The Neuroimmune Axis in Gastrointestinal Disorders - An Underrecognized Problem.

This chapter provides an overview of the impact of parasites on the endocrine system of their host. The review is concerned primarily with helminth parasites of vertebrates and specifically parasites that inhabit the gastrointestinal tract, because that is the area in which the overwhelming bulk of the experimental work has been carried out. In preparing the review, however, it soon became apparent that to discuss endocrine responses in isolation would be a very limiting exercise. In addition to causing changes in the hormonal status of the host, parasites elicit immune responses from the host, induce pathological changes in host tissues, and alter the normal functioning of the gut by disrupting neuroendocrine control mechanisms, epithelial cell functioning, and differentiation of mucosal cells, for example. Moreover, it is becoming increasingly apparent that the various facets of the host response are interlinked with each other and—of particular significance to this review—are involved with peptides, because peptidergic molecules are common to the endocrine, nervous, and immune systems. Consequently, the chapter will follow four main themes. Initially, it will briefly review pathophysiological changes in the gut resulting from parasitism. It will then examine the roles of gut neuroendocrine and immune systems in these responses, highlighting the disruption of peptidergic mechanisms in both the gut endocrine and nervous systems. The review will then consider interactions between the neuroendocrine and immune systems, first establishing general principles, then discussing data relating specifically to peptides and cytokines. Finally, an attempt will be made to draw together the different themes of the review and explore what progress has been made in unravelling connections among the main tissues discussed (namely, endocrine system, nervous system, immune system, and epithelium plus muscle). A number of schemes have been proposed to integrate such interactions into the overall picture of the host response. The models will be examined to determine how comprehensive they are and any weaknesses exposed will serve to highlight potential lines of future research.

The central nervous, endocrine, and immune systems interact at several levels, including cell surface and intracellular molecules as well as compounds facilitating intercellular communication. Molecules produced by components of the immune system, such as reactive oxygen and nitrogen species and some cytokines secreted by brain microglia, may induce disorders of the nervous and endocrine systems if present in excess. Pathologic conditions of these three systems, including neurodegenerative diseases, anxiety, memory loss, ischemia, multiple sclerosis, alterations in weight and metabolism, diseases of insulin dysregulation, and several autoimmune disorders, have several common themes such as changes in iron/Ca$+2$ levels, altered proteosomal activity, mitochondrial dysfunction, and activation of the caspase cascade, leading to apoptosis. The green tea polyphenol epigallocatechin gallate (EGCG) has beneficial activity in a number of human diseases. It mitigates some of the above-listed damage in part by altering intracellular signal transduction pathways, by scavenging reactive oxygen and nitrogen species and iron, and by affecting cytokine production and expression of neurotransmitters or their receptors. This chapter presents these activities of EGCG and how they affect diseases of these related physiological systems.

Immunoregulatory role of neurotransmitters

On the mechanisms and putative pathways involving neuroimmune interactions

TRPV1: The key bridge in neuroimmune interactions

In multicellular organisms, cell signaling through the nervous, immune, and endocrine systems is essential for coordinating metabolic functions among all cells. Signals range from nutrient and metabolite levels in extracellular fluids to specialized systems including chemical messengers, storage and transportation mechanisms, and receptors. Specialized endocrine cells produce chemical messengers (hormones) that interact with receptors in local and distant target cells. There are intimate links between the endocrine and nervous systems such as the hypothalamic–pituitary gland complex in which specialized neurons produce hormones. Depending on the hormone, target cells may be confined to a specific organ or may be more widespread. By binding to receptors and influencing intracellular signaling systems, hormones control many processes at the molecular level during gestation and postnatal life. Major endocrine glands include the pituitary gland, thyroid gland, parathyroid glands, pancreatic islets, adrenal glands, testes, and ovaries. When activated by a hormone, receptors on or in target cells trigger a cascade of intracellular reactions. An agonist is a hormone or chemical that binds to a receptor and induces specific biochemical effects; antagonists compete for binding to a receptor but do not induce the biochemical effects associated with the receptor.

