No room! Microbial metabolites, a dopamine receptor and colonization resistance

There was a table set out under a tree in front of the house, and the March Hare and the Hatter were having tea at it: a Dormouse was sitting between them, fast asleep, and the other two were using it as a cushion, resting their elbows on it, and talking over its head. ‘Very uncomfortable for the Dormouse,’ thought Alice; ‘only, as it’s asleep, I suppose it doesn’t mind.’  The table was a large one, but the three were all crowded together at one corner of it: ‘No room! No room!’ they cried out when they saw Alice coming.
–  Lewis Carroll, Alice’s Adventures in Wonderland, Chapter VII
‘Colonization resistance’ refers to the ability of the endogenous microbiota to limit the ability of exogenous microorganisms to colonize and propagate within the host.   A simple and well-known mechanism is the competition for nutrients, in which the endogenous microbiota obviously hold an edge over any invader.  Another mechanism is the production of various inhibitors by the endogenous microbes, which directly inhibits the growth of exogenous ones.  Neither of these mechanisms are mutually exclusive.    
A research article by Scott, Fu and Chang1 has teased apart yet another mechanism for colonization resistance in mice to infection by the murine pathogen Citrobacter rodentium.   Their work indicates that colonization resistance against pathogens in mice is achieved by activation of the dopamine receptor D2 (DRD2) by microbial metabolites of the common amino acid tryptophan, the most abundant of which are indole, indole-3-ethanol (IEt), indole-3-pyruvate (IPyA), and indole-3-aldehyde (I3A).  They found that the activation of DRD2 by these metabolites or by dopamine and dopamine agonists in intestinal epithelial cells (IEC) results in the inhibition of pedestal formation by IECs.  In turn, the inhibition of pedestal formation prevents colonization by C. rodentium. 
In addition to its core findings, this work provides an additional mechanistic insight into one of the ways in which moderate physical exercise might contribute to overall health by reducing susceptibility to infection2, and not only in mice, but also in humans.  It is known that dopamine is produced in the gut, spleen and pancreas3 as well as in the lungs4. Moderate exercise leads to increased dopamine levels not only in the brain, but also in the gut5.  This discovery of a novel pathway viz., DRD2 activation, that results in colonization resistance by inhibition of pedestal formation in IECs strongly suggests that exercise-induced dopamine in the gut could elicit a similar beneficial effect.  This hypothesis is testable and predicts that moderate exercise, even without dietary tryptophan supplementation, should enhance colonization resistance in normal, but not in the Drd2fl/fl knockout mice that do not express DRD2 in IEC.  Thus, moderate exercise may exert its beneficial effects on innate immunity by increasing levels of DRD2 activation in IECs, resulting in colonization resistance. 
Notes:  
1.  Poster image “A mad tea party”, as illustrated by John Tenniel. 
Disclaimer:  The above post is not medical advice.  No guarantee is expressed or implied regarding the veracity and medical utility of the information provided on external websites and sources.  The opinions expressed herein do not represent the views of the TERI School of Advanced Studies or TERI or the symposium organizers. 
References:

Scott, S. A., Fu, J. & Chang, P. V. Dopamine receptor D2 confers colonization resistance via microbial metabolites. Nature 628, 180–185 (2024).

Romeo, J., Wärnberg, J., Pozo, T. & Marcos, A. Physical activity, immunity and infection.Proc. Nutr. Soc. 69, 390–399 (2010).
Eisenhofer, G.et al. Substantial Production of Dopamine in the Human Gastrointestinal Tract. The Journal of Clinical Endocrinology & Metabolism 82, 3864–3871 (1997).
Adir, Y.et al. Augmentation of endogenous dopamine production increases lung liquid clearance. Am J Respir Crit Care Med 169, 757–763 (2004).
Royes, L. F. F. Cross-talk between gut and brain elicited by physical exercise.Biochimica et Biophysica Acta (BBA) – Molecular Basis of Disease 1866, 165877 (2020).