as obesity, irritable bowel syndrome, tropical enteropathy, antibiotic-associated diarrhea, and vaginitis, and impair the digestion and absorption of nutrients, energy homeostasis, and maintenance of intestinal tissue of the host (Musso et al., 2010;Qin, 2002). Changes in the gut microbiota increase the inflammatory response by stimulating cytokine signaling pathways and indicate intestinal imbalances through changes in some microbial-derived metabolites such as short-chain fatty acids (SCFAs) (Huda-Faujan et al., 2010). ...
Catechins are a phytochemical present in plants such as tea leaves, beans, black grapes, cherries, and cacao, and have various physiological activities. It is reported that catechins have a health improvement effect and ameliorating effect against various diseases. In addition, antioxidant activity, liver damage prevention, cholesterol lowering effect, and anti-obesity activity were confirmed through in vivo animal and clinical studies. Although most diseases are reported as ones mediating various inflammations, the mechanism for improving inflammation remains unclear. Therefore, the current review article evaluates the physiological activity and various pharmacological actions of catechins and conclude by confirming an improvement effect on the inflammatory response.
... However, large amounts of pancreatic proteases can be found in the large intestine or feces of germ-free animals or of those treated with antibiotics or even with some dietary chemicals such as saccharin. 2,3 A study by Bohe et al 6 showed a 100fold increase in trypsin in the fecal extracts of healthy individuals treated with antibiotics. Multiple studies have shown increased activities of pancreatic proteases like trypsin and chymotrypsin in the feces of patients with IBD, including those with either ulcerative colitis or Crohn disease. ...
... Artificial sweeteners, like saccharin and sucralose, were previously linked to increased IBD risk, with a proposed inhibition of gut bacteria and digestive proteases, and thus enhanced digestion of the mucus layer and gut barrier considered the "bacteria-protease-mucus-barrier hypothesis." 61,62 It is difficult, however, to understand why saccharin correlates in different directions with CRP and ESR, respectively. Inconsistency in the inflammatory markers' response to inflammation and their lack of accuracy have been reported frequently. ...
Little is known about the metabolic response of pediatric Crohn’s disease (CD) patients to partial enteral nutrition (PEN) therapy and the impact of disease activity and inflammation. We analyzed plasma samples from a nonrandomized controlled intervention study investigating the effect of partial enteral nutrition (PEN) on bone health and growth throughout one year with untargeted metabolomics using high-performance liquid chromatography (HPLC) coupled with high-resolution mass spectrometry (HRMS). Thirty-four paired samples from two time points (baseline and 12 months) were analyzed. Patients (median age: 13.9 years, range: 7–18.9 years, 44% females) were in remission or had mild disease activity. The intervention group received a casein-based formula for 12 months, providing ~25% of estimated daily energy requirements. Sparse partial least squares discriminant analysis (splsda) was applied for group discrimination and identifying sources of variation to identify the impact of PEN. We also investigated the correlation of metabolites with inflammation markers, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fecal calprotectin. After 12 months, our results show substantial difference between PEN and non-PEN groups in the metabolome of CD patients in remission or with mild disease activity. Inflammatory markers were associated with individual compounds and chemical classes such as isoprenoids and phospholipids. Identified compounds comprise metabolites produced by human or bacterial metabolism, as well as xenobiotics recognized as flavoring agents and environmental contaminants and their biotransformation products. Further longitudinal studies that also include patients with higher disease activity are warranted to evaluate the suitability of these metabolic biomarkers for predicting disease activity.
... Not surprisingly, diet, not only in terms of nutrients but also of dietary chemicals, may have a huge impact on gut microbiota (11,14,15). In fact, it has been long proposed that food additives such as saccharin and sucralose may have played an important causative role in IBD due to their inhibition of gut bacteria and the resultant impaired inactivation of digestive proteases by deconjugated bilirubin through the action of bacterial βglucuronidase (18,19). Papers published in recent years in Nature showed that food additives such as artificial sweeteners and emulsifiers increased the risk of diabetes, obesity, and colitis through their adverse impact on gut bacteria (20,21). ...
Sucralose is a calorie-free high-intensity artificial sweetener that is widely used in thousands of foods and beverages all over the world. Although it was initially regarded as a safe, inert food additive, its adverse effect on gut microbiota and health has drawn more and more attention as evidence accumulates. Studies by us and others revealed that sucralose exacerbated gut damage and inflammation in animal models for inflammatory bowel disease (IBD), including those for both ulcerative colitis, and Crohn's disease. Our study demonstrated that sucralose greatly aggravated dextran sulfate sodium (DSS)-induced colitis along with causing changes in gut microbiota, the gut barrier and impaired inactivation of digestive proteases mediated by deconjugated bilirubin. It is well-documented that IBD greatly increases the risk of colorectal cancer (CRC), the globally third-most-common cancer, which, like IBD, has a high rate in the developed countries. Azoxymethane (AOM)/DSS has been the most commonly used animal model for CRC. In this study, we further explored the effect of sucralose on tumorigenesis and the possible mechanism involved using the AOM/DSS mouse model. First, 1.5 mg/ml sucralose was included in the drinking water for 6 weeks to reach a relatively stable phase of impact on gut microbiota. Then, 10 mg/kg AOM was administered through intraperitoneal injection. Seven days later, 2.5% DSS was put in the drinking water for 5 days, followed by 2 weeks without DSS. The 5 days of DSS was then repeated, and the mice were sacrificed 6 weeks after AOM injection. The results showed that sucralose caused significant increases in the number and size of AOM/DSS-induced colorectal tumors along with changes in other parameters such as body and spleen weight, pathological scores, mortality, fecal β-glucuronidase and digestive proteases, gut barrier molecules, gut microbiota, inflammatory cytokines and pathways (TNFα, IL-1β, IL-6, IL-10, and TLR4/Myd88/NF-κB signaling), and STAT3/VEGF tumor-associated signaling pathway molecules. These results suggest that sucralose may increase tumorigenesis along with dysbiosis of gut microbiota, impaired inactivation of digestive protease, damage to the gut barrier, and exacerbated inflammation.
... Quin et al. published a hypothesis in 2012 claiming saccharin consumption to be causative for the rising incidence of IBD cases, based on the observation that saccharin consumption in the United States significantly correlates with new IBD cases in Monroe County, New York between 1918 and 1970 [6]. As a possible mechanism for saccharin impacting the gut homeostasis, Quin previously suggested saccharin to inhibit inactivation of digestive proteases, resulting in digestion of the protective mucus layer [26]. Interestingly, neither the effect of saccharin on the course of intestinal inflammation nor the proposed mechanism of saccharin-bacteria-protease-mucus interaction have been tested experimentally to date. ...
Non-caloric artificial sweeteners are frequently discussed as components of the “Western diet”, negatively modulating intestinal homeostasis. Since the artificial sweetener saccharin is known to depict bacteriostatic and microbiome-modulating properties, we hypothesized oral saccharin intake to influence intestinal inflammation and aimed at delineating its effect on acute and chronic colitis activity in mice. In vitro, different bacterial strains were grown in the presence or absence of saccharin. Mice were supplemented with saccharin before or after induction of acute or chronic colitis using dextran sodium sulfate (DSS) and the extent of colitis was assessed. Ex vivo, intestinal inflammation, fecal bacterial load and composition were studied by immunohistochemistry analyses, quantitative PCR, 16 S RNA PCR or next generation sequencing in samples collected from analyzed mice. In vitro, saccharin inhibited bacterial growth in a species-dependent manner. In vivo, oral saccharin intake reduced fecal bacterial load and altered microbiome composition, while the intestinal barrier was not obviously affected. Of note, DSS-induced colitis activity was significantly improved in mice after therapeutic or prophylactic treatment with saccharin. Together, this study demonstrates that oral saccharin intake decreases intestinal bacteria count and hence encompasses the capacity to reduce acute and chronic colitis activity in mice.
