Interferon Gamma and Neurophysiology

## **Chapter 6**

## Interferon and HPA Axis: Impact on Neuroimmunological Perturbations

*Apoorv Sharma, Abhishek K. Singh, Vijay Kumar and Hridayesh Prakash*

### **Abstract**

The interplay between the central nervous system (CNS) and the enteric nervous system (ENS) constitutes the gut-brain axis. This represents a dynamic and bidirectional network of signaling pathways involving the vagus nerve, the immune system, and the molecules released by various microorganisms thriving in our gut. Since humans and bacteria have evolved together and learned to live together in a symbiotic relationship, which is decisive for physio/immune homeostasis of the body. Disruption in this (also known as dysbiosis) is associated with various pathological consequences including several neurological disorders. Out of several pathways that are associated with neurological manifestation, the inflammasome pathway is associated with the progression of multiple sclerosis, Alzheimer's, and Parkinson's disease, depression, schizophrenia, and autism. A growing body of evidence now suggests a reciprocal influence of microbiota and inflammasome activation in the brain. In this chapter, we discuss the cross talk between human gut microbiota and the key immunological signaling processes and their role in CNS development and neurological diseases.

**Keywords:** interferon, HPA axis, microbiome, immune plasticity and neurological distress

### **1. Introduction**

The gut-brain axis is an integrated system of the central and enteric nervous system and is made up of both neuronal and non-neuronal components of the central nervous system and the peripheral nervous system. The gut-brain axis functions as a directional communication channel and facilitates the interaction of the brain and with the gastrointestinal (GI) system. The complexity of the gut-brain system allows this system to influence a large variety of physiological processes, which include gastric tone alongside, emotions, motivation, and thinking [1]. Gut function analysis is responsible for monitoring and integrating gut functions with emotional and cognitive centers in the brain with peripheral intestinal functions. These communications involve neuro-immuno-endocrine mediators [2].

The gut-brain axis is the bidirectional communication between the enteric and central nervous systems. The gut microbiota has evolved as a second brain, with interactions between enteric nerves, gastrointestinal tract, and central neural systems leading to important changes in homeostasis [3]. Changes in intestinal microbiota are a major factor in maintaining gut homeostasis, which affects peripheral tissues such as the liver, lungs, spleen, and kidneys. The enteric nervous system communicates with the central nervous system through several pathways including vagus nerve stimulation (VNS), mechanoreceptors from stretch receptors within the intestine that relay sensory information on the mechanical structure of the environment of an organism; hearing (designed for wind movement), smell (for electrical signals) [4]. Enteric neurons also make connections with type II sensory afferents from regions outside the body such as hands' skin or tongue's surface. These connections become prominent during consumption of foods rich in fiber-feces-bacteria interactions, which lead to increased release of gas distending organs and produce similar sensations within intestines/gut via other mechanosensors [5, 6].

## **2. Gut-brain axis interplay between enteric nervous system and central nervous system**

The gastrointestinal system is the main avenue where these two systems interact and amplify endocrine signals that influence behavior quality control, metabolic health coordination involving appetite regulation-autoregulation. Vagus nerve stimulation studies have demonstrated increased excretion zone production and suggested that gastric motility patterns may be modulated by vagus nerve stimuli [7]. Gut microbiome content is now considered a putative indicator of the health of a person. This is well documented with the observation that certain gut microbiota can cure food, drug, and toxin-related sickness. At the cellular level, it mediates the cross talk through immune-system signaling pathways, augmenting the secretion of neurotransmitters such as GABA and subsequent release of endorphins that activate brain receptors [8]. Dysbiotic gut-induced pathogenic inflammation has a direct impact on neurobehavioral functioning, which involves the loss of various neuronal sensing mechanisms, which affect memory performance [2]. The autonomic nervous system is composed of the sympathetic and parasympathetic limbs that help the body regulate the nervous system associated with the gut. It is made up of enteric, spinal, and vagal pathways, which in association with the HPA axis respond and control stress through the efferent axis, which coordinates adaptive responses in the body [9].

The limbic system of the brain is predominantly involved in memory and emotion. Stress and elevated levels of the inflammatory cytokines by HPA activate an opioid system in the brain, leading to the release of cortisol, a stress hormone that connects the brain and the gut reciprocally [10]. The gut microbiome has an important role in these communications as shown in **Figure 1**. The enteric nervous system of the GI tract is derived from a phylum-specific brain known as the enteric central nervous system. This is composed of a sympathetic and inhibitory branch that controls peristalsis and GI motility. In some species, these two divisions are subdivided into separate ganglia [11].

