A Potential Pathway May Guide New Therapies for Inflammatory Bowel Disease and Other Inflammatory Diseases

There is a critical unmet need to help tighten and maintain a healthy intestinal barrier and treat a leaky gut. Researchers have now found that a unique strain of probiotic bacteria, Bifidobacterium bifidum BB1, enhances intestinal barrier function and protects against penetration of bacteria and various harmful agents in the intestine. The findings, detailed in an articleopens in new tab/window in The American Journal of Pathologyopens in new tab/window, published by Elsevier, can help advance the development of novel, targeted, naturally occurring probiotic therapy for patients with inflammatory bowel disease (IBD) and other inflammatory diseases, such as fatty liver disease or alcoholic liver disease, that are associated with a leaky or disordered intestinal barrier.

Lead investigator Thomas Y. Ma, MD, PhD, Penn State College of Medicine, Hershey Medical Center, explains, "There is a critical need to develop nontoxic, patient-friendly, naturally occurring products such as probiotics for treatment of IBD and other inflammatory diseases associated with leaky gut. Our studies suggest that BB1 is such a precision probiotic strain; it has the unique biological activity to produce maximal intestinal barrier enhancement and also protect against the activation of inflammation."

Patients with active IBD have elevated proinflammatory cytokines, including tumor necrosis factor (TNF)-α and IL1β. TNF-α levels are markedly elevated in intestinal tissue, serum, and stool of patients with IBD and at elevated levels produce an increase in intestinal tight junction permeability. TNF-α plays a central role in promoting intestinal inflammation in patients with IBD, and anti–TNF-α antibodies are highly effective in the treatment of the active disease. Previous studies from the laboratory at Penn State College of Medicine have shown that BB1 caused a marked enhancement of the intestinal epithelial barrier function and protects against the development of dextran sulfate sodium–induced intestinal inflammation.

Dr. Ma adds, "Our results show that BB1 prevented the TNF-α increase in intestinal tight junction permeability via a toll-like receptor (TLR)-2 signal transduction pathway inhibition of NF-kB p50/p65 activation and MLCK gene. We also found that a protein called PPAR-γ was a critical intestinal cell mediator that regulated the intestinal barrier protection. Treatment of patients with active ulcerative colitis with a PPAR-γ agonist, rosiglitazone, significantly reduced the ulcerative colitis disease activity index score and resulted in an improved quality of life."

Dr. Ma concludes, "These studies unravel novel intracellular mechanisms of BB1, a unique probiotic bacterial strain, demonstrating the promise of promoting health and treating inflammatory diseases including inflammatory bowel disease by maintaining a healthy intestinal barrier and protecting against leaky gut or intestinal barrier disruption."

IBD, which includes Crohn’s disease and ulcerative colitis, is characterized by inflammation affecting the gastrointestinal tract. The defective intestinal epithelial tight junction barrier is an important pathogenic factor contributing to the development of IBD. Patients with IBD have a defective intestinal tight junction barrier, characterized by increased intestinal permeability and increased luminal antigen penetration. Intestinal epithelial cells cover the entire intestinal mucosal surface and serve as a physical and functional barrier against the intestinal permeation of noxious luminal substances, including bacterial antigens, toxins, digestive enzymes, and food by-products.

Notes for editors

The article is “Bifidobacterium bifidum Strain BB1 Inhibits Tumor Necrosis Factor-α–Induced Increase in Intestinal Epithelial Tight Junction Permeability via Toll-Like Receptor-2/Toll-Like Receptor-6 Complex–Dependent Stimulation of Peroxisome Proliferator-Activated Receptor γ and Suppression of NF-κB p65,” by Raz Abdulqadir, Rana Al-Sadi, Mohammad Haque, Yash Gupta, Manmeet Rawat, and Thomas Y. Ma (https://doi.org/10.1016/j.ajpath.2024.05.012opens in new tab/window). It appears online in The American Journal of Pathology, volume 194, issue 9 (September 2024), published by Elsevier.

The article is openly available for 90 days at https://ajp.amjpathol.org/article/S0002-9440(24)00211-6/fulltextopens in new tab/window.

Full text of the article is also available to credentialed journalists upon request. Contact Eileen Leahy at +1 732 406 1313 or [email protected]opens in new tab/window to request a PDF of the article or more information. To reach the study’s authors contact Thomas Y. Ma, MD, PhD, Penn State College of Medicine, at +1 717 531 0003 ext. 320457 or [email protected]opens in new tab/window.

The studies were supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases R01-DK-121073-01 and the J. Lloyd Huck Chair in Medicine from Penn State College of Medicine.

About The American Journal of Pathology

The American Journal of Pathologyopens in new tab/window, official journal of the American Society for Investigative Pathologyopens in new tab/window, published by Elsevier, seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches. https://ajp.amjpathol.orgopens in new tab/window

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