INTRODUCTION

Post-traumatic stress disorder (PTSD) is a mental disorder that develops due to a powerful psychotraumatic exposure of life-threatening or catastrophic nature, whose symptoms manifest themselves most often 6 months later. The body’s reaction to a stressor alters the sensitivity and responsiveness of all systems of stress-vulnerable individuals so much that the organism cannot return to the initial homeostatic state, the reaction progresses and transforms into a chronic or recurrent form of stress [1]. A disease forms due to inadequate changes in the response sensitivity of the hypothalamic–pituitary–adrenal (HPA) axis, sympathetic nervous system and immune system [2, 3]. While pretty much is known about the responses of the HPA axis and sympathetic nervous system, not enough attention has been paid to the response of the immune system [4–6].

The first wave of the cell danger response comprises the release of metabolic products, such as ATP and ADP, Krebs cycle intermediates, and reactive oxygen species (ROS), and is sustained by purinergic signaling [7]. With a balanced response to a stressor, once the hazard is eliminated or neutralized, a coordinated sequence of restorative reactions is activated in the body of stress-resistant individuals. While stressors of extraordinary intensity induce metabolic disorders in all cells of the body in stress-vulnerable individuals, which disrupt the cooperation of all organ systems and thus evoke changes in behavior, cognitive abilities, and other functions of the CNS. In the mammalian body, the liver, which is the central component of the gastrointestinal tract (GIT), is a master regulator of metabolic homeostasis. Our studies revealed a correlation between the indicators of morphofunctional changes in the liver and those of anxiety-like behavior in rats when modeling PTSD [8].

Since the time of Hans Selye, it has been known that the morphofunctional state of the immune system and GIT changes under stress. The gut microbiota has recently aroused considerable interest in terms of its constituent bacterial species and their potential role in the pathogenesis and treatment of PTSD. The idea of ensuring stress resistance through specific modulation of the gut microbiota has become dominant. Encouraging results have already been obtained in experiments and clinical trials for the treatment of PTSD [9, 10]. Nevertheless, it is impossible to achieve sustainable therapeutic results without studying the functional link between the gut microbiota, hepatobiliary and immune systems.

Tissue-resident immune cells produce the cytoplasmic multiprotein complexes, inflammasomes, which function as sensors of immune danger signals. The sensor system includes pattern recognition receptors (PRRs), complement receptors, and Fc receptors located on the surface of mast cells, B-lymphocytes, dendritic cells, and macrophages, serving to specifically recognize and bind to a fragment of an antibody molecule. PRRs respond to pathogen-associated molecular patterns (PAMPs) and danger signals released from damaged tissues, damage-associated molecular patterns (DAMPs). Upon PRR activation, mast cells, tissue macrophages, and stromal cells begin secreting pro-inflammatory mediators, including lipid mediators and interleukins. Interleukins (IL) bind to their receptors on the surface of neighboring cells, which often entails the expression of even more cytokines [11]. Several genes associated with the immune inflammatory response have been found to be linked to the stress response leading to the development of PTSD [12]. There is already ample evidence that a systemic sluggish inflammation forms in PTSD. The use of non-optimal anti-inflammatory drugs does not allow the disease to be cured [1, 6].

Very little is known about the role of mast cells in the pathogenesis of PTSD, although many people know that mastocytes are the first to respond to any changes in the internal and external environment. Within seconds to minutes upon stimulation, they secrete both pre-formed mediators and molecules synthesized de novo, which act as effectors in communications between the immune, vascular, and nervous systems, as well as in connections between the brain and periphery [1, 13]. Thus, mast cells, being important sources of various mediators, are able to influence both nearby cells and organs and whole body homeostasis. Due to this feature, mastocytes play a crucial role in the regulation of various physiological and pathological processes [13]. It is noteworthy that the role of mastocytes in the pathogenesis of PTSD is most often overlooked [14]. We are convinced that studying mast cell functions will help reveal new pathogenetic mechanisms of PTSD and significantly expand the possibilities of optimal therapy of this disease.

In this review, we aimed to present little known information on gastrointestinal factors that are dynamically involved in the regulation of the CNS stress response, focusing on the hepatobiliary system, gut microflora, and mast cells, whose synergistic trio, according to our hypothesis, is involved in the development and maintenance of such a severe disease as PTSD.