... Additives of interest: At the time of conducting the literature search, ten additives had been implicated as potential causative agents in IBD. These include the thickener Maltodextrin [16,40] (not covered by CODEX), three emulsifiers and/or thickeners (carrageenan [41], carboxymethylcellulouse [11], polysorbate-80 [15]), three artificial sweeteners (aspartame [42], saccharin [43], sucralose [44]), two nanoparticles (the coloring agent titanium dioxide [30,45] and the anti-caking agent sodium aluminosilicate [45,46]), and sulfite preservatives [47]. Factors influencing early life food intake: Factors that impact exposure to food additives in childhood were extrapolated from a model of the home food environment pertaining to childhood obesity [48]. ...
(1) Background: The Food Agricultural Organization/World Health Organization (FAO/WHO) International Food Standards Codex Alimentarius CXS 192e International Food Standards (hereafter, CODEX) declares additives non-toxic, but they have been associated with changes to the microbiota changes and thinning of the mucus layer of the gut. Their widespread use has occurred in parallel with increased inflammatory bowel disease (IBD) incidence. This paper reports on the development and validation of surveys to estimate additive intake. (2) Methods: Dietitians created a food-additive database, with a focus on additives that have been associated with IBD. For each additive, information on the CODEX food-category they are permitted in and the associated maximum permissible levels (mg/kg) was recorded. Based on the database, questions to assess early life (part 1) and recent (part 2) additive intake were written. Forward–backward translation from English to Chinese was undertaken. Thirty-one individuals were evaluated to assess understandability. A further fifty-seven individuals completed the tool on two occasions, a fortnight apart; agreement was assessed using Cohen’s kappa coefficient or the intra-class correlation coefficient (ICC). (3) Results: The participants reported that it was difficult to remember food intake and estimate portion sizes. The participants also noted confusion around the term ‘home-grown’. Instructions and definitions were added; after this, respondents judged the questionnaires as clear. The average kappa coefficient for part 1 and part 2 questions were 0.61 and 0.67, respectively. The average ICC ranged from 0.30 to 0.94; three food lists were removed due to low reliability. (4) Conclusions: Two tools have been created and validated, in two languages, that reliably assess remote and recent food additive intake.
... It is well-documented that increased gut permeability ("Leaky gut") has played a critical role in the pathogenesis of IBD (Michielan and D'Inca, 2015;Vindigni et al., 2016), while proteases would be an important damaging factor for gut barrier due to the strong proteolytic action (Biancheri et al., 2013). In fact, Qin demonstrated that digestive proteases can be inactivated by unconjugated but not conjugated bilirubin (Qin, 2007) and proposed that impaired inactivation of digestive proteases by deconjugated bilirubin as the result of the reduction in gut bacteria, thus bacterial β-glucuronidase, along with improved hygiene and inhibition by dietary chemicals such as the widely used artificial sweetener saccharin in modern society may have played a critical role in the pathogenesis of IBD (Qin, 2002). Similarly, our previous studies using bile duct ligation rats have confirmed that unconjugated bilirubin (UCB) inactivated digestive proteases and protected the integrity of the intestinal barrier (Zhou et al., 2014). ...
Increasingly studies revealed that dysbiosis of gut microbiota plays a pivotal role in the pathogenesis of ulcerative colitis (UC). Fecal microbiota transplantation (FMT) has drawn more and more attention and become an important therapeutic approach. This study aims to examine the facts about the effective components and look into potential mechanisms of FMT. Colitis was induced by 3% (w/v) dextran sulfate sodium (DSS) in drinking water for 7 days. Colitis mice were administered by oral gavage with fecal suspension, fecal supernatant, fecal bacteria, or boiling-killed fecal bacteria from healthy controls and the disease activity index was monitored daily. On the seventh day, mice were euthanized. The length, histological score, parameters related to inflammation, gut barrier functions of the colon, activities of digestive protease and β-glucuronidase in feces were measured. All of the four fecal components showed certain degree of efficacy in DSS-induced colitis, while transplantation of fecal suspension showed the most potent effect as demonstrated by less body weight loss, lower disease activity scores, more expression of tight junction proteins and TRAF6 and IκBα, less expression of TNF-α, IL-1β, IL-10, TLR-4, and MyD88 in gut tissue, as well as restoration of fecal β-glucuronidase and decreases in fecal digestive proteases. These results provide a novel insight into the possible mechanism of FMT and may help to improve and optimize clinical use of FMT.
... A further pursuit on this made me believe that impaired inactivation of digestive proteases due to reduction of gut bacteria, thus the enzyme needed for bilirubin deconjugation, along with improved hygiene and inhibition by food additives such as the widely used artificial sweetener saccharin may have played important causative role in IBD. 4 It led to the further development into a unified hypothesis on etiology of IBD, including the cause and mechanism of IBD as well as the relationship between UC and CD. 5 It explained many puzzles of IBD and was supported by more evidence. Food additives such as the high intencity artificial sweeteners like saccharin and sucralose become heavily used in modern society. ...
... Additives of interest: At the time of conducting the literature search, ten additives had been implicated as potential causative agents in IBD. These include the thickener Maltodextrin [16,40] (not covered by CODEX), three emulsifiers and/or thickeners (carrageenan [41], carboxymethylcellulouse [11], polysorbate-80 [15]), three artificial sweeteners (aspartame [42], saccharin [43], sucralose [44]), two nanoparticles (the coloring agent titanium dioxide [30,45] and the anti-caking agent sodium aluminosilicate [45,46]), and sulfite preservatives [47]. Factors influencing early life food intake: Factors that impact exposure to food additives in childhood were extrapolated from a model of the home food environment pertaining to childhood obesity [48]. ...
Background
Processed food additives are widely used to change food consistency, appearance and shelf life. In the Food Agriculture Organization/ WHO International Food Standards CODEX additives are deemed non-toxic or carcinogenic, but their functional impact is unknown. The global pandemics of metabolic and inflammatory bowel diseases have occurred in parallel with widespread additive use. Additives have been causally linked to microbiota changes and mucus layer destruction. A validated measure of food additive intake does not exist. We report the development and validation of 2 food additive measurement tools.
Methods
Questionnaire design: Two dietitians working in Australia and Hong Kong created a database of food additives (n = 10) implicated in IBD, the CODEX food-categories they are permitted in, and their maximum suggested permissible concentration (mg/kg). Food categories were condensed into 27 food lists, with examples. Intake in early life (part 1) and recently (part 2) were assessed. Part 1 comprised 39 dichotomous questions on breast-feeding, home and processed food consumption up to age 18. Part 2 assessed frequency of consumption for the 27 food lists in the preceding 12 months. Forward–backward translation into Hong Kong Chinese was undertaken. Pilot testing: 31 individuals assessed understandability. Validation: A new cohort of 26 individuals undertook the tool twice, 2 weeks apart, to assess reproducibility. Cohen’s’ Kappa-co-efficient was used to assess percent agreement for part 1 questions. Intra-class correlation coefficient (ICC) was used to assess the agreement between the total annual frequencies of the food lists.
Results
Pilot testing: Participants reported difficulty recalling food intake, estimating portions and confusion around certain terms. Instructions were therefore added for estimating food intake. Validation cohort: Respondents judged the questionnaires easy to understand and complete. The average kappa-coefficient for part 1 questions was 0.5. Eighteen per cent of questions had slight to fair correlations, 36% had moderate correlations, and 46% had substantial to almost perfect correlations. Researchers expect moderate correlations in measures of remote diet intake. For part 2 the ICC for total, annual frequency of the 27 food lists was 0.888 (p < 0.001), indicating good reliability.
Conclusions
Two tools (part 1 and 2) have been developed and validated, in two major languages and cultures, which reproducibly assess early-life and recent intake of food additives. These can be applied to individuals to assess this important emerging field of the relationship between food additive intake and disease.
