The gut flora as a forgotten organ

Abstract

The intestinal microflora is a positive health asset that crucially influences the normal structural and functional development of the mucosal immune system. Mucosal immune responses to resident intestinal microflora require precise control and an immunosensory capacity for distinguishing commensal from pathogenic bacteria. In genetically susceptible individuals, some components of the flora can become a liability and contribute to the pathogenesis of various intestinal disorders, including inflammatory bowel diseases. It follows that manipulation of the flora to enhance the beneficial components represents a promising therapeutic strategy. The flora has a collective metabolic activity equal to a virtual organ within an organ, and the mechanisms underlying the conditioning influence of the bacteria on mucosal homeostasis and immune responses are beginning to be unravelled. An improved understanding of this hidden organ will reveal secrets that are relevant to human health and to several infectious, inflammatory and neoplastic disease processes.

Figure 1

Functions of the intestinal flora. (A) Bacteria density increases in the jejunum/ileum from the stomach and duodenum, and in the large intestine, colon-residing bacteria achieve the highest cell densities recorded for any ecosystem. The most common anaerobic and aerobic genera are listed. (B) Commensal bacteria exert a miscellany of protective, structural and metabolic effects on the intestinal mucosa.

Figure 2

Immunosensory detection of intestinal bacteria. Surface enterocytes secrete many immune mediators in response to antigens, including antibacterial peptides, immunoglobulin A (IgA) and chemokines. Specialized epithelial cells, termed M cells, transport and deliver antigens to antigen-presenting cells, which subsequently process antigens and present them to naïve T cells. Antigen-presenting dendritic cells (DCs) also survey and sample the mucosal microenvironment. Pattern recognition receptors (PRRs) expressed by DCs and enterocytes mediate the detection of bacterial antigens, and DCs modulate immune responsiveness or tolerance by promoting either effector or regulatory T cells.

Figure 3

Schematic illustration of the mechanisms by which some commensal bacteria limit pathogen-induced nuclear factor (NF)-κB signalling. Pathogenic bacteria such as Salmonella typhimurium trigger IκB kinase activation, IκBα degradation and nuclear translocation of p50/p65 NF-κB subunits. Some commensal bacteria offset these affects by promoting the nuclear export of activated p65 through associations with peroxisome proliferator-activated receptor (PPAR)γ, thereby terminating promoter activation. Other commensal bacteria inhibit IκBα degradation.

A.M.O'Hara & F. Shanahan