**Abstract**

Although its most well-written functions are digestion and absorption of nutrients, the gastrointestinal tract (GIT) is the most significant player in the human immune system. The GIT is home to more than 60% of the active immune cells in the entire body. Notwithstanding, the human gut is continuously exposed to antigens ingested with food and resident microorganisms. The density of microorganisms in the lumen of GIT increases aborad and is much higher in the colon. Despite a relatively low bacterial load in the small intestine, the environment is more precarious because it is nutritious and exposed to digestive enzymes. Its lining is made up of a single layer of epithelial cells covered by a thin and attenuated layer of mucus. Despite the continual exposure to the luminal antigens, the gut's immune system is kept in a state of relative immunosuppression. The pathogenesis of some of the common non-communicable diseases includes a systemic inflammatory state initiated by dysbiosis in the gut, increased permeability of the intestinal epithelium, translocation of microbiomes or their products, and then a persistent pro-inflammatory state. Paneth cells are the key players in the innate immunity of the gut and are responsible for maintaining its integrity.

**Keywords:** Paneth cells, microbiome, dysbiosis, antimicrobial peptides, defensins, innate immunity, systemic inflammation