... In addition, data from animal model studies demonstrate that dietary change and/or modification impacts the risk of IBD [44]. More studies report to have seen affirmation suggesting that artificial sweeteners such as saccharin, sucralose, acesulfame potassium (ace K) and cyclamate may have played causative role in the pathogenesis of IBD [228][229][230]. These sweeteners are observed to be distinctive by high stability with little metabolism by the body and long-lasting in the environment but high inhibitory effect on bacteria [231]. ...
The gastrointestinal system where inflammatory bowel disease occurs is central to the immune system where the innate and the adaptive/acquired immune systems are balanced in interactions with gut microbes under homeostasis conditions. This article overviews the high-throughput research screening on multifactorial interplay between genetic risk factors, the intestinal microbiota, urbanization, modernization, Westernization, the environmental influences and immune responses in the etiopathogenesis of inflammatory bowel disease in humans. Inflammatory bowel disease is an expensive multifactorial debilitating disease that affects thousands new people annually worldwide with no known etiology or cure. The conservative therapeutics focus on the established pathology where the immune dysfunction and gut injury have already happened but do not preclude or delay the progression. Inflammatory bowel disease is evolving globally and has become a global emergence disease. It is largely known to be a disease in industrial-urbanized societies attributed to modernization and Westernized lifestyle associated with environmental factors to genetically susceptible individuals with determined failure to process certain commensal antigens. In the developing nations, increasing incidence and prevalence of inflammatory bowel disease (IBD) has been associated with rapid urbanization, modernization and Westernization of the population. In summary, there are identified multiple associations to host exposures potentiating the landscape risk hazards of inflammatory bowel disease trigger, that include: Western life-style and diet, host genetics, altered innate and/or acquired/adaptive host immune responses, early-life microbiota exposure, change in microbiome symbiotic relationship (dysbiosis/dysbacteriosis), pollution, changing hygiene status, socioeconomic status and several other environmental factors have long-standing effects/influence tolerance. The ongoing multipronged robotic studies on gut microbiota composition disparate patterns between the rural vs. urban locations may help elucidate and better understand the contribution of microbiome disciplines/ecology and evolutionary biology in potentially protecting against the development of inflammatory bowel disease.
... I also believe artificial sweeteners, such as sucralose and saccharin, as well as cyclamate and acesulfame potassium, may be more closely related to IBD rather than some other sweeteners, such as fructose and syrup. 3,4 These sweeteners are characterized by high stability, may remain in the gastrointestinal tract for a long time, and also have high inhibitory effect on intestinal bacteria. 5 Furthermore, reduction of intestinal bacteria may impair inactivation of digestive proteases in the lower gut and this in itself may be important for IBD pathogenesis. ...
... I read with great interest the paper by Rodriguez-Palacios et al. published recently in the Journal, demonstrating that the artificial sweetener Splenda can cause dysbiosis of the gut microbiota and promote inflammation in the SAMP mouse model of human Crohn's disease (CD)-like ileitis. 1 Back in 2001, a series of findings led me to suspect that the artificial sweetener saccharin may be an important causative factor for inflammatory bowel disease (IBD), due to its inhibition on the gut microbiota and the resulting impaired deactivation of digestive proteases mediated by deconjugated bilirubin. 2 Ten years later, I further suspected that sucralose/Splenda may also be linked to IBD, which may contribute to its recent worldwide increase. 3 This led me to a unified hypothesis on IBD, including the cause and mechanism of IBD and the relationship between ulcerative colitis and Crohn's disease. ...
... Especially, the therapeutic effect of BBI on IBD patients or experimental animal colitis was confirmed (14,15). The digestive enzymes located in the GI tract are the potential and vital therapeutic targets for IBD treatment accordingly (16,17). ...
The authors previously demonstrated that unconjugated bilirubin (UCB) may inhibit the activities of various digestive proteases, including trypsin and chymotrypsin. The digestive proteases in the lower gut are important in the pathogenesis of inflammatory bowel diseases. The effects of UCB on the inflammation and levels of digestive proteases in feces of rats with colitis have not yet been revealed. The present study investigated the effect of UCB on the inflammatory status and levels of trypsin and chymotrypsin in the feces of rats with trinitrobenzenesulfonic acid (TNBS)‑induced colitis. The data indicated that treatment with TNBS resulted in a marked reduction in weight gain, which was significantly alleviated in UCB‑treated rats. Furthermore, UCB treatment alleviated the inflammation induced by TNBS, detected via macroscopic damage and microscopic inflammation scores, and pro‑inflammatory markers including myeloperoxidase (MPO), tumor necrosis factor (TNF)‑α and interleukin (IL)‑1β. Furthermore, rats with colitis demonstrated significant increases in fecal trypsin and chymotrypsin levels, whereas UCB treatment significantly alleviated these increases. A significant positive correlation was additionally revealed among the pro‑inflammatory markers (MPO, TNF‑α and IL‑1β) and fecal digestive proteases (trypsin and chymotrypsin) in colitis. The results of the present study demonstrated that UCB ameliorated the inflammation and digestive protease increase in TNBS-induced colitis.
... About a decade ago, I found that digestive proteases like trypsin and chymotrypsin can be inactivated by free but not conjugated bilirubin. Further pursuit in the literature led me to suspect that impairment in this process as the result of 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, by virtue of the damage of the protective mucus layer and the gut barrier by the poorly-inactivated digestive proteases [6]. It provided a simple explanation for many puzzles of IBD such as its emergence around the beginning of last century, its dramatic increase since 1950s, and the leveling off or even decrease of IBD around 1980s as seen in multiple studies. ...
... Accumulating evidences indicate that impairment in this process may lead to devastating consequences. Evidences I collected during the last fifteen years suggested that impairment in the bilirubin deconjugation mediated inactivation of pancreatic digestive proteases, as the result of reduction of gut bacteria along with the improved hygiene and inhibition by dietary chemicals such as saccharin and sucralose may have played a critical role in the pathogenesis of inflammatory bowel disease (IBD) including ulcerative colitis and Crohn's disease [9][10][11]. This is also in accordance with the fact that patients with primary sclerosing cholangitis, a disease with impaired release of bile from the liver, are accompanied by high rates of IBD [12]. ...
... The recent large-scale prospective epidemiological study on dietary patterns and risk of IBD across Europe reflected the great effort, with the finding that high sugar and soft drinks are associated with increased risk of ulcerative colitis. 2 Along with evidence collected during the last 15 years, Qin further proposed that dietary chemicals, such as sucralose and saccharin, may have played important causative role on IBD, 3,4 as a result of inhibition of gut bacteria and impairment in inactivation of digestive proteases mediated by deconjugated bilirubin. 5,6 It provided simple explanations for many puzzles in IBD. Despite that, coherent direct experimental evidence for the proposed mechanism is still lacking. ...
... Although Qin (161) suggests a multitude of possible dietary factors affecting IBD, he singles out saccharin and/or sucralose to be a key causative factor in the disease. Proposing a unified hypothesis regarding the aetiology for IBD, Qin suggests that saccharin inhibits both the activity of β-glucuronidase itself as well as the growth of β-glucuronidase-positive bacteria in the gastrointestinal tract which are necessary for the deconjugation of biliary bilirubin (180) , that in turn leads to damage of the protective mucus layer and the underlying gut tissue by the poorly inactivated digestive proteases (181) (the bacteria-protease-mucus-barrier hypothesis) (161) . ...
The intestinal epithelium of adult humans acts as a differentially permeable barrier that separates the potentially harmful contents of the lumen from the underlying tissues. Any dysfunction of this boundary layer that disturbs the homeostatic equilibrium between the internal and external environments may initiate and sustain a biochemical cascade that results in inflammation of the intestine. Key to such dysfunction are genetic, microbial and other environmental factors that, singularly or in combination, result in chronic inflammation that is symptomatic of inflammatory bowel disease (IBD). The aim of the present review is to assess the scientific evidence to support the hypothesis that defective transepithelial transport mechanisms and the heightened absorption of intact antigenic proinflammatory oligopeptides are important contributing factors in the pathogenesis of IBD.
