'Faulty cellular batteries' and leaky gut – a new potential cause of Crohn’s disease and ulcerative colitis

Crohn's Disease and Ulcerative Colitis are the two main forms of Inflammatory Bowel Disease (IBD), affecting more than 300,000 people in the UK. Once diagnosed, they are lifelong conditions as they are incurable. Up to 6,000 new cases a year are diagnosed, and numbers are rising steadily, especially among young people. Like common diseases such as asthma and diabetes, IBD may result from many complex and wide-ranging reasons such as genetics, diet, lifestyle and environmental factors. In a recent study using mouse and human cells published in Mucosal Immunology, researchers at the University of Edinburgh’s MRC Centre for Inflammation Research led by Dr Gwo-tzer Ho found a new potential cause for IBD.

The mitochondria ('cellular batteries') provide energy and play many key roles that maintain the health and function of living cells. Each cell has two main parts: the nucleus and the cytoplasm (like the yolk and white of an egg). The nucleus contains the DNA or instructions for the cell. It determines how the cell functions and what it will be. The cytoplasm is the workshop where the instructions are carried out. It contains tiny 'organelles' which do this work. Some of these organelles are mitochondria and they exist within this protected environment to make energy for cell to live and flourish.

In the gut, a single line of cells provides a barrier against trillions of bacteria, toxins and foreign particles. The mitochondria within the lining of the large bowel are particularly exposed to these damaging factors in the gut. Using a mouse model with many similarities to human inflammatory bowel disease, Dr Ho showed that failure of an important biological ‘extractor pump’ located within the cell wall – the multidrug-resistant 1 (MDR1) transporter that removes these toxins, result in mitochondria damage with a subsequent weakening of the gut barrier leading to a leaky gut, a finding which is frequently observed in human IBD.

In health, these damaged mitochondria ('faulty batteries') are effectively repaired, renewed, re-cycled or packaged away for safe disposal. By analysing the DNA from approximately 90,000 individuals (40,000 with IBD and 50,000 from healthy volunteers), they found many important genes (~30) involved in maintaining the health of the mitochondria are linked to IBD. These findings suggest that biological processes that protect the mitochondria are important, and that they may not work properly or are overwhelmed in IBD.

This research funded by Medical Research Council (MRC) and Crohn’s Colitis UK (CCUK) shows an entirely new and concise causative mechanism. Interestingly, the authors showed drug treatment that protects the function of mitochondria, can improve and treat gut inflammation in mouse IBD. Thus showing realistic promise that future new drug treatments can be developed in humans soon.

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Ho GT, Aird RE, Liu B, Boyapati RK, Kennedy NA, Dorward DA, Noble CL, Shimizu T, Carter RN, Chew ET, Morton NM, Rossi AG, Sartor RB, Iredale JP, Satsangi J. MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation. Mucosal Immunol. 2017 Apr 12. doi: 10.1038/mi.2017.31. [Epub ahead of print], PMID: 28401939

Published paper in Nature.com