Crohn's disease | EPFL Graph Search

Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension, and weight loss. Complications outside of the gastrointestinal tract may include anemia, skin rashes, arthritis, inflammation of the eye, and fatigue. The skin rashes may be due to infections as well as pyoderma gangrenosum or erythema nodosum. Bowel obstruction may occur as a complication of chronic inflammation, and those with the disease are at greater risk of colon cancer and small bowel cancer. Although the precise causes of Crohn's disease (CD) are unknown, it is believed to be caused by a combination of environmental, immune, and bacterial factors in genetically susceptible individuals. It results in a chronic inflammatory disorder, in which the body's immune system defends the gastrointestinal tract, possibly targeting microbial antigens. While Crohn's is an immune-related disease, it does not appear to be an autoimmune disease (the immune system is not triggered by the body itself). The exact underlying immune problem is not clear; however, it may be an immunodeficiency state. About half of the overall risk is related to genetics, with more than 70 genes involved. Tobacco smokers are twice as likely to develop Crohn's disease as nonsmokers. It often begins after gastroenteritis. Diagnosis is based on biopsy and appearance of the bowel wall, medical imaging, and description of the disease. Other conditions with similar symptoms include irritable bowel syndrome and Behçet's disease. There is no known cure for Crohn's disease. Treatment options are intended to help with symptoms, maintain remission, and prevent relapse. In those newly diagnosed, a corticosteroid may be used for a brief period of time to rapidly improve symptoms, alongside another medication such as either methotrexate or a thiopurine used to prevent recurrence. Cessation of smoking is recommended for people with Crohn's disease.

Preexisting Heterogeneity of Inducible Nitric Oxide Synthase Expression Drives Differential Growth of Mycobacterium tuberculosis in Macrophages

John McKinney, Ophélie Rutschmann, Chiara Toniolo

Mycobacterium tuberculosis infection is initiated by the inhalation and implantation of bacteria in the lung alveoli, where they are phagocytosed by macrophages. Even a single bacterium may be sufficient to initiate infection. Thereafter, the clinical outcome is highly variable between individuals, ranging from sterilization to active disease, for reasons that are not well understood. Here, we show that the rate of intracellular bacterial growth varies markedly between individual macrophages, and this heterogeneity is driven by cell-to-cell variation of inducible nitric oxide synthase (iNOS) activity. At the single-cell level, iNOS expression fluctuates over time, independent of infection or activation with gamma interferon. We conclude that chance encounters between individual bacteria and host cells randomly expressing different levels of an antibacterial gene can determine the outcome of single-cell infections, which may explain why some exposed individuals clear the bacteria while others develop progressive disease. IMPORTANCE In this report, we demonstrate that fluctuations in the expression of antimicrobial genes can define how single host cells control bacterial infections. We show that preexisting cell-to-cell variation in the expression of a single gene, that for inducible nitric oxide synthase, is sufficient to explain why some macrophages kill intracellular M. tuberculosis while others fail to control bacterial replication, possibly leading to disease progression. We introduce the concept that chance encounters between heterogeneous bacteria and host cells can determine the outcome of a host-pathogen interaction. This concept is particularly relevant for all the infectious diseases in which the number of interacting pathogens and host cells is small at some point during the infection.

AMER SOC MICROBIOLOGY2022

Preexisting Heterogeneity of Inducible Nitric Oxide Synthase Expression Drives Differential Growth of Mycobacterium tuberculosis in Macrophages

John McKinney, Ophélie Rutschmann, Chiara Toniolo

AMER SOC MICROBIOLOGY2022