Commensal Clostridia: leading players in the maintenance of gut homeostasis

Abstract

The gastrointestinal tract is a complex and dynamic network where an intricate and mutualistic symbiosis modulates the relationship between the host and the microbiota in order to establish and ensure gut homeostasis. Commensal Clostridia consist of gram-positive, rod-shaped bacteria in the phylum Firmicutes and make up a substantial part of the total bacteria in the gut microbiota. They start to colonize the intestine of breastfed infants during the first month of life and populate a specific region in the intestinal mucosa in close relationship with intestinal cells. This position allows them to participate as crucial factors in modulating physiologic, metabolic and immune processes in the gut during the entire lifespan, by interacting with the other resident microbe populations, but also by providing specific and essential functions. This review focus on what is currently known regarding the role of commensal Clostridia in the maintenance of overall gut function, as well as touch on their potential contribution in the unfavorable alteration of microbiota composition (dysbiosis) that has been implicated in several gastrointestinal disorders. Commensal Clostridia are strongly involved in the maintenance of overall gut function. This leads to important translational implications in regard to the prevention and treatment of dysbiosis, to drug efficacy and toxicity, and to the development of therapies that may modulate the composition of the microflora, capitalizing on the key role of commensal Clostridia, with the end goal of promoting gut health.

Figure 1

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.