... Inflammatory bowel diseases (IBD) characterizes a chronic disease manifested by recurrent inflammation of intestinal mucosa that results from aberrant regulation of the In IBD, both UC and CD are characterized by a weakened gut barrier, with increased infiltration of gut bacteria. Recruitment of neutrophils and formation of crypt abscess following antigen infiltration is typical for UC, where as in CD, macrophages are recruited with formation of granulomas [32,33]. Tissue damage occurs mainly due to heavy infiltration of CD4+ T lymphocytes which are recruited from blood stream via enhanced production of chemoattractants such as CCL25 which promotes migration of CC chemokine receptor 9 (CCR9)-expressing T-cells to the intestinal mucosa [34]. ...
Inflammatory bowel disease (IBD) characterizes chronic gastrointestinal inflammation manifested by abdominal pain, diarrhea, malabsorbtion and bleeding, of which two phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC) have been described [1-3]. It affects about 1.4 million people in the USA and 2.2 million people in Europe [4, 5]. The nuclear receptor farnesoid X receptor senses intracellular bile acid levels. In response to elevated levels of intracellular bile acids, activated FXR induces gene expression of bile acid efflux transporters whereas the expression of bile acid uptake transporters are down regulated, thus protecting against bile acid toxicity in the liver and intestine. FXR regulates several genes that can protect against intestinal inflammation and bacterial overgrowth. FXR-deficient mice have increased ileal concentrations of gut bacteria and exhibit defects in the integrity of the intestinal epithelial barrier. Furthermore, in rodent models of colitis and in CD patients, it has been reported that reduced expression of FXR is associated with colon inflammation [6]. The fact that FXR thus appears to play a role in the protection of the integrity of the intestinal epithelial barrier and its inverse correlation with the level of intestinal inflammation suggest a potential connection between FXR and the molecular pathogenesis of IBD. In the first chapter of this thesis, we have investigated five FXR single nucleotide polymorphisms - two common SNPs and three rare variants - which have been previously studied in the context of human disease, in a well sized IBD vs non-IBD cohort, and report that two of these genetic variants are associated with IBD. NF-κB activity is upregulated in patients with IBD, characterized by high circulatory levels of cytokines especially tumor necrosis factor (TNF). Low plasma concentration of high density lipoprotein (HDL) cholesterol is a marker and considered as a risk factor for coronary heart disease, diabetes mellitus, and several cancers including colorectal cancers [7-9]. The intestine plays a crucial role in HDL metabolism. In addition, the classical anti-atherogenic function of HDL, the mediation of reverse transport of excess cholesterol from macrophages of the arterial wall to the liver is completed by biliary excretion of cholesterol into the intestine. Intestinal dysfunction and inflammation leads to decrease in serum levels of HDL cholesterol and ApoA1 [10-13]. Consistent with this, clinical studies show significantly lower HDL-cholesterol levels in patients with active IBD [14]. Traditionally, the low HDL cholesterol in IBD patients is interpreted as the consequence of IBD. The association of low HDL-cholesterol with IBD together with the many anti-inflammatory properties of HDL however raises the question of whether HDL and its protein and lipid components have any causal impact on intestinal inflammation in IBD patients. In the second chapter of the thesis, we approached this question and investigated the effect of HDL and ApoA1 on intestinal inflammation both in vitro and in vivo. Autophagy, a catabolic process involving intracellular degradation of organelles and proteins, has been shown to be compromised in many human diseases including IBD. Autophagy malfunction has been attributed to defective clearance of pathogens and dysfunction of paneth and goblet cells, which are relevant for pathogenesis of IBD. In the third chapter of the thesis, we put forward autophagy as a mechanism by which HDL suppress intestinal inflammation.
... I read with great interest the paper by Carroll and Maharshak [1] regarding the role of enteric bacterial proteases in the pathogenesis of inflammatory bowel disease (IBD), which succeeded another review on the similar topic [2] . I take a special interest in this paper as I also suspected proteases, not from the bacteria, but rather originated from the pancreas that failed to be inactivated in the lower gut due to a reduction in gut bacteria, may have played a critical role in the pathogenesis of IBD, which was first published more than a decade ago [3] and discussed again in more detail in a paper published in this journal in 2012 [4] . It would be necessary to differentiate the proteases from these two sources, as in situations such as after treatment with antibiotics, the gut bacteria and bacterial proteases activity may be reduced as discussed in the paper by Carroll and Maharshak [1] , but multiple studies demonstrated that treatment with antibiotics in animals or human results in dramatic increase of pancreatic proteases like trypsin and chymotrypsin in feces and luminal contents of the lower intestine [5][6][7][8] . ...
In a recent review paper, Carroll and Maharshak discussed a critical role of enteric bacterial proteases in the pathogenesis of inflammatory bowel disease (IBD). I take a great interest in this paper as I also suspected proteases, not from the bacteria, but those originated from the pancreas that failed to be inactivated in the lower gut due to a reduction in gut bacteria, may have played a critical role in the pathogenesis of IBD, which was first published more than a decade ago and discussed again in more detail in a recent paper published in this journal. Antibiotics may result in a big reduction in gut bacteria and bacterial proteases, but multiple studies demonstrated dramatic increased of pancreatic proteases like trypsin and chymotrypsin in the feces of animals or patients treated with antibiotics. Multiple large-scale studies also demonstrated use of antibiotics caused an increase but not decrease in the risk of developing IBD, suggesting impaired inactivation and degradation of pancreatic proteases may have played a more critical role in the pathogenesis of IBD.
... Meanwhile, the complex carbohydrate fiber (but not starches), such as that found in fruits and vegetable, appear to reduce inflammation in both humans [26][27][28][29][30][31][32] and mice [33]. The impacts of artificial sweeteners are less clear; provocative, yet highly limited, evidence implicates saccharin and sucralose as contributors to Crohn's and Ulcerative Colitis via interference with homeostatic inactivation of digestive proteases [34,35]. However this evidence is only epidemiologic correlation and animal modeling, and lacks direct human investigation. ...
While numerous changes in human lifestyle constitute modern life, our diet has been gaining attention as a potential contributor to the increase in immune-mediated diseases. The Western diet is characterized by an over consumption and reduced variety of refined sugars, salt, and saturated fat. Herein our objective is to detail the mechanisms for the Western diet's impact on immune function. The manuscript reviews the impacts and mechanisms of harm for our over-indulgence in sugar, salt, and fat, as well as the data outlining the impacts of artificial sweeteners, gluten, and genetically modified foods; attention is given to revealing where the literature on the immune impacts of macronutrients is limited to either animal or in vitro models versus where human trials exist. Detailed attention is given to the dietary impact on the gut microbiome and the mechanisms by which our poor dietary choices are encoded into our gut, our genes, and are passed to our offspring. While today's modern diet may provide beneficial protection from micro- and macronutrient deficiencies, our over abundance of calories and the macronutrients that compose our diet may all lead to increased inflammation, reduced control of infection, increased rates of cancer, and increased risk for allergic and auto-inflammatory disease.
... A decade ago, a series of accidental findings made me suspect that the impaired inactivation of digestive proteases due to the inhibition of gut bacteria by dietary chemicals, such as saccharin, play a causative role in IBD as a result of the accelerated degradation of the mucous layer and underlying endothelium (7). It provided an explanation for many puzzles in IBD such as the dramatic increase of IBD in the 1950s and 1960s, and its levelling off since the latter part of the 1970s, as observed in many western countries including Canada (4,7). ...
Lay Summary
Building on my long-standing hypothesis that impaired inactivation of digestive proteases by deconjugated bilirubin may be the unifying feature and mechanism of inflammatory bowel disease (IBD), this paper explores potential connections among different subtypes of IBD through sequential changes in total serum bilirubin.