Psychoneuroendocrinoimmunology: The basis for a novel therapeutic approach in aging

Chronic epipharyngitis/chronic nasopharyngitis has traditionally been understood as a localized inflammatory disease, but clinically, it often presents with systemic symptoms that span the nervous, immune, and endocrine systems, such as headaches, fatigue, low-grade fever, impaired concentration, orthostatic dysregulation, joint pain, anxiety, and sleep disorders. Epipharyngeal abrasive therapy (EAT) is a treatment that applies chemical and physical stimulation to the mucous membranes of the epipharynx/nasopharynx using a cotton swab soaked in a 1% zinc chloride solution. Recently, there have been increasing reports of its efficacy in controlling chronic inflammation and improving multisystem symptoms. Regarding the mechanism of action of EAT, autonomic nervous system stimulation, immune system stimulation, and endocrine system stimulation have been reported; however, many aspects of the mechanism of action remain unclear.A review of the existing research literature shows that EAT stimulates the autonomic nervous system through changes in parasympathetic activity mediated by the trigeminal-vagus reflex and has an immediate effect of inducing inflammatory reflexes. In addition, as a long-term effect, the autonomic nervous system balance is reestablished due to changes in the plasticity of the reflex pathway, chronic inflammation is controlled, and the immune response is normalized. Furthermore, continuous EAT stimulation influences the immune and endocrine systems, leading to the resynchronization of the body's homeostasis network.This article systematizes the mechanisms by which EAT exerts its multi-systemic therapeutic effects on the nervous, immune, and endocrine systems, redefines EAT from a conventional local treatment to a systemic treatment, and presents the new framework of EAT field theory. This article is presented as a narrative and conceptual review rather than a systematic review, aiming to synthesize the clinical findings and theoretical perspectives into the proposed EAT field theory.

Gastroesophageal reflux disease (GERD) is a common clinical digestive disorder with a complex pathological mechanism. Traditional understanding of its mechanisms primarily focuses on factors such as lower esophageal sphincter dysfunction, impaired esophageal clearance, delayed gastric emptying, and abnormal gastric acid secretion. In recent years, the introduction of the brain-gut axis (BGA) theory has provided a new perspective for the systematic understanding of GERD’s pathogenesis. However, there remains a significant lack of understanding regarding the specific mechanisms of BGA in GERD, particularly in terms of the interactions between the nervous, endocrine, and immune systems, and how they influence the symptoms and progression of gastroesophageal reflux. This paper aims to review the abnormal mechanisms of the nervous, endocrine, and immune systems in GERD based on the BGA theory, clarify the relationships between these systems in the development of GERD, and explore the current gaps in knowledge and future research directions. Studies have shown that GERD patients often present with neurological abnormalities such as central nervous system hypersensitivity, autonomic nervous imbalance, and enteric nervous system remodeling. Additionally, activation of the HPA axis and prolonged elevation of cortisol exacerbate esophageal injury, while local and systemic immune inflammation further induces visceral hypersensitivity, creating a stress-induced “neuroimmune loop”. Based on the BGA mechanism, future individualized treatments for GERD, which integrate the regulation of central nervous function, endocrine levels, and the immune microenvironment, may provide new strategies and clinical interventions, leading to breakthroughs in relevant therapies.

The concept of an integrated bidirectionally regulated neuroendocrine-immune adaptive response to stress has strong experimental support. The quality and intensity of this coordinated response to stress varies depending upon age, gender, reproductive status, and other genetically determined factors as well as the types and magnitudes of environmental challenges. These factors and dysfunctional communication between the nervous, endocrine, and immune systems appear to contribute to the development of autoimmune diseases in the Lewis and BB rats, the OS chicken, and the NOD, MRL, NZB, NZW, and NZB/NZW F1 mice. Neuroendocrine-immune dysfunction also contributes to the pathogenesis of human autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, thyroid diseases, and others. This review highlights these concepts. It includes discussions on various aspects of the stress response, the hypothalamic-pituitary-adrenal and -gonadal axes, corticotropin releasing hormone, luteinizing hormone releasing hormone, interleukin-1 and -6, corticosteroids, estrogens, testosterone, dehydroepiandrosterone, growth hormone, prolactin, and thyroid hormone. The role of the nervous and endocrine systems in regulating thymopoiesis and T cell development is also emphasized.

