The microbiome drives circadian rhythms in inflammation
Description: The circadian clock is an internal biological timer that allows animals to tune their physiology to the 24h environment created by the rotation of Earth on its axis. Inflammation - the response of specialised cells within the body to attack- is regulated by the circadian clock. Human chronic inflammatory diseases, such as rheumatoid arthritis, show day-to-night variation in their symptoms. Patients suffering from rheumatoid arthritis (0.6 million people in the UK) often report pain and joint stiffness is increased during the early morning. We have recently shown in a mouse model of inflammatory arthritis that this is due to the circadian clock directing the inflammatory responses within affected limbs. This localised inflammation shows 24h fluctuations in severity, with significant reductions during the night. We propose that this night-time repression is due to the increased activity of T-regulatory cells (Tregs), immune cells with anti-inflammatory properties. In keeping we have shown that Treg numbers within inflamed joints increase during the night, but fall in the day.
This proposal describes a novel and exciting programme of work which will investigate daily changes in activity of Tregs within inflamed joints.
First we will analyze how timing mechanisms control the activity and movement of Tregs around the body, and into inflamed joints. We will use novel technology that allows us to "paint" cells of interest, and count them as they travel. Then we will investigate how the timing of meals, which is regulated by the clock, orchestrates Treg numbers and trafficking. We have preliminary evidence that the microbial content of the gut, which fluctuates over 24h in response to feeding, directs the clock control of the movement of Tregs around the body. It is known that short chain fatty acids (SCFA), which are produced by gut microbes during the breakdown of fibre, can regulate Treg numbers and function. We will investigate this circuit by using timed-feeding interventions to target the microbes. Then, we will test the idea that the Tregs are directly responding to SCFAs by selectively deleting the SCFA receptor, a sensor, on the surface of the Tregs. Finally, we will test the presence of a timing signal in circulating SCFAs by directly regulating serum levels, and assess the downstream impact on inflammatory disease.
Funder: Medical Research Council
Amount: £662,500
Funding type: research
Start date: 2019-03-31
End date: 2022-11-30
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Funded outputs count: 13
Funder award ID: MR/S002715/1
OpenAlex ID: G7420289137