A groundbreaking study from the RIKEN Center for Integrative Medical Sciences in Japan sheds new light on a medical paradox that has mystified clinicians and researchers for decades: Why does smoking, generally harmful to health, seem to alleviate inflammation in ulcerative colitis, a form of inflammatory bowel disease? Published in the journal Gut, this research led by Dr. Hiroshi Ohno elucidates a novel mechanism involving oral bacteria, gut metabolites, and immune modulation that explains the protective effect smoking imparts on ulcerative colitis patients.
Ulcerative colitis and Crohn’s disease represent the two major categories of inflammatory bowel disease (IBD), both characterized by chronic and debilitating inflammation of the gastrointestinal tract. Interestingly, smoking exacerbates the risk and severity of Crohn’s disease, yet paradoxically affords protection against ulcerative colitis. This contradictory phenomenon has puzzled scientific minds since the 1980s, owing to the complex interplay between environmental factors, gut microbiota, and host immunity. Dr. Ohno’s team ventured to decipher this biological enigma by focusing on alterations in microbial populations and metabolic products within the gut of smokers afflicted with ulcerative colitis.
Using a multifaceted approach blending human clinical observations and meticulously controlled murine experiments, the researchers uncovered that smokers with ulcerative colitis harbor distinct populations of oral bacteria in their colonic mucosa—specifically, species within the Streptococcus genus. Normally, these oral microbes transit through the gut without establishing residence; however, smoking promotes conditions conducive to their colonization. The presence of Streptococcus in the colonic mucosal layer, where inflammation initiates and propagates, was notably absent in non-smokers and ex-smokers, suggesting a direct link between smoking-induced changes and bacterial relocation.
The researchers probed deeper to understand what smoking triggers in the gut environment to favor Streptococcus proliferation. By analyzing gut metabolites—small molecules produced through microbial and host metabolic interactions—they identified elevated levels of aromatic compounds such as hydroquinone in smokers. Hydroquinone is known for its antioxidative properties and its ability to influence microbial growth dynamics. In experimental models, hydroquinone supplementation encouraged the establishment and growth of Streptococcus within the gut mucosal biofilm, effectively mimicking the microbial landscape observed in human smokers with ulcerative colitis.
Elucidating the immunological ramifications of this microbial shift was central to understanding the disease-modifying effects of smoking. The team isolated several bacterial strains from smoker saliva and administered them to mouse models genetically and chemically induced to replicate ulcers found in Crohn’s disease and ulcerative colitis. Remarkably, administration of Streptococcus mitis replicated the anti-inflammatory benefits seen in human smokers with ulcerative colitis, whereas it intensified inflammation in mice modeling Crohn’s disease. This bifurcated immune response underscores the nuanced role of host-microbial interactions within the context of distinct inflammatory pathologies.
Central to these findings is the modulation of T helper cell subtypes by S. mitis. Specifically, the bacterium stimulates the activation of helper T cell type 1 (Th1), a subset traditionally associated with pro-inflammatory responses. Paradoxically, in ulcerative colitis, the pathological inflammation is driven by an overactive Th2 immune response. The Th1 cells induced by S. mitis suppress this aberrant Th2 activation, thereby attenuating inflammation. Conversely, in Crohn’s disease, where Th1-mediated inflammation predominates, further activation of Th1 cells by S. mitis aggravates disease symptoms.
The clinical implications of these findings are profound, highlighting a microbial-metabolite-immune axis as the mediator of smoking’s dichotomous effects on inflammatory bowel diseases. Smoking-induced hydroquinone creates a niche favorable to Streptococcus colonization, which in turn modulates mucosal immunity through Th1 activation, mitigating ulcerative colitis pathology while worsening Crohn’s disease. Understanding the specificity of this interaction opens avenues for therapeutic interventions that replicate smoking’s beneficial influences without the accompanying health risks.
Dr. Ohno emphasizes that smoking itself, with its well-documented detrimental impact on cancer, cardiovascular health, and respiratory function, can never be recommended as a treatment modality. Instead, the insights garnered encourage the development of probiotic therapies utilizing S. mitis or analogous bacterial strains to harness the immunomodulatory benefits safely. Additionally, prebiotic compounds like hydroquinone or its derivatives may be engineered to create gut environments favorable for beneficial bacterial colonization, offering symptom relief to ulcerative colitis patients through microbiota-targeted strategies.
This study advances the broader understanding of the gut microbiota’s role in immune homeostasis and disease modulation. By delineating the mechanism behind the paradoxical effect of smoking on two related but immunologically distinct disorders, it exemplifies how microbial ecology and host metabolism interlace to dictate disease outcomes. Moreover, these findings might inspire research into other microbial metabolites with the potential to reshape immune responses in chronic inflammatory states.
The methodological rigor—combining human microbiome analyses, metabolic profiling, and functional in vivo experiments—adds persuasive weight to the conclusions. The isolated pinpointing of S. mitis as a key mediator represents a significant step forward in microbiome research and its translational potential in gastroenterology. Future research will likely explore optimal dosages, safety profiles, and delivery methods for probiotic or prebiotic therapies based on these findings.
As the scientific community grapples with the complex interdependencies between environmental exposures, microbial ecosystems, and immune function, this study sets a precedent for integrating multidisciplinary research approaches to resolve longstanding clinical paradoxes. By transforming a harmful behavior like smoking into a mechanistic blueprint for novel treatments, the work led by RIKEN IMS illuminates an innovative path in both microbiology and immunotherapy.
In conclusion, the discovery that smoking-derived metabolites foster the colonization of oral bacteria such as Streptococcus mitis in the gut, triggering a beneficial Th1 immune response that counterbalances harmful Th2 activity, explains the protective effect of smoking in ulcerative colitis. Leveraging this insight, future interventions may safely mimic smoking’s advantages without exposing patients to its risks, heralding a new era in personalized microbiota-based therapies for inflammatory bowel diseases.
Subject of Research: Ulcerative colitis, Crohn’s disease, gut microbiota, immune modulation, smoking-related metabolites
Article Title: Smoking’s Paradoxical Protection Against Ulcerative Colitis Explained by Gut Microbiota and Immune Response Modulation
News Publication Date: August 25, 2025
Web References: DOI: 10.1136/gutjnl-2025-334922
Image Credits: RIKEN
Keywords: Health and medicine, Life sciences, Microbiota, Human gut microbiota, Gut microbiota, Diseases and disorders, Gastrointestinal disorders, Inflammatory bowel diseases, Ulcerative colitis, Crohn disease, Metabolism, Metabolites, Public health, Tobacco, Disease susceptibility
