Inflammatory bowel disease comes in two main varieties, Crohn’s disease and ulcerative colitis. Although both cause chronic abdominal pain, diarrhea, fatigue and weight loss, their causes and the exact type and location of the inflammation differ. Along with these differences is a mystery that has puzzled doctors and scientists for over 40 years; smoking increases the risk of Crohn’s disease but somehow protects against ulcerative colitis. As both diseases are related to gut inflammation—which is an immune response— and gut immunity depends in part on the types of bacteria in the gut, Ohno and his team at RIKEN IMS set out to investigate whether the differential effects of smoking on these diseases can be explained by gut bacteria.
The researchers used a combination of human clinical data and experiments with mice to reach their conclusions. Among those with ulcerative colitis, they found that smokers had certain bacteria usually found in the mouth, such as Streptococcus, growing in the gut, specifically in the colonic mucosa that cover the inner lining of the intestines. This phenomenon did not occur in ex-smokers. Thus, while these bacteria normally pass all the way through the digestive system as we swallow saliva throughout the day, smoking somehow allows them to settle down in the gut mucosa.
The next question was why? The researchers also examined gut metabolites—small substances produced in the gut when food is broken down and processed by the body and gut bacteria. They found that levels of several gut metabolites were higher in smokers with ulcerative colitis than in ex-smokers with colitis. In mice, the researchers found that one of these metabolites, called hydroquinone, promoted the growth of Streptococcus in the gut mucosa. So, smoking-related metabolites like hydroquinone allow mouth bacteria like Streptococcus to flourish in the mucus layer that covers the inner lining of the intestines. But how do these bacteria help reduce inflammation? And why don’t they help in Crohn’s disease?
Diagram showing the mechanism discovered in the study. Inflammation of the intestines in ulcerative colitis results from an excessive helper Th2 immune response (white cells). Smoking leads to aromatic compounds like hydroquinone (red dots) in the colonic mucosa. This allows oral bacteria like Streptococcus (green bacteria) to thrive there, which triggers an immune response in the form of helper Th1 cell activation (black cells). Th1 cells suppress the Th2-immune response, thus alleviating the inflammation and protecting against ulcerative colitis.
The researchers then went back to the oral bacteria that they had discovered was growing in the gut mucosa of smokers with ulcerative colitis, and isolated 10 strains from the saliva of smokers. When they treated mouse models of Crohn’s disease and ulcerative colitis with each of these 10 strains for five days, they found that giving the mice S. mitis had almost the same effect as smoking. Inflammation was reduced in mice with ulcerative colitis and exacerbated in mice with Crohn’s disease.
Analysis showed that S. mitis triggered the emergence of helper Th1 cells, which are an important part of the gut’s immune response to invaders. In Crohn’s disease this likely worsens the condition because the original inflammation is actually caused by these same helper Th1 cells. But in colitis, the Th1 cells fight against an initial Th2-immune response, and this ends up reducing inflammation.
As smoking poses high risks for cancer, heart disease, and many other illnesses, it is not a sustainable treatment for ulcerative colitis. “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,” says Ohno. “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.”
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