Lay Summary
This article discussed the likely bell-shaped complicated impacts of antibacterial agents such as food additives like some artificial sweeteners on inflammatory bowel diseases including ulcerative colitis and Crohn’s disease along with decrease in gut bacteria.
Objective
Inflammatory bowel diseases (IBD) including ulcerative colitis and Crohn's disease are devastating diseases of the gut. At present, all the treatments are mainly targeting symptoms like inflammation. The disease remains regarded as incurable, largely due to lacking of knowledge on its etiology. Our previous studies suggested that impaired inactivation of digestive proteases by deconjugated bilirubin in experimental colitis, thus bacterial β-glucuronidase for catalyzing the reaction, may have played critical role in the pathogenesis of IBD.
Methods
We first analyzed β-glucuronidase activity in gut tissue and feces of mice by a colitis model. Then the effect of β-glucuronidase on experimental colitis was investigated in detail by administration of β-glucuronidase (from E. coli) and fecal material transplantation to mice with 3% DSS in drinking water for 7 days.
Results
Mice with colitis showed unchanged activity of β-glucuronidase in colon tissue but decreased activity in feces. Treatment with bacterial β-glucuronidase at 100 U or above alleviated DSS-induced colitis as demonstrated by the less body weight loss, less disease activity score, increased expression of tight junction proteins and decreased gut permeability, decreases in MPO, TNF-α, IL-1β, TLR-4 and MyD88, and increase in IL-10 and IκBα in gut, restored fecal β-glucuronidase and gut microbiota along with decreases in fecal digestive proteases. Transplantation of fecal material from control to colitis mice showed similar effects as treatment with β-glucuronidase.
Conclusions
Bacterial β-glucuronidase showed strong inhibition on colitis along with the reduction in fecal digestive proteases, which may be a crucial diagnostic and therapeutic target for IBD.
Inflammatory bowel disease (IBD) is a group of intestinal non-specific inflammatory diseases with unclear pathogenesis, characterized with the impaired intestinal mucosal barriers and the activated immune system. Mucus layer is the vital protector over the intestinal epithelia cells (IECs). Mucus layer with impaired function could not provide isolated protection for IECs and thus proteases and pathogens from the gut lumen attacked and damaged the epithelial layer. Clinical manifestation and histopathology suggest that IBD might be a self-digestive inflammatory disease caused by digestive enzymes. In this review, we specifically focus on the role of intestinal mucosal barriers and aim to summarize the relationship among mucus layer, self-digestion and inflammation in IBD. We also propose a “Two Hits” Self-Digestion theory to explain the role of self-digestion in IBD and assess the application of mucus protectors to treat IBD.
Recent study shows that germ-free and antibiotic-treated animals are highly susceptible to gut epithelial injury. This paper addresses that impaired inactivation of digestive proteases may be the key factor for the increased susceptibility.
Food additives are chemicals that are added intentionally to food to fulfill a specific function during its processing to preserve food, enhance flavor, and/or color, or are included unintentionally during processing. The increased use of processed food during the past century has led to the use of many food additives, some of which (e.g., boric acid) were found to be toxic and subsequently banned, resulting in a need for regulating their safety. This has in turn necessitated the regulation of their use through legislations in many countries. Despite regulations that require the safety evaluation of food additives and guarantee the use of only safe concentrations of these chemicals, some studies have demonstrated the harmful effects of the combined consumption of food additives in children. Further studies have linked some artificial food additives to cancer, digestive problems, neurological conditions and ADHD, heart disease or obesity. Despite reports linking some food additives with diseases and health risks, these chemicals are necessary for preserving food and also for providing nutrients, color and flavor.
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
The American Journal of Gastroenterology is published by Nature Publishing Group (NPG) on behalf of the American College of Gastroenterology (ACG). Ranked the #1 clinical journal covering gastroenterology and hepatology*, The American Journal of Gastroenterology (AJG) provides practical and professional support for clinicians dealing with the gastroenterological disorders seen most often in patients. Published with practicing clinicians in mind, the journal aims to be easily accessible, organizing its content by topic, both online and in print. www.amjgastro.com, *2007 Journal Citation Report (Thomson Reuters, 2008)
On comparing germ-free and conventional rats, inactivation of the tryptic activity was found to take place in the caecum of conventional adult rats only. A microbial intestinal inactivation of the tryptic activity was established in suckling conventional rats within 10 days after birth. At 3 weeks of age, suckling germ-free rats were found to have less faecal tryptic activity than their early-weaned littermates.
Rectal biopsy specimens from control subjects, patients with either active or quiescent ulcerative colitis, and patients with Crohn's colitis were examined histologically and assayed for marker enzymes associated with tissue organelles. They were catalase (peroxisome); neutral alpha-glucosidase (endoplasmic reticulum); alkaline phosphatase (plasma membrane); malate dehydrogenase (mitochondria); lactate dehydrogenase (cytosol). There was no significant change in these enzyme activities in patient samples compared with controls. Activities of three acid hydrolases (lysosomal enzymes), beta-glucuronidase, acid phosphatase, and N-acetyl-beta-glucosaminidase, were also assayed in the biopsy samples. Decreased activities of all three enzymes were noted in ulcerative colitis, particularly in active disease. Normal values were obtained in Crohn's colitis. Measurement of lysosomal integrity by assays of latent N-acetyl-beta-glucosaminidase activity revealed similar results in control and colitic subjects. It is suggested that the lysosomal changes reflect a specific tissue release of enzyme and may be implicated in the pathogenesis of the tissue damage.
The rising incidence of inflammatory bowel disease (IBD) since the Second World War coincides with profound changes of the dietary pattern. The aim of the study was to investigate the possible pathogenic role of some characteristic 'modern life' dietary factors in IBD.
Case-control, studying risk factors in recently diagnosed cases, 290 with Crohn's disease and 398 with ulcerative colitis, compared with 616 population controls. Smoking, age, gender and education were taken into account by using logistic regression analysis.
Hospital cases and population controls.
Questionnaires.
Logistic regression-derived odds ratios.
A positive association with cola drinks [OR: 2.2 (95% CI 1.5-3.1)], chewing gum [OR: 1.5 (95% CI: 1.1-2.1)] and chocolate consumption [OR: 2.5 (95% CI: 1.8-3.5)] and a negative association with citrus fruit consumption [OR: 0.5 (95% CI 0.3-0.7)] and the development of Crohn's disease were found. Consumption of cola drinks [OR: 1.6 (95% CI 1.1-2.3)] and chocolate consumption [OR: 2.5 (95% CI 1.8-3.5)] were positively associated with developing ulcerative colitis. There was a negative association between the intake of citrus fruits [OR: 0.5 (95% CI 0.4-0.8)] and 'having a stuffed pet' for a period longer than 5 years [OR: 0.6 (95% CI 0.4-0.9)] and developing the disorder. No association with the frequency of tooth brushing and developing IBD was found.
All the nutritional items mentioned may be true risk factors or they just might be the expression of a modern life-style also involving other risk factors for the development of IBD which at the present are still unknown.
Inflammatory bowel diseases (IBD) are complex disorders. While the exact etiology of these diseases remains unknown, recent progress in the epidemiology and genetics of IBD has clearly demonstrated both environmental and genetic factors to play a role in the development of the disease, and it is expected that some risk factors are common for both Crohn's disease (CD) and ulcerative colitis (UC). The environmental factor(s) are associated with the Western way of life in the second half of the twentieth century. Cigarette smoking is presently the best known environmental factor. However, the effect of tobacco is opposite in CD and UC. A familial history of IBD is the most important risk factor for developing the disease, suggesting a genetic predisposition to IBD. This hypothesis has recently been confirmed by the localization of at least two susceptibility loci on chromosomes 12 and 16. These genes seem to play a role in both CD and UC. They must now to be identified.
There is significant geographic variation in the reported incidence of ulcerative colitis.
To update the incidence and prevalence of ulcerative colitis in Olmsted County, Minnesota, examine temporal trends, and determine overall survival.