The peripheral GABAergic system as a target in endocrine disorders

The interactions between the nervous, endocrine and immune systems require a complex communication network. The central nervous system (CNS) affects the immune system through endocrine, paracrine and neuronal mechanisms. Evidence that this bidirectional communication plays a vital role in the regulation of physiological homeostatic mechanisms while a disfunction of the neuroendocrineimmune balance favors the susceptibility to a number of diseases is derived largely by animal models but also by an increasing number of clinical studies in different fields, including endocrinology, reproductive physiology, pediatrics, oncology, neurology and psychiatry. An increasing number of endocrine hormones, neurotransmitters and neuropeptides are expressed in immune tissues and cells and are actively involved in the physiological regulation of immunity. Conversely, the endocrine and nervous systems harbor receptors for a wide variety of immunologically-derived substances, suggesting potential regulatory feedback loops between the three major integrative bodily systems. Major implications for the reproductive endocrinology field are that psychoneuroendocrine processes may alter fertility via immunomodulation, and that events that occur as part of immune responses influence the neuroendocrine axes, which in turn counter-regulate immune function. In the present article, some features of reproductive-immune interactions will be described, and the neuroendocrineimmune dialogue via the chief reproductive hormone, luteinizing hormone-releasing hormone (LHRH), will be summarized as prototype of intersystem crosstalk. A particular emphasis will be given to the cytokine-LHRH interrelationships both at central (i.e. especially with the astroglial compartment) and peripheral levels. The surprisingly similar communication network systems used by the gonads and the thymus will be summarized, and the sexually-driven dimorphisms dictating female versus male reproductive and immunological capacities reviewed. Evidence that neural, endocrine and immune systems work together as a single unit are emphasized in animal models and human pathologies where interruption of NEI feedback loops results in long lasting pathological consequences for the nervous, endocrine and immune functions.

Microplastics (MPs) and nanoplastics (NPs), formed as a result of plastic product degradation, pose a global environmental threat by penetrating biological systems and inducing systemic pathological changes. This systematic review, conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews guidelines, aims to analyze the molecular and cellular mechanisms of the toxic effects of MPs and NPs on the human cardiovascular, nervous, reproductive, urinary, and digestive systems. The primary mechanisms include oxidative stress, inflammation, mitochondrial dysfunction, apoptosis, autophagy, ferroptosis, and impaired barrier functions. In the cardiovascular system, MPs and NPs contribute to endothelial dysfunction, disorders of lipid metabolism, and fibrosis; in the nervous system, they promote neuroinflammation, pathological protein aggregation, and psychiatric disorders; in the reproductive system, they lead to hormonal imbalance and reduced fertility; in the kidneys, they cause inflammation, and fibrosis and lead to deterioration of kidney function; and in the gastrointestinal tract, they contribute to dysbiosis and metabolic disorders. The literature search was conducted in the PubMed, Web of Science, and Scopus databases without limitations on date, language, or access. Studies were selected based on criteria of transparency, statistical validity, sample representativeness, and correctness of data interpretation. The review emphasizes the necessity of an interdisciplinary approach to developing prevention and treatment strategies, including reduction in exposure, antioxidant and immunomodulatory therapy, and restoration of barrier functions and microbiota. The data obtained reveal research gaps and identify directions for further study.

Objective: The characteristic biological effects of low-frequency electromagnetic fields (EMFs) appear to be functional changes in the central nervous, endocrine and immune systems. For unapparent reasons, however, the results of similar studies have often differed markedly from one another. We recognized that it had generally been assumed, in the studies, that EMF effects would exhibit a dose-effect relationship, which is a basic property of linear systems. Prompted by recent developments in the theory on nonlinear systems, we hypothesized that there was a nonlinear relationship between EMFs and the effects they produced in the endocrine and immune systems. Methods: We developed a novel analytical method that could be used to distinguish between linear and nonlinear effects, and we employed it to examine the effect of EMFs on the endocrine and immune systems. Results: Mice exposed to 5 G, 60 Hz for 1–175 days in 7 independent experiments reliably exhibited changes in serum corticosterone and lymphoid phenotype when the data were analyzed while allowing that the field exposure and the resulting effects could be nonlinearly related. When the analysis was restricted to linear relationships, no effects due to the field were found. Conclusions: The results indicated that transduction of EMFs resulted in changes in both the endocrine and immune systems, and that the laws governing the changes in each system were not the type that govern conventional dose-effect relationships. Evidence based on mathematical modeling was found suggesting that the coincident changes could have been causally related.

The enteric nervous system (ENS) controls and modulates various functions of the digestive tract such as motility, exocrine and endocrine secretion, local microcirculation, inflammation and neuroimmunity. This system is autonomous from the central nervous system (CNS), although they share many neurons and neurotransmitters. The CNS may exert a modulatory role on ENS through brainstem and subcortical areas, peripheral and autonomic fibers. The brain-gut axis is the complex system regulating the interactions and mutual influences between the nervous system and the gut. This axis is divided into various levels through receptors, afferents, integration centers, efferents and effectors, and exploits multiple messengers belonging to the nervous, immune and endocrine systems. The proper functioning of this apparatus is essential in intestinal physiology, its involvement has been recognized as one of the leading pathophysiological basis of many digestive disorders and a target for current and future therapeutical approaches.