**6. Microbiome and autoimmune diseases: the gut-brain axis in GI autoimmune diseases**

Mammalian microbiota consists of a variety of microorganisms, such as bacteria, archaea, fungi, and viruses. A symbiotic relationship exists between humans and bacteria, most of which are present in the gastrointestinal system [266]. An essential component of the host's health and well-being is the gut microbiota, the collection of intestinal microorganisms throughout the GI tract [267]. Assemblage of the gut microbiome begins during birth, primarily from the mother's vaginal and fecal microbiomes if naturally delivered, or from the skin and environmental microbes if delivered via cesarean section [268–270]. There are more than 100 trillion microorganisms living within the GI tract, which together form the microbiota, a complex biosystem. Microbiota are organisms belonging to all domains of life, including Eukaryotes, Bacteria, and Archaea. The main components that comprise this microuniverse belong to the bacterial group and are divided into four phyla: Actinobacteria, Proteobacteria, Bacteroidetes, and Firmicutes [271]. In terms of host health, microbes found in the gut are involved in nondigestible carbohydrates metabolism, immune system development, and drug metabolism. Human diseases linked to gut microbiota

include IBD, metabolic diseases, allergic diseases, and neurodevelopmental diseases [272, 273]. The microbiome of a newborn infant is affected by nutrition, physiochemicals, and biological properties of the body, as well as life events [274]. In this period of life, while breast milk is the primary source of nutrients, there are big shifts in bacterial taxa and much more variation between infants than between adults. Different immune responses to the microbes colonizing the host or other lifestyle factors could account for the large functional and phylogenetic variability [275]. The gut and brain developed from the same tissue, the neural crest, during embryogenesis and influence each other tightly [276].

As both are parts of the immune system, the gut, the brain, and multiple organs can all be affected by disturbances in this system. Communication between the gut and brain is known as gut-brain axis [277]. Communication between the brain and gut involves neural pathways, such as the enteric nervous system (ENS), vagus, sympathetic, and spinal nerves, as well as humoral pathways involving cytokines, hormones, and neuropeptides as signaling molecules [278]. The ENS controls the functions of the gut and includes blood flow absorption, motility, and secretion, and these four compromise the main function of the gut-brain axis [267]. The alteration of the gut microbiota by any factor can lead to signaling to ENS resulting in an alteration in the hormone secretion. Chemical signals from the intestinal epithelium, enteric endocrine system, and immune system are highly receptive to this area, and it provides input to sensory pathways that signal the emotional and cognitive centers of the brain. ENS also receives efferent information from the brain via autonomic neural connections (sympathetic and parasympathetic) and hormonal pathways that modulate digestive functions [279]. Food intake regulation, glucose metabolism, and modulation of the GI-associated immune system include digestive processes, GI tract synchronization of physical and emotional states are all part of brain-gut axis interactions [267]. The relationship between gut-brain axis and stress, depression, and anxiety is well established. These psychological conditions have biological mechanisms and manifestations. Allostasis is process in which the body's ability to restore homeostasis can result these psychological conditions. In allostasis, the hypothalamicpituitary-adrenal (HPA) axis regulates the body's stress response systems, including neuroendocrine signaling and the glucocorticoids it produces, and BDNF it regulates, help with memory and learning [280]. Glucocorticoids is released from adrenal glands during stressful events, and it controls the homeostatic conditions. However, it can result anti-inflammatory responses [281]. It was shown that the gut microbiota helps to regulate the stress response as its absence results in an overproduction of Glucocorticoids after stressful events, particularly through Lactobacillus spp. in stress. In addition, it was shown that *Lactobacillus rhamnosus* reduces anxiety and Bifidobacterium spp. improves stress.

There is bidirectionality between gut and the microbiota in stress management. Through the release of cytokines and neurotransmitters, inflammation of the GI tract stresses the microbiome [282]. In conjunction with the increase in intestinal permeability, these molecules then travel systemically. Rogue molecules from the permeable gut (leaky gut) are amplified when blood levels of TNF-a and MCP (monocyte chemoattractant protein) are elevated [283, 284]. Anxiety, depression, and memory loss result from their release [285]. It was reported that there is a relationship between elevation of IL-5 and TNF-a with depression and anxiety that suggest that these pro-inflammatory cytokines are involved in the development of anxiety and

## *Autoimmune Diseases of the GI Tract Part I: Etiology and Pathophysiology DOI: http://dx.doi.org/10.5772/intechopen.106184*

depression which is also manifested in chronic inflammation and altered immune cells in the peripheral blood [284]. The hypothalamicpituitary- adrenal (HPA) axis can be simulated with pro-inflammatory cytokines. The hypothalamus can release corticotropin releasing factors simulating the adenohypophysis to release adrenocorticotropic hormone (ACTH). The ACTH can induce the release of cortisol which is a stress hormone from the adrenal gland which acts as negative feedback in the proinflammatory signal transduction. Hyperactivity of the HPA axis is a major cause of psychological responses such as stress, anxiety, and depression [286].

The research focus on gut-brain axis is recent and it's not proceeding with the pace that it was expected to be. Nevertheless, it's a complicated area of research due to variety of factors that are involved in the process and the multiple pathways that could play a vital role in the processes. In addition, the components of the gut microbiota are huge. Several neural, hormonal, metabolic, immunological, and microbial signals drive gut-brain communication [287]. In autoimmune diseases, many patients have reported psychological comorbidities and it's not confirmed whether these comorbidities are due to quality of life with the disease, or they are one of the inducers that are involved in the pathogenesis of the disease. It could be bidirectional, nevertheless. There is an autoimmune component to major psychiatric disorders. In psychiatric disorders, disequilibrium of cellular processes in the GI tract is likely to contribute to immune dysfunction [288]. Symptoms of gastrointestinal diseases worsen psychological complaints and vice versa, suggesting a significant role for an imbalance in the gut-brain axis in both conditions. The gut is strongly implicated in a variety of neurological diseases via direct and indirect mechanisms, according to growing evidence. Intestinal microbes and their products (e.g., metabolites) as well as immune education in the mucosal immune system, including the release of proinflammatory cytokines, are key components. The intestinal epithelium regulates these processes by translating signals from bacteria and inflammation to the immune system and secreting hormones and peptides which are involved in the metabolic processing of dietary nutrients [289]. Some of GI autoimmune diseases mechanisms of gut-brain axis role and the clear direct relationship of stress, anxiety and depression are well established such as IBD [290, 291] and CD [292]. Since this is a growing area of the research, more investigations need to be done to cover the relationship between the involved components.
