**1. Introduction**

The gastrointestinal tract (GIT) is the largest organ in the body and is constantly exposed. At least 60% of active immune cells reside in the tissues of the GIT. An everyday healthy lifestyle requires a structurally intact and normal functioning GIT. The integrity of the GIT is maintained through continuous replacement of surface epithelial cells, which exfoliate and have to be replaced every 4–5 days [1]. Other key factors which are important for the physical integrity of the epithelium throughout the GIT are tight intercellular junctions, fine-tuning of the gut microbiome and active dampening down of the immune response. Dysbiosis followed by an ongoing systemic inflammatory state is involved in the pathogenesis of several gastrointestinal and extra-gastrointestinal conditions [2]. Medical conditions linked with a sustained pro-inflammatory state are inflammatory bowel disease (IBD), obesity, malignancies, arthritis, diabetes mellitus and acute or chronic organ-system dysfunction [1–3].

Dysbiosis is a prelude in the pathogenesis of inflammatory bowel disease (IBD), obesity, and other diseases associated with the prolonged systemic inflammatory

state. It is defined as a change in the number or type of luminal microorganisms. Dysbiosis leads to the appearance of allochthonous organisms at various niches in the GIT, especially in the lumen of the small intestine and or the colon [3]. Dysbiosis leads to translocation of luminal microorganism and their products such as endotoxins, immune activation, and initiation of systemic inflammation. This chronic systemic inflammatory state is resistant to insulin and is obesogenic, diabetogenic, carcinogenic, and thrombogenic [1]. Dysbiosis and systemic inflammation also play a role in the pathophysiology of some of the complications associated with chronic human immunodeficiency virus (HIV) infection before or during treatment with antiretroviral (ARV) drugs [2]. Dysbiosis and chronic stimulation of gut immunity and subsequently systemic inflammation are purported to be among the factors which induce progressive deterioration of systemic immunity and depletion of CD4 T-lymphocytes count, and why HIV is currently not curable.

The integrity of the epithelium throughout the GIT, especially at the small intestine region, has to remain intact to ensure a healthy life. The gut immune system can defend the body from a state of perpetual systemic pro-inflammation because of a robust innate immunity that functions in liaison with elements of adaptive immunity. Every plant and animal species has a built-in mechanism to secrete antimicrobials (defensins) that prevent invasion by pathogenic organisms. Neutrophils are responsible for the secretion of defensins throughout the entire body in mammals, including the skin and parts of the GIT. Human alpha defensins are only produced by Paneth cells in the small intestine. Paneth cells are the key player in the innate immunity of the small intestine and are responsible for the robustness of gut immunity [1, 3–9].
