## 3 Secretory Profile of Exosomes in Metabolic Tissues
### Small Intestine  
The small intestine is one of the key organs for the body's physiology, with primary roles in digestion and nutrient absorption as well as critical functions in inter-organ communication. The digestive system is exposed to food, countless pathogens, and elevated levels of antigens. Notably, the composition and effects of exosomes released by the gut microbiota have been studied [68; 76]. Exosomes derived from enterobacteria within the microbiota can promote virulence through cytotoxic factors and interfere with the host's immune system mediators, primarily those associated with Gram-negative bacteria [63; 77]. Their content may include membrane-binding proteins, enzymes (autolysins), toxins, polysaccharides, and peptidoglycans [69; 78]. Enterocytes also use this communication pathway to modulate the immune system.  
Enterocytes use for inter-organ communication as well as antigen presentation involves exosomes. Exosomes are released to secondary organs such as the mesenteric lymph nodes located in the lamina propria [79]. The presence of the A33 antigen, a receptor-like biomolecule from the immunoglobulin superfamily, has been used to track the migration of epithelial exosomes after their release from the basolateral membrane [71; 80].  
Small intestine exosomes play a crucial role in diabetes and intestinal diseases [72; 81]. They can modulate inflammation by reducing the production of proinflammatory cytokines, such as IL-17A, through interactions with T cells in the lamina propria. This mechanism helps regulate inflammation both locally and systemically. Additionally, exosomes can induce immune tolerance, particularly in contexts of chronic inflammation. Research has also explored exosomes in intestinal lymph that carry elevated levels of complement proteins C3/C5 and albumin. Given the pivotal role of complement C3/C5 in initiating inflammatory responses, these exosomes may hold promise for diagnostic and therapeutic applications in inflammatory bowel diseases (IBD) [73; 82].  
In diabetes research, a mouse model for prediabetes was developed using a diet with a higher percentage of lipids. This led to hepatic steatosis and insulin resistance. Subsequently, intestinal exosomes were isolated, revealing that pathways such as glycolysis, gluconeogenesis, and pyruvate metabolism were among the most affected due to a decrease in glycolytic proteins within the exosomes [72; 81]. A prediabetes murine model with a lipid enriched diet led to hepatic steatosis and insulin resistance.  
In another study conducted in Korea, patients with type 2 diabetes mellitus exhibited intestinal exosomes in urine, serum, and stool, unlike healthy individuals, where these exosomes were less likely to cross the intestinal barrier [74; 83]. This phenomenon has been linked to persistent insulin resistance in non-alcoholic fatty liver disease (NAFLD), attributed to increased permeability to lipopolysaccharide, which promotes insulin secretion [75; 84].  
In inflammatory bowel diseases such as Crohn's disease, it has been documented that patients have an increased number of exosomes circulating in the blood with an overexpression of miR-376a-3p, which may be associated with alterations in the immune system. The elevated expression of miR-376a-3p has the ability to modify genes involved in Toll-like receptor (TLR) signaling or the major histocompatibility complex (MHC) [85]. This affects how the immune system identifies and reacts to intestinal microorganisms and other stimuli [76; 86].