The Crohn’s disease polymorphism, ATG16L1 T300A, alters the gut microbiota and enhances the local Th1/Th17 response
| Autor: | Aleksander Kostic, Ashwin N. Ananthakrishnan, Carey Ann Gallini Comeau, Sydney Lavoie, Wendy S. Garrett, Humberto Jijon, Kara G. Lassen, Hera Vlamakis, Monia Michaud, Hui Pan, Jonathan N. Glickman, Kara L. Conway, Jonathan M. Dreyfuss, Ramnik J. Xavier, Eunyoung Chun, Jessica K. Lang |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Mouse Autophagy-Related Proteins Crohn's Disease Disease Gut flora Inflammatory bowel disease Bacteroides ovatus Feces Mice Immunology and Inflammation 0302 clinical medicine Crohn Disease Bacteroides Gene Knock-In Techniques Biology (General) ATG16L1 Microbiology and Infectious Disease Crohn's disease biology General Neuroscience digestive oral and skin physiology General Medicine Fecal Microbiota Transplantation Ulcerative colitis 3. Good health 030220 oncology & carcinogenesis gut Medicine medicine.symptom Research Article Risk Genotype QH301-705.5 Science Inflammation digestive system General Biochemistry Genetics and Molecular Biology ATG16L1T300A 03 medical and health sciences Immune system medicine Animals Humans Alleles Polymorphism Genetic General Immunology and Microbiology business.industry T cell Th1 Cells medicine.disease biology.organism_classification Gastrointestinal Microbiome 030104 developmental biology Immune System Immunology Dysbiosis Th17 Cells business |
| Zdroj: | eLife, Vol 8 (2019) eLife |
| Popis: | Inflammatory bowel disease (IBD) is driven by dysfunction between host genetics, the microbiota, and immune system. Knowledge gaps remain regarding how IBD genetic risk loci drive gut microbiota changes. The Crohn’s disease risk allele ATG16L1 T300A results in abnormal Paneth cells due to decreased selective autophagy, increased cytokine release, and decreased intracellular bacterial clearance. To unravel the effects of ATG16L1 T300A on the microbiota and immune system, we employed a gnotobiotic model using human fecal transfers into ATG16L1 T300A knock-in mice. We observed increases in Bacteroides ovatus and Th1 and Th17 cells in ATG16L1 T300A mice. Association of altered Schaedler flora mice with B. ovatus specifically increased Th17 cells selectively in ATG16L1 T300A knock-in mice. Changes occur before disease onset, suggesting that ATG16L1 T300A contributes to dysbiosis and immune infiltration prior to disease symptoms. Our work provides insight for future studies on IBD subtypes, IBD patient treatment and diagnostics. eLife digest Trillions of bacteria live inside the human gut. From helping to digest our food to producing vitamins, these bacteria can have a big impact on our health, yet some people tolerate these bacteria better than others. In some cases, the body reacts badly to its own bacteria, stimulating an over-exuberant immune response. The gut becomes too inflamed, causing pain and diarrhoea, which could lead to an inflammatory bowel disease such as Crohn’s disease or ulcerative colitis. The symptoms of inflammatory bowel disease can vary from person to person, and how someone responds to treatment can be as individual as the symptoms as well. The causes of inflammatory bowel disease are complex; our genes, immune system and gut bacteria all play a role. Previous research has found hundreds of mutations in our genes that increase a person’s risk of developing inflammatory bowel disease. No single mutation is the root cause for every one person with inflammatory bowel disease, and individuals with these mutations may not even develop the condition. For those who do develop the disease, certain immune cells can be found in high numbers, such as the white blood cell known as Th17 cells. People with inflammatory bowel disease may also house different bacteria compared to someone with a healthy gut. In some cases of inflammatory bowel disease, there are elevated amounts of one type of bacteria called Bacteriodes. It is not clear how these mutated genes, the types of bacteria that live inside our gut, and the immune response are all related. Lavoie et al. focused on a mutated gene, known as ATG16L1T300A, which increases risk of Crohn’s disease in humans, and the experiments compared mice that had this human mutated gene with those that did not. The mice started off germ-free, meaning that they did not have any gut bacteria. Lavoie et al. then exposed the mice to samples of human stools, which contain gut bacteria, and after a month they analysed the guts of the mice. On average, the mutant mice had more Bacteriodes and Th17 cells in their guts than the normal mice. However, none of the mice developed inflammatory bowel disease, suggesting that changes to gut bacteria and immune cells may occur before the disease can be diagnosed. Together these findings show how just one mutated gene affects the bacteria and immune cells in the gut; but there are hundreds of other known mutations linked with inflammatory bowel disease. By unravelling the effects of more of these mutations, scientists could begin to learn more about the causes of this condition, and potentially improve its treatment options. |
| Databáze: | OpenAIRE |
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