All Olmsted County residents diagnosed with ulcerative colitis between 1940 and 1993 (incidence cases), and all residents with ulcerative colitis alive on 1 January 1991 (prevalence cases).
Incidence and prevalence rates were adjusted using 1990 US census figures for whites. The effects of age, sex, and calendar year on incidence rates were evaluated using Poisson regression. Survival from diagnosis was compared with that expected for US north-central whites.
Between 1940 and 1993, 278 incidence cases were identified, for an adjusted incidence rate of 7.6 cases per 100 000 person years (95% confidence interval (CI), 6.7 to 8.5). On 1 January 1991, there were 218 residents with definite or probable ulcerative colitis, for an adjusted prevalence rate of 229 cases per 100 000 (95% CI, 198 to 260). Increased incidence rates were associated with later calendar years (p<0.002), younger age (p<0.0001), urban residence (p<0.0001), and male sex (p<0.003). Overall survival was similar to that expected (p>0.2).
The overall incidence rate of ulcerative colitis in Olmsted County increased until the 1970s, and remained stable thereafter. Incidence rates among men and urban residents were significantly higher. The prevalence rate in Rochester in 1991 was 19% higher than that in 1980. Overall survival was similar to that of the general population.
Changes of activity of intestinal acid β-galactosidase, β-glucuronidase, N -acetyl-β-glucosaminidase and arylsulphatase were studied in suckling rats treated with cortisone (5mg/100g body wt. daily, started on day 9 postnatally) and compared with changes in control animals. Specific activities were not changed within the first 72h, but all enzymes decreased similarly 96h after the first injection. Total activities per ileum and animal were not changed within the first 48h, but within 72h a significant decrease was observed. Calculation of the rate of decrease of the hydrolases studied in cortisone-treated animals shows that it proceeds faster than the rate of renewal of enterocytes in this period.
The search for the cause of inflammatory bowel disease through epidemiologic investigation is centered on documenting disease variability and determining the reason for such variability. An examination of the person, place, and time variability of inflammatory bowel disease can provide important clues to disease pathogenesis.
Although there is a great deal of variability in the epidemiology of inflammatory bowel disease among populations, there is little difference in these populations between Crohn’s disease and ulcerative colitis with regard to person, place, or time variability.³⁶ With notable exceptions, such as cigarette smoking, the epidemiologic variability of ulcerative colitis and Crohn’s disease is remarkably similar. Such similarities are unlikely to be coincidences. The possible implications from this observation are that ulcerative colitis and Crohn’s disease are actually different expressions of the same disease, expressions determined by such factors as cigarette smoking, or that two separate diseases share a near complete set of risk factors. Whichever theory is correct, environmental risk factors, which are preventable, are certain to be involved in causative mechanisms.
The most important development in the study of the pathogenesis of inflammation in inflammatory bowel disease was the publication of three papers demonstrating that genetically manipulated mice developed chronic intestinal inflammation similar to human inflammatory bowel disease. Two of these genetic models comprised cytokine knockouts (interleukin-2 and interleukin-10), the third model included a series of genetic defects in the T-cell receptor (a and (3 chains) or the class II major histocompatibility complex. One striking characteristic of these models was the limitation of pathology to the gastrointestinal tract, even though these were all defects in systemic immunity that might have been expected either to cause widespread pathology or to be incompatible with life. The second striking characteristic of these models was the influence of colonic bacteria on the development of pathology.
Many centers worldwide have reported an increased incidence of Crohn's disease, but population-based data in North America are sparse. We studied the incidence and prevalence of Crohn's disease in Olmsted County, Minnesota, and examined temporal trends in incidence and survival.
Residents diagnosed with Crohn's disease between 1970 and 1993 were incidence cases, and residents with Crohn's disease who were alive on January 1, 1991, were prevalence cases. Cases from previous studies were reconfirmed. Rates were adjusted using 1990 U.S. Census figures for whites. Incidence trends were evaluated with a Poisson regression model. Survival from diagnosis was compared with that expected for U.S. north-central whites.
Between 1940 and 1993, 225 incidence cases were identified, for an adjusted incidence rate of 5.8 per 100,000 person-years. On January 1, 1991, there were 145 residents with Crohn's disease, an adjusted prevalence rate of 133 per 100,000, 46% higher than that seen in 1980. Incidence rates before 1964 were significantly lower than those of 1989-1993. Observed survival was less than expected (P = 0.007).
The incidence of Crohn's disease has stabilized since the 1970s at a rate higher than that seen previously. Prevalence has increased by 46% since 1980. Overall survival is slightly decreased.
Of 213 patients with proctitis of all etiologies seen between 1977 and 1987, we studied an original cohort of 96 patients with idiopathic ulcerative proctitis (mean follow-up of 62 months). The diagnosis was made according to strict inclusion criteria, and all cases with any initial feature suggestive of Crohn's disease were excluded. Follow-up showed that 13 patients (13.6%) eventually progressed to Crohn's disease, usually within the first 3 years of the initial diagnosis of idiopathic ulcerative proctitis. Their clinical, endoscopic and histological features at initial presentation were indistinguishable from those in whom the diagnosis remained that of idiopathic ulcerative proctitis. In nine of 13 of these patients (70.0%), the clinical course was characterized by a more protracted course and a poorer response to standard treatment. Such features were not found in those in whom the diagnosis of idiopathic ulcerative proctitis was maintained. Clinicians should be aware that Crohn's disease may present initially as apparent idiopathic ulcerative proctitis.
Publications involving the clinical epidemiology of inflammatory bowel disease were plentiful in 1993. Greater understanding was made in the diagnosis, etiology, and natural history of disease. Specifically, a newer diagnostic technique of technetium-labeled leukocyte scanning appeared to be as accurate with lower radiation exposure than other nuclear medicine alternatives. Etiologically, work continued on two fronts. Genetic studies demonstrated homogenous groups within these heterogenous diseases, groups that may share etiologic, prognostic, and therapeutic advantages. Also, promising work continued the search for the infectious agents responsible for inflammatory bowel disease. Prognosis in patients with ulcerative colitis appears to be directly related to extent of disease at diagnosis. Inroads were made in finding some of the genetic mutations responsible for neoplastic transformation and cancer-related motility reduction through either risk factor intervention or surveillance of high-risk patients remained an area of considerable interest. Despite these insights, this year's literature seemed to uncover more questions than were answered.
Fecal levels of trypsin and α-chymotrypsin in patients with Crohn’s disease (CD) were compared with those in healthy subjects. About one-third of the patients with CD had higher levels of trypsin and α-chymotrypsin than the healthy subjects studied. Patients in whom the ileum was affected had higher median values than those in whom the disease was confined to the colon. Possible consequences of high levels of proteolytic enzymes in feces of patients with CD are discussed.Copyright © 1982 S. Karger AG, Basel
The intestinal beta-glucoronidase was studied in germfree, monocontaminated and conventional rats. The greater part of the beta-glucuronidase of the caecum and the large intestine of the contaminated animals was of bacterial origin. No bacterial beta-glucuronidase was found in the small intestine. Monocontamination with Escherichia coli gave activities corresponding to those of the conventional rats, whereas content from the caecum and the large intestine of the rats monocontaminated with Streptococcus pyogenes showed an activity approximately 10 per cent of that of the conventional rats.
Saccharin and its salts are the most extensively consumed artificial sweeteners in the United States today. The current controversy about the risks of their use to human health has surfaced from research findings that report an increased incidence of cancer, primarily of the urinary bladder, in certain animal species and man chronically exposed to these agents. The April 1977 proposal by the Food and Drug Administration to restrict use of saccharin was based on these investigations. The intense public response against any ban has led to Congressional deliberations over the fate of saccharin during the present moratorium and information-gathering period. Since diabetic patients are among the principal users of this compound, it appears timely to review the evidence for and against its carcinogenic potential.