LIPID DISTRESS SYNDROME IN PTSD

Our works and studies by other authors documented a disorder of lipid profile and lipid metabolism regulation in animal models of PTSD and in people diagnosed with PTSD. Their blood contained the products of lipid peroxidation (LPO) [8, 15].

In 1998, the Russian surgeon Academician V.S. Saveliev formulated the concept of lipid distress syndrome as a systemic pathological body’s reaction based on lipid metabolism disorders in the form of multiple pathophysiological, pathobiochemical and pathomorphological processes going beyond the specific target organ affected and promoting the progression of existing diseases or the emergence of new, comorbid pathologies. The same author developed a fundamentally new approach to diagnosing and treatment of many diseases caused by lipid metabolism disorders. Lipid distress syndrome was named after Saveliev [16, 17]. Developmental patterns of lipid metabolism disorders, characterizing Saveliev’s lipid distress syndrome, do not depend on nosology and concern pathological processes common to all diseases and based on dyslipoproteidemia, endotoxinemia, epithelial and endothelial dysfunction. Lipid distress syndrome is always shaped against the background of lipid metabolism disorders, namely dyslipoproteidemia [18].

The most important lipid is cholesterol, a monohydric fat-soluble alcohol that can be considered as the principal sterol of all higher animals (Fig. 1) [19]. Normal serum cholesterol concentration in an adult human is ~ 200 mg/dL, which corresponds to the dynamic equilibrium of cholesterol, when its amount absorbed by the body is equal to its amount excreted therefrom. If blood cholesterol levels exceed the normal, it indicates its retention in the body, which is a risk factor for the development of atherosclerosis. Cholesterol is omnipresent in cells and tissues of humans and many animals, being mainly synthesized in the liver (~ 50%) and small intestine (~ 20%), as well as in the skin, adrenal cortex and gonads (Fig. 1) [19, 20]. About 25–30% of the total cholesterol in the body come from food. Together with phospholipids, cholesterol is the major component of animal cell membranes (Fig. 1). It is essential for the production of bile and many other important bioactive substances, specifically, it is required for the biosynthesis of steroid hormones by the adrenals (cortisol, aldosterone, sex hormones, progesterone, etc.) (Fig. 1) [19, 20].

The basis of cholesterol homeostasis is the enterohepatic circulation of bile acids between the liver and small intestine. Primary bile acids are synthesized in hepatocytes from cholesterol and metabolized into bile as part of glycine-taurine conjugates (Fig. 2) [20]. Bile is involved in fatty acid metabolism, it is essential for the regulation of intestinal peristalsis, normal functioning of the GIT glands (specifically, the pancreas), as well as for sustainig the balance of intestinal microflora. In the small intestine, numerous digestive enzymes deconjugate bile acids to produce bile salts involved in the formation of micelles, required for the absorption of fats. After fat absorption, bile acids remain in the cavity of the small intestine and, through a feedback mechanism, are absorbed from the ileum into blood (Fig. 2) [20]. Triglycerides (TGs), produced due to the cleavage of dietary fats, also enter the bloodstream. In the bloodstream, cholesterol and TGs are present as parts of lipoproteins performing a transport function. Low-density lipoproteins (LDL) transport cholesterol and TGs to peripheral cells, while high-density lipoproteins (HDL) transport cholesterol to the liver (Fig. 2). Lipoprotein secretion by the liver is modulated by a variety of intestinal, pancreatic, adipose tissue factors, as well as CNS nerve impulses. Functional disorders of enterohepatic circulation and/or intrahepatic cholestasis due to decreased activity of reticuloendothelial Kupffer cells result in dyslipidemia [20, 21].

In PTSD, impaired lipid metabolism evokes a significant elevation of LPO markers, such as lipid hydroperoxides and conjugated dienes, accompanied by a marked decrease in the activity of enzymatic and non-enzymatic antioxidants, such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, reduced glutathione, vitamins C and E [21–23]. LPO products activate inflammasomes, large multiprotein complexes acting as intracellular sensors for pathogen recognition or danger signals, which are located in mast cells, macrophages, neutrophils, monocytes, microglia, and other cells. Inflammasomes, in turn, activate innate immunity, including mast cells, which initiates the production of pro-inflammatory interleukins IL-1β and IL-18 [2].

