Study Reveals How Smoking Confers Protection Against Ulcerative Colitis

A team led by Hiroshi Ohno at the RIKEN Center for Integrative Medical Sciences has uncovered the mechanism behind the long-standing puzzle of why smoking appears to protect people with ulcerative colitis, a chronic inflammatory disease of the large intestine. Published in Gut, the study demonstrates that smoking produces metabolites that allow bacteria from the mouth to thrive in the intestines, where they trigger immune responses. The findings suggest that therapies using prebiotics like hydroquinone or probiotics with bacteria such as Streptococcus mitis could offer similar benefits without the health risks linked to smoking.

Inflammatory bowel disease (IBD) exists in two major forms: Crohn’s disease and ulcerative colitis. Both involve chronic gut inflammation and symptoms such as abdominal pain, diarrhea, and weight loss, but they differ in where and how the inflammation occurs. For decades, researchers have noted a paradox: while smoking raises the risk of Crohn’s disease, it seems to protect against ulcerative colitis. Because gut immunity is shaped in part by bacterial composition, Ohno’s group set out to investigate the role of bacteria in this phenomenon.

Using patient data alongside mouse models, the researchers discovered that smokers with ulcerative colitis harbored oral bacteria, particularly Streptococcus, in the mucosal lining of the colon. This was absent in ex-smokers, meaning that smoking specifically enabled these bacteria to establish themselves in the intestinal lining instead of just passing through with swallowed saliva.

Further analysis showed that gut metabolites were key to this effect. Smokers with ulcerative colitis had higher levels of several metabolites compared to ex-smokers, including hydroquinone. In mouse experiments, hydroquinone promoted the growth of Streptococcus within gut mucosa. These findings linked smoking-induced metabolites to bacterial shifts in the intestine.

To test whether these bacteria directly influenced inflammation, the researchers isolated ten strains from smokers’ saliva and treated mouse models. One strain, Streptococcus mitis, reduced inflammation in ulcerative colitis but worsened it in Crohn’s disease. The explanation lay in immune interactions: S. mitis triggered helper Th1 cells. In Crohn’s, this aggravated disease because Th1-driven inflammation was already central, but in ulcerative colitis, Th1 cells countered Th2 responses, easing inflammation.

Given the severe long-term risks of smoking, the study points toward developing therapies that replicate its protective effect without tobacco exposure. As Ohno explains, “Our results indicate the relocation of bacteria from the mouth to the gut, particularly those of the Streptococcus genus, and the subsequent immune response in the gut, is the mechanism through which smoking helps protect against the disease. Logically, direct treatment with this kind of bacteria, or indirect treatment with hydroquinone, is thus likely to mimic the beneficial effects of smoking but avoid all the negative effects.”