The concerted activity of the neuronal and immune systems keeps the gut healthy by regulating the food we eat and the viruses and bacteria we encounter. *Interferon and HPA Axis: Impact on Neuroimmunological Perturbations DOI: http://dx.doi.org/10.5772/intechopen.106090*

#### **Figure 1.**

*Gut-brain axis and physiological purturbatin. It shows the role of brain gut-microbiota axis in alleviating the physiological/mood disorders, anxiety, depression, etc., caused due to stress and the interaction between the central nervous system/enteric nervous system (ENS) and gut microbiota. Vagus nerve modulates the gut brain axis. HPA axis; hypothalamus pituitary adrenal Axis, GABA; gamma amino butyric acid, 5HT; 5-hydroxytryptamine, ACTH; adrenocorticotropic-hormone, CRH; corticotropin-releasing hormone.*

The enteric nervous system (ENS) senses and reacts to the environment by transmitting chemical signals to the gut cells. This system helps the gut to digest food and fight off infections, which are quite an intricate aspect of the gut-brain axis. Given this, this chapter focuses the mechanism on the neural tubes/connections that maintain gut immune homeostasis. Recent studies on ENS have revealed its importance for microbe-induced immune responses in the gut. It is estimated that the human body hosts approximately 100 trillion microbes, which are essential for proper digestion and metabolic health while others are bad. For instance, bacteria have been associated with gastrointestinal (GI) conditions such as Crohn's disease or colitis. A plethora of evidence revealed the association of gut flora with food allergies including celiac disease. The gut microbiota and their metabolites act as ligands to various cognate receptors that alter epithelial cells' biology as well as their polarity to orchestrate signals from the GI tract to other organs of the body such as the brain or liver [12]. A study found that gut microbiota alters neurons and decreases anxiety levels through neurotransmitter release from neurons into the blood circulation [13].

Recent studies have demonstrated that dysbiosis promotes the prognosis of autism and schizophrenia [14] for which several hypotheses were proposed. Of those, immune metabolic programming of the host seems to be one potential mechanism that predisposes us more susceptible to certain diseases. Alterations in gut microbiota have also been shown to promote obesity, particularly in people with a history of food allergies or an autoimmune disease such as Hashimoto's thyroiditis [15].

#### **3. Inflammatory signaling across the gut-brain axis**

The hypothalamus-pituitary–adrenal axis is the main system that controls the production of hormones by the adrenal glands. The hypothalamus controls the production of corticotropin-releasing hormone (CRH), which stimulates the pituitary to produce adrenocorticotropic hormone (ACTH). ACTH then stimulates the production of glucocorticoids by the adrenal glands. Neuro-immunological systems involve interactions between neuronal and immune cells. These systems are responsible for protecting the brain and spinal cord from damage by harmful agents, such as toxins or bacteria. The adrenal hormones cortisol and aldosterone play an important role in this protection. GI tract and the central nervous system (CNS) remain continuously exposed to external and internal antigens. This tweaks intricate cellular networks comprising immune and neural cells, which actively sense harmful stimuli and orchestrate local and systemic bidirectional inflammatory responses. It occurs in both the afferent ("gut-to-brain") and efferent ("brain-to-gut") ways across the gut-brain axis to advocate the host's health status toward homeostasis [16].

GALT (gut-associated lymphoid tissue) responds quickly to intestinal assaults caused by the gut microbiota and/or their primary and secondary metabolites also known as by-products. The first line of defense against intestinal threats is provided by the innate immune cells that are dendritic cells (DCs), M cells, macrophages, mast cells, natural killer (NK) cells, and type 1, 2, and 3 innate lymphoid cells (ILCs). On the other hand, the adaptive immune cells such as CD4+ T effector cells as well as cytotoxic CD8+ T cells [T helper 1 cells (TH1 cells), TH2 cells, and TH17 cells], and regulatory T cells, not only can act directly but also move to distant organs, including the brain [17]. ENS protects the intestinal barrier by secreting RET receptor ligands, which cause ILC3-dependent synthesis of interleukin-22 (IL-22). Through BMP2- BMPR signaling, macrophages engage with enteric neurons to improve neuronal survival and alleviate inflammation-induced bowel dysmotility [18].

