Messages from the Inside. The Dynamic Environment that Favors Intestinal Homeostasis

Abstract

An organism is defined as "an individual living thing capable of responding to stimuli, growing, reproducing, and maintaining homeostasis." Early during evolution multicellular organisms explored the advantages of a symbiotic life. Mammals harbor a complex aggregate of microorganisms (called microbiota) that includes bacteria, fungi, and archaea. Some of these bacteria have already defined beneficial roles for the human host that include the ability to break down nutrients that could not otherwise be digested, preventing the growth of harmful species, as well as the ability to produce vitamins or hormones. It is intuitive that along the evolutionary path several mechanisms favored bacteria that provided advantages to the host which, in return, avoided launching an aggressive immunological response against them. The intestinal immunological response does not ignore the lumenal content, on the contrary, immune surveillance is favored by continuous antigen sampling. Some intestinal epithelial cells (ECs) are crucial during the sampling process, others actively participate in the defense mechanism. In essence the epithelium acts as a traffic light, communicating to the inside world whether conditions are safe or dangerous, and thus influencing immunological response. In this review we will discuss the dynamic factors that act on the intestinal ECs and how they directly or indirectly influence immune cells during states of health and disease.

Keywords: DCs; intestinal epithelial cells; intestinal evolution; intestinal inflammation; mucosal immunology.

Figure 1

Crucial steps of intestinal tract evolution. Seven hundred millions of years ago sponges were the first multicellular organisms to obtain and digest food particles by filtering water. Six hundred millions of years ago Cnidarians evolved a single opening followed by a cavity that serves as a digestive space. The opening served both as the entrance for food and the exit for waste. It was not until about 100 million years later that, with the Nemertea, waste was eliminated through a second opening, thus maximizing food absorption potential. The first mammals evolved 180 million years ago, but the human intestine first appeared about 160 million years later.

Figure 2

Time progression, from homeostasis to inflammation and inflammation remission. (A) Homeostasis: lumenal and epithelial derived factors imprint an inflammatory impaired phenotype to the intestinal resident DCs. These can sample antigens from the lumen but also from the capillary, but migrating to the MLNs will not produce inflammatory cytokines and will not activate an aggressive adaptive response. Incoming DCs progenitor will enter a favorable environment becoming inflammatory impaired. Sampling circulating antigens these DCs may be crucial to sustain tolerance toward self. (B) Inflammatory insult: epithelial barrier loss or invasive bacteria can change the intestinal milieu, which will lose the ability to condition incoming DCs progenitors. These will possibly encounter lumenal antigens and migrate to the MLN to begin a Th1/Th17 adaptive response. Neutrophils will be recruited as well by the epithelial produced IL-8/KC. Production of this chemokine appears to be mediated by TLR5 engagement that happens in cases of infection. Previously conditioned DCs will not be able to produce an inflammatory response, but migrating to the MLN their effect will be stochastically surmounted by the freshly recruited DCs if the inflammation is prolonged. (C) Inflammation: incoming inflammatory cells release TNFα that promotes mucus production by goblet cells. A thicker mucus layer better protects from lumenal antigen exposure, important to create the conditions to interrupt the pro-inflammatory cascade. At the same time neutrophils and macrophages clean-up the lamina propria. Incoming DCs progenitors retain the possibility of becoming inflammatory, but the chances decrease in relation with the successful resolution of the infection. Intestinal DCs that sample circulating antigens in pro-inflammatory conditions inside the capillaries may erroneously induce inflammatory responses toward self-antigens. This may enlighten new aspects related with systemic inflammatory responses observed in patients affected by chronic intestinal inflammation. (D) Inflammatory remission: the epithelial barrier is back to normal and epithelial cells are exposed to sustainable amount of antigens. The ECs cytokine cocktail favors DCs polarization to the conventional intestinal phenotype. DCs migrating to the MLN will produce increasing amounts of anti-inflammatory cytokines and correct intestinal homeostasis is finally completed.