Dyslipidemia and associated metabolic disorders include not only the issues of atherosclerosis and its multifocal ischemic manifestations (coronary heart disease and cerebrovascular diseases) but also alimentary constitutional obesity with metabolic disorders in the organs of the hepatobiliary system. It has long been established that plasma lipid profiles are altered in PTSD: total cholesterol, TGs, LDL, and very-low-density lipoproteins (VLDL) are significantly elevated, while HDL levels are markedly reduced [8]. In this regard, the risk factor for the development of atherosclerosis and coronary heart disease is increased by 1.5–2 or more times. In dyslipidemia, the development of fatty hepatosis occurs in 43–81% and in obesity—in more than 75% of patients, with about half of them having histological alterations represented by inflammation or fibrosis, which is a pathomorphological substrate for the development of steatohepatitis [18, 21]. There has been shown a strong correlation between liver diseases (steatosis, cirrhosis, etc.) and the prevalence of psychiatric diagnoses [22, 23]. In our works, a correlation was revealed between the indicators of morphofunctional hepatic transformation and those of anxiety-like behavior in rats while modeling PTSD [8]. In the works by other authors, performed on individuals with hepatic encephalopathy and nonalcoholic fatty liver disease, a causal relationship between liver diseases and changes in the volume of the cortical brain structures was documented. The latter was manifested by the signs of neuropsychiatric disorders, behavioral transformation, and cognitive deficits, i.e. the symptoms characteristic of PTSD [22, 23]. A recent work by Bell et al. [24] identified common genes determining the function of both the liver and the brain, specifically, the PCSK9 gene encoding proprotein convertase subtilisin/kexin type 9 (PCSK9), the enzyme involved in cholesterol and lipid metabolism [25–27]. PCSK9 has been found to increase the rate of LDL receptor metabolic degradation, preventing LDL diffusion from plasma into cells and thus contributing to the increase in plasma levels of lipoprotein-bound cholesterol. Cerebral expression of PCSK9 is low but significantly increases in disease states [28]. PCSK9 is known, among other things, to play a role in neurogenesis, neuronal differentiation, metabolism of central LDL receptors, neuronal apoptosis, neuroinflammation, Alzheimer’s disease, and some neuropsychiatric diseases [25–27]. It has been shown that gain-of-function mutations lead to persistent hypercholesterolemia accompanied by cardiovascular and hepatic diseases. At the same time, loss-of-function mutations typically result in hypocholesterolemia, so targeting this gene may prove to be effective in the protection against these pathologies and, probably, CNS diseases as well [25–27]. The work on obtaining evidence for a crucial role of PCSK9 in pathogenic processes, including in the CNS, is underway. However, the causal links between liver diseases and changes in the brain have not yet been fully elucidated [25–27].

The lipid profile of blood largely depends on the state of intestinal microbiota and changes under stress, accompanied by deep microecological disorders in the intestine. Gut microorganisms are actively involved in cholesterol metabolism, acting on the enzyme systems of host cells, involved in the synthesis of endogenous cholesterol and recycling of bile acids [29]. The disruption of the microbial ensemble manifests itself in an increased number of anaerobes, hemolytic Escherichia coli, staphylococci and fungi, with a simultaneous decrease in the number of lactobacilli (family Lactobacillaceae) and bifidobacteria (family Bifidobacteriaceae) [30]. Intense bacterial multiplication in the small intestine due to stress-induced dysbiosis [30] leads to enhanced deconjugation of bound bile acids, yielding their toxic endogenous salts that disrupt the microcirculation in the intestinal wall and increase the reabsorption and return to the liver of up to 100% of bile acids excreted into the lumen of the small intestine (Fig. 3). The synthesis of bile acids by hepatocytes decreases compensatorily through feedback, due to which the plasma cholesterol content increases. Thus, the formation of dyslipoproteidemia and lipid distress syndrome is based on a disruption of the principal natural mechanism of cholesterol homeostasis, enterohepatic circulation of bile acids (Fig. 3) [30].

Current studies demonstrate that the liver interacts with the intestine and components of the intestinal barrier, which incorporates a host of mast cells, through bile acids, gut microbiota and, of course, nervous system [8, 31, 32]. A decreased production of bile acids by the liver induces dysbacteriosis, because of which opportunistic bacteria and their lipopolysaccharides get into the liver through the portal vein, evoking the activation of mast cells that secrete inflammatory mediators. At the same time, the overproduction of bile acids induces the death of hepatocytes and leads eventually to the same inflammatory effect [31, 32].