It is stated that 10-20% of cases of non-specific inflammatory bowel disease cannot be classified. Thirty such cases, designated colitis indeterminate at the time of colectomy, were identified from the pathology files of St. Mark's Hospital. The Histopathological features of the surgical specimens and any available biopsy specimens were studied. In nearly all the cases urgent surgery had been required and the features of incipient or established fulminating disease were present. The pathology of these cases of Crohn's disease and ulcerative colitis overlapped, and differentiating features were scant or unreliable. Accepted criteria of Crohn's disease--namely, fissuring ulceration, transmural inflammation, and a maintained goblet-cell population--were found in cases subsequently proved to be ulcerative colitis. Disease activity greatly affected the evaluation of morphological features. Many of the difficulties were resolved when biopsy material obtained during a quiescent phase was examined. The specimens gave a dynamic perspective of the disease process, often more valuable than the static, non-specific picture of acute disease seen in the surgical specimens. Case of colitis indeterminate form a small distinctive group in the spectrum of inflammatory bowel disease which is characterised by a common pattern of pathology that presents a diagnostic dilemma.
We conducted a population-based case-control study of inflammatory bowel disease and dietary habits in Stockholm during 1984-1987. We obtained retrospective information about food intake 5 years previously by a postal questionnaire for 152 cases with Crohn's disease, 145 cases with ulcerative colitis, and 305 controls. The relative risk of Crohn's disease was increased for subjects who had a high (55 gm or more per day) intake of sucrose (relative risk = 2.6, 95% confidence interval = 1.4-5.0) and was decreased for subjects who had a high (15 gm or more per day) intake of fiber (relative risk = 0.5, 95% confidence interval = 0.3-0.9). The most striking finding was an increased relative risk of both Crohn's disease and ulcerative colitis associated with consumption of fast foods: the relative risk associated with consumption of fast foods at least two times a week was estimated at 3.4 (95% confidence interval = 1.3-9.3) for Crohn's disease and 3.9 (95% confidence interval = 1.4-10.6) for ulcerative colitis. Although coffee seemed to provide a protective effect for both diseases, there are reasons to consider this finding an artifact.
Of 213 patients with proctitis of all etiologies seen between 1977 and 1987, we studied an original cohort of 96 patients with idiopathic ulcerative proctitis (mean follow-up of 62 months). The diagnosis was made according to strict inclusion criteria, and all cases with any initial feature suggestive of Crohn's disease were excluded. Follow-up showed that 13 patients (13.6%) eventually progressed to Crohn's disease, usually within the first 3 years of the initial diagnosis of idiopathic ulcerative proctitis. Their clinical, endoscopic and histological features at initial presentation were indistinguishable from those in whom the diagnosis remained that of idiopathic ulcerative proctitis. In nine of 13 of these patients (70.0%), the clinical course was characterized by a more protracted course and a poorer response to standard treatment. Such features were not found in those in whom the diagnosis of idiopathic ulcerative proctitis was maintained. Clinicians should be aware that Crohn's disease may present initially as apparent idiopathic ulcerative proctitis.
The function of the intestinal microflora was studied in patients with ulcerative colitis before and after colectomy. The following six microflora-associated characteristics (MACs) were investigated: formation of coprostanol and urobilinogen; degradation of mucin, water-soluble protein, and beta-aspartylglycine; and presence of faecal tryptic activity. In 12 unoperated patients without sulphasalazine as maintenance therapy the six MACs were similar to those in normal subjects. In 12 unoperated patients receiving sulphasalazine the formation of coprostanol and urobilinogen was significantly lower (p less than 0.01 and p less than 0.001, respectively) and the level of faecal tryptic activity was significantly higher (p less than 0.01) than in normal subjects. The functional capacity of the microflora in operated patients treated by colectomy combined with one of four surgical procedures (ileorectal anastomosis, ileoanal anastomosis with pelvic pouch, Kock's continent ileostomy, or conventional ileostomy) was disturbed with regard to all six MACs. The disturbance was most pronounced in patients with conventional ileostomy.
Rats fed a diet containing 2.5% sodium saccharin (NaSacc) displayed a rapid (24-36 hr) increase in tryptic and chymotryptic activity in the lower half of the small intestine and the cecum compared with control animals. Cecal pH of rats fed NaSacc was lower than controls. The effect of NaSacc on enzymatic activity of intestinal contents and on indigenous bacterial microflora was studied further in vitro. Intestinal contents incubated anaerobically with or without NaSacc revealed that the presence of NaSacc led to higher tryptic and chymotryptic activity and higher final pH. Changes in pH do not appear, however, to be important for the increased proteolytic activity induced by NaSacc since autodigestion of trypsin and chymotrypsin in filter-sterilized samples was only slightly affected by pH during in vitro incubation. Amylolytic activity, on the other hand, was stabilized by higher pH values. Saccharin stabilized chymotryptic and led to almost complete loss of amylolytic activity during incubation of filter-sterilized samples maintained at adjusted pH values. The amount of reducing sugars remaining in the NaSacc-containing contents from either cecum (in vivo) or from in vitro incubation of unsterilized small intestinal samples was greater than controls not containing NaSacc. The growth of six bacterial strains isolated from small intestinal contents and incubated in laboratory media was inhibited by NaSacc. Extracellular proteolytic activity from bacterial sources was undetectable after incubation of intestinal bacteria in laboratory media. The present results suggest that the effect of NaSacc upon digestive enzyme composition in the small intestine of rats is not mediated through a direct physiological effect of NaSacc on pancreatic exocrine secretion. It is hypothesized that an inhibition of enzymatic activity by NaSacc in the small intestine and the bacteriostatic effect of NaSacc on bacteria may be responsible for the increased proteolytic activity observed in vivo in the cecum following the feeding of a NaSacc-containing diet to rats.
The mucosal enzyme activities of 11 marker enzymes from the brush border, basolateral membrane, and lysosomes of 45 patients with an active duodenal ulcer (DU) were determined by analysis of homogenized biopsy specimens obtained from the duodenal bulb and descending duodenum at endoscopy. They were compared with activities measured in 22 controls. In the duodenal bulb lactase (p less than 0.005), neutral-alpha-glucosidase (p less than 0.0005), and monoamine oxidase (p less than 0.0005) were significantly decreased in DU patients. In the descending duodenum all the brush border enzymes except sucrase were significantly decreased when compared with controls. DU patients with inflammation in the biopsy specimens from the duodenal bulb had decreased levels of lactase (p less than 0.05), sucrase (p less than 0.05), neutral-alpha-glucosidase (p less than 0.05), leucyl-beta-naphthylamidase (p less than 0.05), and acid phosphatases (p less than 0.05) when compared with DU patients with normal histology in this region. In the descending duodenum the activities of leucyl-beta-naphthylamidase (p less than 0.05) were decreased in patients with inflammation compared with those without such histologic changes. DU patients who had taken antacids before the investigation had decreased activities of lactase (p less than 0.05) in the descending duodenum when compared with those who had not taken antacids. Activities of lactase (p less than 0.005), sucrase (p less than 0.005), neutral-alpha-glucosidase (p less than 0.05), and acid beta-glucuronidase (p less than 0.0005) in the descending duodenum were significantly lower in smokers than in non-smokers with active DU.
The specific susceptibility of the intestinal mucosa to low blood flow states is related to the "physiologic" makeup of the intestinal milieu. Pancreatic proteases appear to play a crucial role in the ischemic autodigestion of the intestinal mucosa. Moreover, trypsin can activate the conversion of xanthine dehydrogenase into superoxide radicals producing xanthine oxidase. Oxygen-derived free radicals account for at least part of the damage to the postischemic intestinal mucosa.
