Growth factor VEGF-B sustains intestinal Tfh cell stemness to restrict Taurinivorans outgrowth and microbiota-driven obesity

Autocrine signaling through vascular endothelial growth factor receptor-1 (VEGFR-1) reprograms T cell metabolism upon TCR stimulation. We found that mice bearing conditional deletion of Flt1 (encoding VEGFR-1) in T cells developed spontaneous obesity with advancing age. Analyses of lymphoid and metabolic tissues identified a VEGFR-1⁺ T follicular helper (Tfh) population in Peyer's patches and mesenteric lymph nodes. Flt1 deletion impaired Tfh fitness and reduced secretory IgA in the gut, resulting in unrestricted expansion of the pathobiont Taurinivorans. Taurinivorans overgrowth depleted host taurine, which drove obesity via suppressed adipocyte lipolysis and thermogenesis. Mechanistically, a VEGFR-1-AKT signaling axis promoted Tfh cell stemness by limiting p53-mediated senescence. This Tfh-microbiota-obesity pathway was also observed in diet-induced obese mice and in humans. Oral administration of IgA reduced Taurinivorans and alleviated adiposity, highlighting the therapeutic potential of this axis. Tfh cell senescence impairs IgA production, disrupting gut microbial homeostasis, with consequences to host metabolic disease.