New paper by the Grassi Lab on a regulatory circuit in the gut, which controls immune system response to commensals to promote a beneficial ecosystem for host metabolic homeostasis
on Tuesday, March 21, 2017
The intestine of mammals is colonized by trillions of commensal bacteria. These bacteria contribute to the metabolic balance of the organism, for example by influencing energy harvest from food or by generating useful substances. The intestine is patrolled by cells of the immune system, which are equipped to defend our body by invading microorganisms. However, in the gut this defensive potential is extensively limited to allow useful bacteria to bloom. The mechanisms regulating this non-aggression pact between immune system and useful commensals are largely unknown. Perruzza et al. have found that adenosine-triphosphate (ATP), the energy currency of all cells, is released by bacteria and represents an important signal for dampening immune system response against commensals. In fact, a lymphocyte subset defined T follicular helper cells, which promote the generation of secretory IgA antibodies in the small intestine, senses ATP via a receptor called P2X7 and limits IgA response, thus allowing bacteria to flourish. Lack of this regulatory circuit dramatically affects commensals composition due to excessive IgA secretion and enhanced clearance of bacteria. The paper published in Cell Reports shows that the altered sensing of microbiota by the gut immune system in the absence of P2X7 results in the generation of an altered microbial community, which provokes alterations in glucose homeostasis and obesity. A novelty of the study is the identification of ATP as an inter-kingdom signaling molecule important not only for limiting IgA response to commensals by modulating Tfh cells activity via P2X7 receptor but also for selecting a beneficial microbial community for host metabolism. Since this receptor is expressed in human Tfh cells, intervening on this regulatory circuit of the gut immune system might be useful not only to improve antibody secretion against pathogenic bacteria but also to condition systemic metabolism of the host in pathological conditions.
The image shows bacteria in the lumen of the small intestine targeted by IgA. The IgA shooting cannon represents the adaptive immune response to bacteria controlled by bacteria-derived ATP that partially destroys the cannon. Image concept by Fabio Grassi. Design and artwork by Gaia Codoni.
The work published in Cell Reports on March 14thby Lisa Perruzza et al. in the group of Fabio Grassi, is the result of a collaboration with the University of Milan, the Italian National Research Council, the University of Rome, the University of Bern and the University of Zurich. The work was supported by Swiss National Science Foundation (SNSF), Novartis Stiftung für medizinisch-biologische Forschung, Nano-Tera project, Fondazione Ticinese per la Ricerca sul Cancro, Fondazione per la Ricerca sulla Trasfusione e sui Trapianti and Converge Biotech.
T Follicular Helper Cells Promote a Beneficial Gut Ecosystem for Host Metabolic Homeostasis by Sensing Microbiota-Derived Extracellular ATP
L. Perruzza, G. Gargari, M. Proietti, B. Fosso, A. M. D'Erchia, C. E. Faliti, T. Rezzonico-Jost, D. Scribano, L. Mauri, D. Colombo, G. Pellegrini, A. Moregola, C. Mooser, G. Pesole, M. Nicoletti, G. D. Norata, M. B. Geuking, K. D. McCoy, S. Guglielmetti, F. Grassi
in Cell Rep (2017) vol. 18 pp2566-2575