The impairment of cholesterol metabolism and sterol degradation to their end products provokes an increase in the concentration of cholesterol, TGs, and other fats [33], which causes the formation of hepatic steatosis (Fig. 3). Lipids, circulating in the blood, begin to deposit in cells of the organs not adapted for their storage, such as the liver, myocardium, and muscle fibers. As a result, such cells die through apoptosis. Patients with chronic fatty liver disease represent a group at the increased risk of developing PTSD [33], cardiovascular diseases, atherosclerosis, arterial hypertension, etc. (Fig. 3). The diagnosis of hepatic steatosis by ultrasound presents no difficulty, but it is to be verified by biochemical methods and liver biopsy [18].

The treatment tactics for lipid distress syndrome, developed by Saveliev, is based on changes in the host–microbiota system as the principal natural mechanism of cholesterol homeostasis, which has often been disregarded thus far. A restoration of the normal population of the intestinal microflora is supposed to be the main goal of various conservative and surgical methods to treat lipid metabolism disorders. This priority condition, advanced by Saveliev, is substantiated by the fact that the host resident and transient microflora, by synthesizing, transforming, or degrading exogenous and endogenous sterols, is actively involved in cholesterol metabolism, being the critically important metabolic and regulatory system that cooperates host cells and organs in maintaining homeostasis [16–18].

Fig. 1.
figure 1

Biological roles of cholesterol.

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Fig. 2.
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Enterohepatic circulation of bile and microbial transformation of bile acids. Large green arrow—passive absorption and active transport of bile from the intestine to the liver. Small solid green arrows—direction of bile flow. Dotted arrows show the impact of microbiota. BA+Glyc+Taur—bile contains bile acids (BA), glycine (Glyc), and taurine (Taur).

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Fig. 3.
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Developmental pathway of liver and other diseases in hypercholesterolemia. TG—triglycerides, LDL—low-density lipoproteins, CV—cardiovascular.

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INVOLVEMENT OF GUT MICROBIOTA IN PTSD PATHOGENESIS

Over the past decade, it has been discovered that the gut microbiota is able to contribute significantly to the etiopathogenesis of neurodegenerative and neuropsychiatric disorders, such as depression, PTSD, etc. [34, 35], through neuroimmune modulation. An active analysis of the intestinal microflora microbial diversity allowed the identification of a number of microorganisms, including bifidobacteria and lactobacilli, as potential psychotropic probiotics (Fig. 4) [36].

Shaping and multiplication of the gut microbiome begins at birth, and the modification of its repertoire mainly depends on genetic, epigenetic, nutritional and some other factors. Shifts in the gut microbiota balance can lead to health worsening and the development of numerous ailments, ranging from inflammatory diseases of the GIT to metabolic, immunological and mental disorders (Fig. 4) [36, 37]. Convincing evidence indicates that the human gut microbiome, a diverse community of microorganisms inhabiting the GIT, plays a crucial role in the development and functioning of the host nervous system, as well as in complex behaviors, and cognitive processes. A correlation between the number and composition of human gut microbiota and mental illness has long been established [38, 39]. Genome-wide association studies of the human genome and gut microbiota have revealed important host–microbiota interactions. A bidirectional gut microbiome–brain communication also implies the involvement of such a mechanism as the activation of the host intestinal immune system (including the activation of mast cells) by microbial metabolites that influence the vagus nerve [35, 37]. Gut dysbacteriosis accompanies various mental disorders. The gut microbiome produces many neurotransmitters and may contribute to the development of such a psychiatric disorder as PTSD by altering signal transmission and thus impacting stress responses [35, 37].

An analysis of human genome and gut microbiome with two samples between microbiological features and mental diseases demonstrated that Bacteroides eggerthii and Bacteroides thetaiotaomicron are positively associated with PTSD. It has also been determined that those genes that typify the microbiota are also expressed in human brain tissue [40].

