Peculiar role of commensal Clostridia in modulating gut homeostasis. Establishing a close relationship with gut cells (interfold region), Clostridia spp. exert a strong influence on the host immune system. They may be sensed by intestinal epithelial cells and can promote the development of αβ T cell receptor intraepithelial lymphocytes (IEL) and immunoglobulin A (IgA)-producing cells through the induction of IL-6, IL-7 and TGF- β. They are also able to induce colonic T regulatory cell (Treg) accumulation through the activation of Dendritic cells (DCs) and the induction of indoleamine 2,3-dioxygenase (IDO), matrix metalloproteinases (MMPs) and TGF-β in colonic epithelial cells. Furthermore, Clostridia play an important role in the metabolic welfare of colonocytes by releasing butyrate as an end-product of fermentation. Butyrate is the preferred energy source for colonocytes, but also inhibits the activation of the transcription factor, NF-kβ, in gut cells. Increased production of IL-10 in Treg cells and decreased expression of NF-kβ lead to a consequent intestinal and systemic anti-inflammatory effect. Finally, Clostridia, enriched in β-glucuronidase activity, could be responsible for generating free catecholamines, including Norepinephrine (NE) and Dopamine (DA), from the glucuronide-conjugated biologically inactive form and could be involved in neuro-enteric system modulation.