Microscopic messengers: Extracellular vesicles shaping gastrointestinal health and disease

Abstract

The field of extracellular vesicles (EVs) is advancing rapidly, and this review aims to synthesize the latest research connected to EVs and the gastrointestinal tract. We will address new and emerging roles for EVs derived from internal sources such as the pancreas and immune system and how these miniature messengers alter organismal health or the inflammatory response within the GI tract. We will examine what is known about external EVs from dietary and bacterial sources and the immense anti-inflammatory, immune-modulatory, and proliferative potential within these nano-sized information carriers. EV interactions with the intestinal and colonic epithelium and associated immune cells at homeostatic and disease states, such as necrotizing enterocolitis (NEC) and inflammatory bowel disease (IBD) will also be covered. We will discuss how EVs are being leveraged as therapeutics or for drug delivery and conclude with a series of unanswered questions in the field.

Keywords: bacteria; exosome; inflammation; intestine.

FIGURE 1

The intestinal epithelium interacts with extracellular vesicles (EVs) from internal and external sources. EVs are double‐lipid membrane‐enclosed nanoparticles that carry biological information and are produced by a variety of cell types and sources. Given the barrier nature of the intestinal epithelium, it interacts with EVs from numerous internal and external sources, influencing health and disease states.

FIGURE 2

Extracellular vesicles (EVs) have pro‐ and anti‐inflammatory effects in the GI tract dependent upon the source and context. (a) Many EVs can be anti‐inflammatory and beneficial during intestinal inflammation. EVs from dendritic cells and neutrophils interact with IECs or pathogenic fungi, respectively, to resolve inflammation. Plant‐derived EVs have many anti‐inflammatory effects via effects on macrophages, dendritic cells, intestinal epithelial cells (IECs), or bacteria. Mesenchymal stem cell (SC) EVs can decrease inflammation via macrophages. Milk EVs interact with the immune and IECs to limit inflammation. The EVs of specific bacterial or parasites can also induce anti‐inflammatory effects in IECs. Finally, IEC‐derived EVs can act locally to attenuate inflammation. (b) On the contrary, EVs from these same sources in different contexts can exacerbate inflammation. EVs from pathogenic bacteria act on macrophages or IECs to potentiate inflammation. Lipopolysaccharide from gram negative bacteria can stimulate macrophages to produce pro‐inflammatory EVs that act on IECs. IECs themselves can promote their inflammation in an autocrine manner through IEC‐EV interactions. Collectively, these findings indicate that the cell type and context in which EV production and secretion occur have a sizable impact on EV cargo and target tissue response.