GLOW.coli
The importance of gut health has gained significant recognition in recent years. Research has shown that the composition of the gut microbiome, can help in the prevention or exasperation of many diseases including but not limited to Diabetes, Cardiovascular Disease, Rheumatoid Arthritis and Inflammatory Bowel Diseases (IBDs).[1] IBDs is an umbrella term for disease s such as Crohn’s Disease, Ulcerative Colitis and many more, which are at a rising prevalence worldwide.[2] In 2019 approximately 4.9 million cases were recorded, most of them from countries such as the US and China.[2] While IBDs have been linked to certain genetical factors[3], the main risk factors appear to be environmental[4], such as diet and pollutants. New studies have specifically linked IBD development to gut dysbiosis, a changed gut microbiome composition associated with a reduction in beneficial bacteria and associated compounds. [5]
A crucial component of a healthy gut microbiome are short-chain fatty acids (SCFAs), which are produced by bacteria in the large intestine, specifically Firmicutes and Bacteroidetes. SCFAs are fatty acids less than 6 carbons in length, most common in the human organism are acetate (C2), propionate (C3) and butyrate (C4) which - in the healthy gut - appear in the ratio of 57:22:21. They are not only a source of energy, but also have essential functions in maintaining gut integrity and regulating the immune response.[6–9]
Alterations in SCFA concentrations and ratios have been associated with various diseases such as Multiple Sclerosis, Alzheimer’s, Hypertension and IBD.[10]
Treatment options for IBDs are limited with many patients reporting a significant decrease in quality of life especially with disease progression. Preventative methods such as microbiome screening or SCFA quantification could be highly effective in disease progress mitigation and could even prevent disease manifestation.
Currently, the most common method for detecting SCFAs is mass spectrometry. However, this approach is rarely used in routine testing of patient samples due to its complexity and cost. As a result, individuals with high risk factors, such as genetic predispositions or dietary restrictions may not receive SCFA screening, which could aid in early detection and proactive management of gut-related conditions.
Our goal is to develop on an early detection system that would enable people to check for patterns in dysbiosis linked to IBDs in order to discover autoimmune inflammation early which would allow for prompt intervention and prevent serious inflammation flares and damage to the gut which leads to the severe quality of life reduction that many patients report.
For that we will develop a device c apable of detecting SCFA concentration as well as ratios in the gut using an engineered E. coli strain: our GLOW.coli.
The GLOW.coli will carry a reporter construct controlled by specific promoters that activate upon binding to acetate, butyrate, or propionate. The promotors then induce the expression of a fluorescent protein reporter gene (e.g., GFP) which will allow us to quantify the amount of SCFA in a given sample, proportional to fluorescent intensity.
This novel approach has the potential to significantly improve our understanding of gut health and enable timely interventions, particularly for individuals with risk factors or those already affected by gut-related disorders.
IBDs have become so common that almost everyone knows one person with an IBD at least tangentially. And even though the disease is so common many patients can only be treated when they have acute flares. And even then, some patients try many different medications and approaches before they find one that works for them. This together with the sometimes quite severe impairment in taking part in everyday life inspired us to find a way to make diagnosis much easier ant allow earlier intervention to prevent lasting damage.
[1] Shreiner, A. B., Kao, J. Y. & Young, V. B. The gut microbiome in health and in disease. Current Opinion in Gastroenterology vol. 31 69–75 Preprint at https://doi.org/10.1097/MOG.0000000000000139 (2015).
[2] Alatab, S. et al. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol 5, 17–30 (2020).
[3] Loddo, I. & Romano, C. Inflammatory bowel disease: Genetics, epigenetics, and pathogenesis. Frontiers in Immunology vol. 6 Preprint at https://doi.org/10.3389/fimmu.2015.00551 (2015).
[4] Ananthakrishnan, A. N. Epidemiology and risk factors for IBD. Nature Reviews Gastroenterology and Hepatology vol. 12 205–217 Preprint at https://doi.org/10.1038/nrgastro.2015.34 (2015).
[5] Santana, P. T., Rosas, S. L. B., Ribeiro, B. E., Marinho, Y. & de Souza, H. S. P. Dysbiosis in Inflammatory Bowel Disease: Pathogenic Role and Potential Therapeutic Targets. International Journal of Molecular Sciences vol. 23 Preprint at https://doi.org/10.3390/ijms23073464/ (2022).
[6] Kotlyarov, S. Role of Short-Chain Fatty Acids Produced by Gut Microbiota in Innate Lung Immunity and Pathogenesis of the Heterogeneous Course of Chronic Obstructive Pulmonary Disease. Int J Mol Sci 23, (2022).
[7] Morrison, D. J. & Preston, T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 7, 189–200 (2016).
[8] He, J. et al. Short-Chain Fatty Acids and Their Association with Signalling Pathways in Inflammation, Glucose and Lipid Metabolism. Int J Mol Sci 21, 1–16 (2020).
[9] Olsson, A. et al. Serum Short-Chain Fatty Acids and Associations With Inflammation in Newly Diagnosed Patients With Multiple Sclerosis and Healthy Controls. Front Immunol 12, (2021).
[10] Yadav, S., Dwivedi, A., Tripathi, A. & Tripathi, A. K. Therapeutic potential of short-chain fatty acid production by gut microbiota in neurodegenerative disorders. Nutrition Research 106, 72–84 (2022).