Male Sprague-Dawley rats were fed a purified fibre-free diet containing 5% (w/w) sodium saccharin for 4 weeks or 20 weeks and changes in caecal bacterial numbers and enzyme activities (endogenous ammonia production, beta-glucosidase, beta-glucuronidase, nitrate reductase, nitroreductase, aryl sulphatase) determined in vitro. Saccharin treatment gave marked caecal enlargement but had no effect on bacterial concentration at either treatment period, and significantly decreased beta-glucuronidase, nitrate reductase and sulphatase activities/g caecal contents. The incubation of a suspension of caecal contents from control rats with saccharin (75 mM) in vitro inhibited beta-glucuronidase and nitrate reductase activities, and ammonia production from endogenous substrates. Such changes may decrease the rate of formation of toxic bacterial products in the hindgut.
Changes of activity of intestinal acid beta-galactosidase, beta-glucuronidase, N-acetyl-beta-glucosaminidase and arylsulphatase were studied in suckling rats treated with cortisone (5mg/100g body wt. daily, started on day 9 postnatally) and compared with changes in control animals. Specific activities were not changed within the first 72h, but all enzymes decreased similarly 96h after the first injection. Total activities per ileum and animal were not changed within the first 48h, but within 72h a significant decrease was observed. Calculation of the rate of decrease of the hydrolases studied in cortisone-treated animals shows that it proceeds faster than the rate of renewal of enterocytes in this period.
Saccharin, first synthesized in 1879, eventually became popular as an inexpensive substitute for sugar, particularly as a non-caloric sweetner. The dispute concerning the safety of saccharin for human consumption is almost as old as saccharin itself. In this article, the history concerning the uses of saccharin and the accompanying controversy are reviewed. In addition, the spectrum of toxicological and epidemiological studies to which saccharin has been subjected are also examined. While the toxicological data indicate that saccharin is probably the agent solely responsible for the bladder tumors observed in second generation male rats, the epidemiological studies provide, at best, an equivocal relationship between the consumption of saccharin and bladder cancer. A benefit-risk evaluation for saccharin showed few, if any documentable benefits from the use of saccharin and much genuine uncertainty concerning the potential risks for ingestion by man. This element of genuine uncertainty as to the extent of human risk posed to man is the crux of saccharin's past and its foreseeable future.
Impressive evidence has accumulated over the past 12 years indicating that one of the potentially important biophysical characteristics of mucus relates to its hydrophobic character. This surface property is region specific and reaches high values in the stomach and colon, where barrier properties against noxious agents in the lumen are most important. The hydrophobic properties of mucus appear to be related to its lipidic constituents and specifically to the presence of phospholipid surfactants that are synthesized, stored, and secreted by GI mucus cells in a regulated fashion.
The aim of the study was to examine microflora-associated characteristics in patients with inactive ulcerative colitis, receiving sulphasalazine, in relation to the spread of the disease. The conversion of cholesterol to coprostanol, the production of urobilinogen, and the degradation of tryptic activity (FTA) and beta-aspartylglycine were measured in faecal samples from patients with proctitis or left-sided or total ulcerative colitis and in age- and sex-matched controls. No significant differences in the results were observed in patients with various degrees of extension of inflammatory bowel disease. However, the coprostanol ratio and the urobilinogen level were lower and the FTA was higher in patients with colitis than in the controls (p < 0.05). Beta-aspartylglycine was not found in any faecal sample. The results indicate that patients with ulcerative colitis taking sulphasalazine have a microflora with abnormal metabolic characteristics.
Enzymes produced by colonic microflora have been proposed for triggering local delivery of antiinflammatory azo-bond drugs and prodrugs to the colon. This approach could be advantageous in steroid treatment of inflammatory bowel diseases, thus sparing steroids' side effects. We recently demonstrated that the metabolic activity of digestive flora, assessed on the activity of fecal glycosidases, was decreased in patients with active Crohn's disease. In the present study, the azoreductase activity in feces of 14 patients with active Crohn's disease was decreased (11.39 +/- 7.93 mU/g F) as compared with 12 healthy subjects (51.13 +/- 21.39 mU/g F). beta-D-Glucosidase and beta-D-glucuronidase activities in fecal homogenates incubated under anaerobic conditions were also decreased in patients. These data bring into question the therapeutic usefulness for those patients of azo-bond drugs and glycoside prodrugs. They could explain the therapeutic failure of some of those drugs in active ileocolic and colic Crohn's disease.
During the past 20 years there has been growing interest in the importance of nutritional factors in the pathogenesis of inflammatory bowel disease. There are so far no definite links between ulcerative colitis and diet, but links with Crohn's disease have been studied by both epidemiologists and clinicians. Epidemiological studies, although retrospective, have suggested that patients with Crohn's disease eat more sugar and sweets that control individuals; however, when dietary sugar is restricted, there is little clinical benefit. The clinical approach to nutrition in Crohn's disease has been by the use of elemental diets, which will produce symptomatic and objective remission in up to 90% of compliant patients. Those who return to normal eating soon relapse but, in some studies, have enjoyed prolonged remission on exclusion diets. The foods excluded have been not sugar, but predominantly cereals, dairy products and yeast. Attention has now switched to the possible harmful role of fat in Crohn's disease. The efficacy of elemental feeds appears to depend not on the presentation of nitrogen but on the amount of long chain triglyceride present. Increases in recent years in the frequency of Crohn's disease in Japan have been correlated with increased dietary fat intake, and a recent study suggested that W-3 fatty acids, which are metabolized by immunomodulatory leukotrienes and prostaglandins, may have a beneficial role to play. The links between nutrition and Crohn's disease have now become strong and the role of fat may be the most exciting of all.
Based on clinical studies, the Rome Criteria for the irritable bowel syndrome (IBS) were developed by consensus. The criteria emphasize the presence of abdominal pain and the link between pain and changes in bowel habit. The reliance on a clinical gold standard rather than a biological marker remains one of the major limitations in refining diagnostic criteria. A convincing argument can be mounted that IBS is a disease (a cause of unease). Approximately 10-15% of the general population have IBS, and it affects females more often than males, for unexplained reasons. The annual incidence is probably 1-2%. The onset of symptoms is balanced by symptom loss, so the prevalence remains stable from year to year. Up to one half have symptom improvement over time. Only a minority present for medical care; pain severity as well as psychological distress in part explain health-care seeking. IBS significantly impacts on quality of life. The economic impact is enormous, representing a multi-billion dollar problem in the United States. The development of acceptable, symptom-based diagnostic criteria has advanced the field, stimulating interest in the pathophysiology and targeted pharmacological therapy, which are essential steps if the disease burden is to be reduced.
Proteinase-activated receptors (PARs) have the common property of being activated by the proteolytic cleavage of their extracellular N-terminal domain. The new NH2-terminus acts as a ‘tethered ligand’ binding and activating the receptor itself. Four members of this family have been cloned, three of which are activated by thrombin (PAR-1, PAR-3 and PAR-4) while the fourth (PAR-2) is activated by trypsin or mast cell tryptase.
In physiological or pathophysiological conditions, the gastrointestinal tract is exposed more than other tissues to proteinases (digestive enzymes, proteinases from pathogens or proteinases from inflammatory cells) that can activate PARs. Since PARs are highly expressed throughout the gastrointestinal tract, the study of the role of PARs in these tissues appears to be particularly important.
It has already been shown that PAR-2 activation induces calcium mobilization and eicosanoid production in enterocytes as well as changes in ion transport in jejunal tissue segments. PAR-2 activation also causes calcium mobilization and stimulates amylase release from pancreatic acini. Moreover, both PAR-1 and PAR-2 activation can alter the gastrointestinal motility. In inflammatory or allergic conditions, the proteinases that constitute the major agonists for PARs (thrombin, trypsin and mast cell tryptase) are usually released. The activation of PARs by these proteinases might contribute to the gastrointestinal disorders associated with these pathologies.
A complete understanding of the role of PARs in the gastrointestinal tract will require the development of selective receptor antagonists that are not yet available. Nonetheless, the use of PAR agonists has already highlighted new potential functions for proteinases in the gastrointestinal tract, thus the control of PAR activation might represent a promising therapeutic target.
The genetics of ulcerative colitis and Crohn's disease
- Yang