May artificial sweeteners not sugar be the culprit of dramatic increase of inflammatory bowel disease in China?

As we know, inflammatory bowel disease (IBD) is typically used as a general term for ulcerative colitis (UC) and Crohn's disease (CD), two highly related debilitating diseases of the digestive tract with similar clinical, pathological, and epidemiological features.1,2 Both UC and CD are most prevalent in young adults and still incurable. The patients usually depend on constant heavy medication and frequently need multiple devastating surgeries such as bowel resection, proctocolectomy, ileostomy, and ileal pouch-anal anastomosis.2,3 IBD emerged and dramatically increased in the last century, started from industrialized countries in the West,1,2 which made people suspect that IBD may be caused by the improved hygiene.4,5 However, IBD in the industrialized countries in Asia remains much lower than those in the West, and there were ups and downs in the incidence of IBD even in the developed countries in the West,1,2,6 suggesting some agents in the environment may have played a critical role. In China, the incidence of IBD used to be very low, but multiple recent studies revealed a dramatic increase. For instance, the study by Wang et al showed that the incidence of pediatric IBD in Shanghai increased 12-fold during 2000–2010.7 More surprisingly, another recent prospective, population-based study found that “China had the highest incidence of IBD in Asia,” with Guangzhou (China) having an even higher incidence of IBD than the neighboring Hong Kong (China) and Macau (China).8 There would be an urgent need to find out the cause behind this. I find it interesting for the recent paper by Wang et al9 regarding their multicenter case-control study in China on risk factors for UC, which has been the main form of IBD in the country. This is a large-scale study with more than a thousand patients and controls from 17 hospitals located in multiple cities all over China and included multiple risk factors such as smoking, appendectomy, stress, socioeconomic conditions, nonsteroidal anti-inflammatory drugs, oral contraceptives, diet, breastfeeding, infections, and family sanitary conditions. It revealed three risk factors: spicy food, sugar, and stress.9 As stress is a mental problem, sugar and spicy food thus are the two environmental risk factors found. The study by Ng et al8 revealed that Guangzhou, the capital city of Guangdong Province with sugar usually an important ingredient in its cuisine has an IBD incidence of 3.44/1 00 000 (CD 1.09, UC 2.05), while Chengdu, the capital city of Sichuan Province, well known for its hot and spicy cuisine, has an IBD incidence of only 0.58 (CD 0.15, UC 0.42) that is almost the same as Xi'an (IBD 0.50, CD 0.05, UC 0.41, undetermined 0.04), the capital city of Shaanxi Province with plain flavor cuisine, suggesting sugar but not spicy food would likely have more tight link with IBD. This increased intake of sugar in IBD patients is in accordance with many other previous studies across Europe, America, and Asia.10–20 However, some in-depth studies revealed that there was no coherent relationship between sugar consumption and the geographic and temporal patterns of CD.21 Controlled clinical trials also failed to show a beneficial effect with the restricted use of sugar.22 These studies suggest sugar is unlikely the direct cause of IBD. Then, how to explain the close relationship between sugar and IBD as shown in the many studies? About a decade ago, a series of findings made me suspect that saccharin, the first and oldest artificial sweetener that has been used by human since later 1880s, may have played an important causative role in IBD through its inhibition on gut bacteria and the resultant impaired inactivation of digestive proteases and excessive damage of the mucus layer and the underlying gut tissue.23 It provided simple explanations for many puzzles in IBD such as the emerging of clustered cases of IBD a century ago, the dramatic increase of IBD in the Western countries since the 1950s, and the leveling off or decrease of IBD seen in multiple studies during later 1970s and early 1980s at the time when saccharin was found causing cancer in animals. A couple of years early, I further found that sucralose, a new generation of artificial sweetener may also be linked to IBD through a similar mechanism as saccharin, which may provide an explanation of the recent worldwide increase of IBD.24 This eventually led me publishing in 2012 a unified hypothesis on the etiology of IBD, including the cause and mechanism of IBD as well as the relationship between UC and CD.25 It included some evidences collected at that time suggesting the possible link between sucralose and IBD such as the remarkable increase of IBD in Alberta of Canada since the early 1990s, in Brisbane of Australia since the mid-1990s, in north California of the USA since the end of 1990s, and in South-Eastern Norway since the mid-2000s, shortly after the approval of sucralose in Canada in 1991, in Australia in 1993, in the USA in 1998, and by the European Union in 2004. After the publication of that paper, more epidemiological studies from Ireland, Singapore, Saudi Arabia, Sweden, and so on came out and they all can be easily explained by the unified hypothesis proposed earlier.26–31 Sucralose was approved in China by the end of the last century, which is again in accordance with the recent dramatic increase of IBD seen in children in Shanghai.7 Therefore, I suspect that the increased intake of artificial sweeteners such as saccharin and sucralose but not the sugar itself may be the real culprit responsible for the recent dramatic increase of IBD in China and recommend checking out this possibility.

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