It has been found that the results of PTSD therapy with suboptimal medications often lead to the development of liver cirrhosis in combat veterans [35]. It has been shown that PTSD can induce hepatic encephalopathy by altering the hepatobiliary system–microbiome–brain axis. Ninety-three male combat veterans aged 42–58 years were included in the study. It has been found that male veterans with liver cirrhosis against PTSD exhibited a lower microbial diversity, a greater number of transient pathobionts, and a reduced composition of autochthonous taxa. In contrast to a comparison group, patients with PTSD had a much higher number of pathobionts (Enterococcus and Escherichia/Shigella) and a lower number of autochthonous bacteria referring to the families Lachnospiraceae and Ruminococcaceae. An increase in the number of bacteria from the genus Enterococcus, as well as a change in the ratio of bacteria from the genera Escherichia/Shigella, correlated with cognitive decline [35, 41].

A study of the gut microbiota in combat veterans diagnosed with PTSD also revealed a significantly higher abundance of Enterococcus and Escherichia/Shigella pathobionts and a lower number of the autochthonous genera Lachnospira and Ruminococcus, families Lachnospiraceaeae and Ruminococcaceae [3].

The prevalence of PTSD and depression has increased dramatically worldwide since the COVID-19 pandemic (2019–2022). Effective treatment of these conditions requires a comprehensive insight into all pathophysiological factors. In a study by Spanish researchers, there were analyzed microbial communities from fecal samples of 198 individuals, 8.8% of whom had PTSD. A study included 16S ribosomal RNA (V3–V4) gene amplicon sequencing and the assessment of the microbial diversity, community structure, and a relative taxonomic abundance. In individuals with a comorbid PTSD + depression + anxiety states, the bacterial abundance of the species Fusicatenibacter saccharivorans turned out to be reduced. At the same time, higher levels of bacteria of the genus Turicibacter positively correlated with a psychological childhood trauma, while individuals who had suffered life-threatening physical trauma showed lower levels of bacteria of the class Lentisphaerae [41–43]. Given the suboptimal response to modern treatments for PTSD and that cognitive abilities are linked to the gut microbiota [44, 45], which represents a novel therapeutic target, targeting the gut microbiota may benefit the gut–brain axis.

Many strategies and tactics of modulating the balance of the gut ecosystem have recently been considered. Pearson-Leary et al. [10] obtained experimental data indicating that the behavioral anxiety-related phenotype can be transmitted between two rat populations, resistant and nonresistant to social defeat stress, via transfer of fecal microbiota. Stress-sensitive animals exhibited anxiety-like behavior and depression, which correlated with neuroinflammation in the ventral hippocampus. Fecal microbiota analysis in these rats revealed increased expression of bacteria of the genus Clostridium, exhibiting immunomodulatory abilities. Once the fecal microbiota was transferred from stress-nonresistant to control or stress-resistant animals, there was observed an increase in the microglia density and expression of the pro-inflammatory interleukin IL-1β in the ventral hippocampus, which was accompanied by depression-like behavior. Taken together, the results obtained indicated that fecal microbiota transplantation (FMT) can impact the microbiome, CNS, and behavior of recipient animals. Currently, FTM has begun to be used not only in inflammatory bowel diseases but also in metabolic syndrome and mental disorders, specifically, in PTSD [46, 47].

In general, an insight into the mechanisms, by which the gut microbiota can be manipulated, is an important step forward in elucidating the long-term safety of FTM and the efficacy of PTSD treatment. Because the existing pharmacological therapies for PTSD often have negative effects on the gut microbiota, they are not always appropriate for the treatment of this condition [45]. Therefore, the concept of providing stress resistance through specific modulation of the gut microbiota may be a main direction for the new search for PTSD therapeutic options. Presumably, the treatment would be aimed at normalizing the microbiome composition.

Fig. 4.
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Functions of the normal intestinal microflora.

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MAST CELL INVOLVEMENT IN PTSD PATHOGENESIS

The intestinal mucosa is the body’s main line of defense against the adverse effects of the intestinal luminal content, including bacterial toxins. The mucosal surface is lined with epithelial cells that physically separate the intestinal lumen from the internal environment, thus preventing the penetration of potentially harmful substances into the bloodstream, while preserving the absorption of nutrients and electrolytes. Intestinal barrier functions are strictly regulated via the immune and nonimmune mechanisms in which mast cells (mastocytes) play a central role. Specifically, mediators released by mastocytes impact the integrity and viability of the intestinal epithelium, blood flow, coagulation and vascular permeability, contribute to ion and water secretion, and also participate in neuroimmune interactions that promote peristalsis (Fig. 5) [11, 13].