There are three primary mechanisms for bidirectional transmission of inflammatory signals between the gut and the CNS. The first one is the humoral pathway that involves the secretion of gut-derived inflammatory factors (IL-1,6, and 17) and 17, IFN γ. These cytokines disrupt BBB integrity [19] and cause developmental abnormalities in the brain. This activates the HPA axis that causes systemic glucocorticoid release, which alters intestinal functions [20]. The second one is the cellular immune pathway in which the intestinal immune cells directly modulate neuroimmune homeostasis and cognitive response toward inflammation. Stress-induced neuroinflammation alters the gut microbiome and releases toxic antigens, which in turn induce maturation of B cells into immunoglobulin A (IgA)-secreting plasma cells, which govern luminal microbial populations. Gut-derived cells may potentially instruct local immune cells in the CNS. A subpopulation of IFNγ-producing meningeal NK cells stimulates the formation of neuro-immunoregulatory astrocytes expressing LAMP-1 and TRAIL [21] as shown in **Figure 1**. Furthermore, the gut microbiota influences the activity of these gut-derived NK cells and their capacity to control astrocytes formation. The third pathway is the neuronal pathway, which is connected with afferent and efferent vagal nerves. The afferent vagal nerve originating from the gut projects into the nucleus solitarius of the brainstem, is endowed with inflammation detecting receptors in the intestines [22]. The impulses are sent to high brain order through the afferent vagal nerve, which triggers the HPA axis. This in turn activates the neural circuits implicated in sickness behavior [23]. Enteric neurons stimulated by cholinergic vagal efferent fibers potentially inhibit the production of

inflammatory cytokines IL-1b, IL-6, IL-18, and TNF-a [24] and retune M-1 effector macrophage toward M2 macrophages. These retuned macrophages secrete histamine, 5-HT, enhance voltage-gated channel activity, and promote the excitability of nociceptor neurons [25] for acquiring homeostasis.

## **4. IFN and intestinal homeostasis**

IFN is one of the dual-edge components of the intestinal immune system, which orchestrates intestinal homeostasis and inflammation [26]. Imbalance of the IFN system results in resulting in severe inflammation, cancer, and intestinal damage. A fine balance in the cell proliferation and immunological response is decisive for the GI homeostasis. Type I interferons (IFN-α and β) are pleiotropic cytokines and have both pro and anti-inflammatory manifestations in the gut [26]. Type I IFN counteracts the effects of locally produced IL-17 by blocking the secretion of IL-1, IL-23, osteopontin and increasing the synthesis of IL-27 in DCs [27], which are the main source of Type I IFN [28] and play a crucial role in modulating T-cellmediated antigen recognition. Type I IFN is known to promote the secretion of anti-inflammatory cytokines (e.g., IL-10, IL-27, and IL-1RA) by triggering the negative feedback PIAS (protein inhibitor of activated STAT) and SOCS (suppressor of cytokine signaling) proteins in phagocytes and T cells [29, 30]. Type I IFN promotes the differentiation of CD4+ Th cells into regulatory T-cells and aids in the maintenance of intestinal homeostasis under constant inflammatory microbial assault during dysbiosis [31].

## **5. The involvement of gut microbiota in age-related neuro-immune dysbiosis**

The gut microbiome is important for healthy aging and long life, and problems with gut dysbiosis may lead to unhealthy aging and shorter lives [32]. Age-related gut dysbiosis tweaks innate immune response and triggers meta-inflammation, which leads to many age-related degenerative pathologies. Disturbance of these communications by age-related dysbiotic gut can affect host health and life span. This also changes the ratio of good v/s bad microbiome, which ultimately dictates host health [33]. With age, gut microbiota becomes more diverse and variable. A disturbed gut microbiome is known to activate the innate immune response and chronic low-grade inflammation, which can lead to many age-related diseases and premature aging. The gut microbiota communicates with the host through various biomolecules, nutrient signaling-independent pathways, and epigenetic mechanisms. These communications can be disrupted by gut dysbiosis in older people, which can affect their health and life span.

Microbiota may be associated with irritable bowel syndrome (IBS) including IBD [34], which has a significant influence on GBA, which is due to enhanced interaction of intestinal cells and ENS locally, but also with CNS peripherally via neuroendocrine and metabolic pathways. One analysis prudently demonstrated the significant improvement and recovery in patients with hepatic encephalopathy after their treatment with antibiotics [35] indicating the significance of gut microbiome on disease management. Other compelling studies support the importance of the gut microbiome in influencing anxiety and depressive-like behaviors [36].

Additional lines of evidence potentially suggest that dysbiotic gut is a common etiological factor of autism [37]. Dysbiosis is common in people with functional gastrointestinal disorders (FGIDs) and is linked with mood disorders [38]. Data show that both brain and gut dysfunctions occur in people with FGIDs, the former being more dominant in people with irritable bowel syndrome (IBS) [39]. This disruption in the gut determines changes in intestinal motility and secretion, causes visceral hypersensitivity, and leads to cellular alterations in the entero-endocrine and immune systems.