The intestinal mucosa harbors specialized immune structures, such as the Peyer’s pathches, as well as recirculating immune cells. In the intestine, both B1- and B2-cells are a source of IgA, whereas T lymphocytes may be involved in the induction and/or regulation of IgM production in response to TH2 antigens [48]. All these cells are interspersed with mast cells which, apart from a host of other receptors, have receptors for IgA. Mastocytes represent a key link that fulfills several roles in maintaining local and general homeostasis [11, 13]. The GIT is equipped with the body’s largest population of mast cells. In the intestine, mastocytes account for about 2–3% of the lamina propria pool of immune cells; in addition, they reside in the muscular and serous layers (3000–25000 cells/mm3), where they are in a strategic proximity to blood and lymphatic vessels, as well as nerve endings [11, 13].

All components of the mucosal immune system must function in concert to generate an immune response which, on the one hand, protects the host from pathogens and, on the other hand, promotes tolerance shaping to food antigens and commensal bacteria. Innate immune cells, including mastocytes and dendritic cells, train adaptive immune cells and intestinal epithelial cells to establish symbiotic relationships with commensal bacteria (Fig. 5) [11, 49]. Mast cells make a master contribution to the shaping of mucosal immune tolerance to food antigens by secreting IL-9, which induces the release of the enzyme indolamine 2,3-dioxygenase by dendritic cells. It has been found that the deficiency of IL-9 and Toll-like receptor 5 (TLR5, receptor that recognizes flagellin, a flagellar protein found in many bacteria) expressed by mastocytes entails inflammatory dysbiosis [49], indicative of the microbial ensemble regulation by mast cells (Fig. 5). There is evidence that mastocyte-mediated modulation of the intestinal microflora composition and abundance under normal physiological conditions contributes to CNS neuroprotection, affects behavior, and positively influences neurodegenerative processes [11, 50]. Mastocyte heparin, abundantly represented on the mucosal surface, is involved in the regulation of bacterial translocation in the intestinal lumen [51].

Apart from their influence on the intestinal wall permeability and microflora, mastocytes play a key role in the regulation of bile transport, modifying the ductal response by impacting the fibroblast growth factor 15 (FGF15) and its receptors. The same pathway of influence has been characterized in a study of the mast cell involvement in the regulation of bile acid synthesis in the liver (Fig. 5) [52]. Thus, mastocytes exert both mediated and direct effects on host body’s metabolism.

Acute and chronic stress can lead to mastocyte activation [11, 53, 54] and modulate paracellular and transcellular permeability. Mast cells interact with other immune and nonimmune cells [11, 53]. This property allows them to influence a multitude of cells, organs and systems. Specifically, releasing such biologically active substances as histamine, acetylcholine, serotonin, norepinephrine, corticotropin-releasing hormone, etc., and immune mediators (cytokines), mastocytes are essential players of the interplay between the intestinal nervous system and CNS (Fig. 5) [11, 53]. Mastocytes play a crucial role in physiological and pathological responses, influencing the body’s neuroimmunoendocrine system through feedback loops. Mast cells emerged more than 500 million years ago, when animals had not yet developed the immune system. There is an assumption that they originally served as a prototype of neuroimmunoendocrine cells, and then evolved into the master regulator of such interactions, the more that most known diseases are linked to neuroinflammation, which increases under stress [55].

Stressor exposure exerts a significant effect on intestinal functions and mastocyte activation in both the GIT and CNS [56, 57]. Most mastocytes are located on the abluminal side of blood vessels, where they interact with neurons, glia, and endothelial cells. A stressor, due to activation of mastocytes, simultaneously increases the permeability of both the blood-brain barrier (BBB) and the intestinal epithelial barrier. Under stress conditions, the CNS can influence the hepatobiliary system and gut microbiota through the major stress system, the HPA axis, by regulating cortisol secretion. Cortisol, in turn, is able to transform intestinal permeability and barrier function, as well as alter the state of the hepatobiliary system. Mastocytes are sensitive to changes in the state of the HPA axis because they have receptors for corticotropin-releasing hormone, so mast cells are activated upon HPA axis excitation. Mediators, released by peripheral mast cells, penetrate through the BBB and modulate the functions of microglia, astrocytes, and neurons [56, 57]. There are plenty of mastocytes in the CNS. In the brain, glia and mast cells reactivate each other, co-stimulating the production of a wide range of biologically active substances. The mast cell mediator release pattern is multiphasic, as ready-to-use mediators are secreted into the environment within seconds, while newly synthesized mediators are released within the next few hours. Therefore, mast cells function as catalysts that enhance and prolong many cellular vasoactive, neuroactive, immunoreactive, and endocrine responses. In this regard, mast cells are important effectors of the hepatobiliary system–gut microbiota–brain axis, which convert stress signals into the release of a wide range of neurotransmitters and pro-inflammatory cytokines. For this reason, the role of mastocytes in mental disorders, as we hypothesize, should be considered as particularly important, the more that this hypothesis is supported by numerous experimental findings [11, 55–57].