Based on several ongoing discussions among the community, we believe that microbiota may be involved in the pathophysiology of various IBS symptoms [34] also. Supplementation of probiotics in conjunctions of antibiotics for curing IBS [40] provides experimental evidence that bad microbiome is directly linked to IBS pathogenesis. [41, 42]. Furthermore, many studies have demonstrated that the microbiota has a role in regulating GBA. Germ-free animals show altered neural function and behavior due to a lack of microbiota colonization [43]. Studies have shown that gut bacterial colonization is important for the development and maturation of the ENS and the CNS [44].

The absence of gut bacteria is associated with alterations in expression and turnover of a neurotransmitter, delayed gastric emptying and intestinal transit, reduced migrating motor complex cyclic recurrence and distal propagation, and enlarged cecal size [45]. Neuromuscular abnormalities resulting from a lack of gut bacteria are restored after animal colonization in a bacterial-species-specific manner. A comparative study between non-germ-free and germ-free (GF) animals has found that the microbiota affects stress reactivity and anxiety-like behavior [46].

The microbiota regulates the thresholds of HPA activities, which is revealed by decreased anxiety of GF animals over non-GF animals toward ACTH and cortisol mediated stress levels supporting the idea that a critical period exists during which the brain is particularly sensitive to the effects of the microbiota. This was further supported by increased memory dysfunction, changes in brain-derived neurotrophic factor (BDNF), alterations in the microbiota, and an increase in serotonin turnover [2] in dysbiotic animals.

Studies have shown that changes in gut microbiota can help in managing anxiety and improve the body's response to stress. These studies also show that manipulating gut microbiota affects brain neurochemistry, with some changes occurring in regions associated with anxiety and stress [47]. This was supported by the observation that probiotics can lower the levels of GABAAα2 mRNA levels in the prefrontal cortex and amygdala but increased them in the hippocampus. This was paralleled by a reduction in stress-induced cortisol release, decreased anxiety and depression-related behavior, and an increase in hippocampal BDNF expression [48]. Several groups have identified that probiotics can increase BDNF levels, reduce age-related changes in the hippocampus, and reverse neonatal maternal separation-induced pain hypersensitivity. These effects are likely due to changes in the microbiota composition of the animals treated with probiotics.

Microbiota communication with the brain involves the vagus nerve, which transmits information from the luminal environment to the CNS. The vagus nerve may play a role in the anxiolytic effect of probiotics. Bacteria communicate with the brain by using the vagus nerve, which transmits information from the surrounding environment to the brain [5]. Studies with animal colitis model caused by anxiety suggest anxiolytic effects of *Bifidobacterium longum* vagotomized animals [48]. Similarly, *Lactobacillus helveticus* R0052 and *B. longum* R0175 prevented changes in hippocampal neurogenesis and expression in hypothalamic genes involved in synaptic plasticity [49].

## **6. Current and future perspective**

The reciprocal exchange of inflammatory signals via the gut-brain axis is critical for the control of physiological activities as well as the pathophysiology of inflammation-related disorders. Intestinal immune cells can be driven to the brain in the afferent direction, but the underlying mechanism remains elusive so far. The gut microbiota has been identified as one of the key regulators of immune cells in the gut-brain axis. Accumulating data suggest that the microbiota communicates with the brain in several ways, including via the vagus nerve, the immune cells, several cytokines, and the luminal environment. Dysbiosis has been linked to several inflammation-related diseases and risk factors such as age, nutrition, and stress. However, it is dubious if dysbiosis has a causative role in these situations. Thus, identifying ways by which certain intestinal microbiota antigens and by-products impact intestinal immune cells or maybe cross the BBB to affect CNS cells would aid in answering dysbiotic-related neuronal disorders.

## **Author details**

Apoorv Sharma1 , Abhishek K. Singh1 , Vijay Kumar1 and Hridayesh Prakash1,2\*

1 Amity Institute of Neuropsychology and Neurosciences, Amity University, Noida, India

2 Department of Biotechnology, MM College of Engineering, Maharishi Markandeshwar (Deemed to be University), Mullana, Ambala, Haryana, India

\*Address all correspondence to: hprakash@amity.edu; hridayesh.prakash@mmumullana.org

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## *Edited by Hridayesh Prakash*

This book discusses the significance of interferon (INF) in the clinical aspects of the disease. Chapters address the biological, chemical, and physiological aspects of IFN and how IFN can assist various targeted health interventions. The information contained herein is useful for designing IFN gamma–directed strategies for managing various diseases discussed in the text.

Published in London, UK © 2022 IntechOpen © selvanegra / iStock

Basic and Clinical Aspects of Interferon Gamma

Basic and Clinical Aspects of

Interferon Gamma

*Edited by Hridayesh Prakash*