The COVID-19 pandemic has forced researchers to take a fresh look at the role of mast cells in many diseases. The paramount enigma of that pandemic was why the immune system responded so suddenly and catastrophically in only some patients, while remaining quite manageable in most others. A mast cell dysfunction theory has resulted from randomized controlled trials. This hypothesis suggests that mastocyte dysfunction is most likely a genetic problem that pre-exists in some people before coronavirus or any other disease, manifesting itself in a severe form of the inflammatory response. It is also possible that the exposure to an exceedingly strong stressor determines a persistent increase in the number of dysfunctional mast cells. Apparently, due to complex interactions between epigenetic abnormalities and stressor-induced cytokine storm, an additional mutation in stem cells, progenitors of dysfunctional mast cells, is implemented [58–60].

Mast cell dysfunction is now considered a chronic multisystemic inflammatory disease characterized by periodic exacerbations. In this regard, the recurrent symptoms of COVID-19 infection, observed in some patients, have been attributed to the fact that they suffered from an initial attack of infection followed in a short while by a symptomatic exacerbation due to activation of mastocytes with signs of dysfunction [61]. In addition, the mental disorders, common in COVID-19, have been shown to be mainly associated with inflammation and coagulopathy. It is now believed that these disorders arise more from mastocyte dysfunction. This opinion is supported by the fact that the application of some drugs (famotidine, aspirin), which inhibit mast cell activation and the release of inflammatory mediators by them, has brought tangible benefits despite the fact that they have no antiviral effects [60, 61].

Mast cell dysfunction remains as yet unrecognized disease despite its high prevalence, which is masked by the huge heterogeneity of its clinical manifestations due to extraordinary mutational heterogeneity [61]. Mast cell dysfunction is in most cases an idiopathic disease solely because their clonality defies demonstration by available clinical tests. Mastocyte dysfunction is usually diagnosed in association with one or another primary disease despite the fact that it is the dysfunction that is a primary disease. The studies on sequencing mast cell isolates obtained from patients with mastocyte dysfunction have found that almost all such patients demonstrate a wide range of mutations in the KIT gene (only not in codon 816), as well as in dozens of other mastocyte regulatory genes. Another test is a flow cytometry method for CD117 co-expression with CD25 and/or CD2 on the cell surface [62]. However, in some patients, mast cell dysfunction may be purely secondary to another process (e.g., autoimmune or oncological disease). It should be emphasized that none of the patients with mast cell dysfunction, diagnosed and treated during coronavirus disease, had a severe clinical course of the infection [62].

The potential implications of the proposed hypothesis are great for both PTSD and other diseases that have an inflammatory component. The hypothesis suggests that once the fact of mast cell hyperactivation is established, no further diagnostic testing for the presence of mast cell dysfunction syndrome is needed in contrast to basal therapy correction (including histamine H1 and H2 receptor antagonists), which is strongly recommended at the earliest possible time. It is noteworthy that most therapies targeting the above syndrome are quite safe. The use of stabilizers and blocking mast cell mediators in patients with inflammatory diseases can help “calm down” mast cells and preclude cytokine storms, which can lead to better outcomes, including lower mortality rates. In addition, the use of such mastocyte stabilizers as antihistamines and cromolyn, may help prevent a significant increase in cases of inflammatory disease chronization. It is very likely that the use of mastocyte stabilizers would be very appropriate in PTSD, as this disorder is characterized by the presence of systemic subclinical inflammation with marked neuroinflammation [62].

Fig. 5.
figure 5

Normal functions of intestinal mast cells.

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CONCLUSION

PTSD is a maladaptive reaction that alters the sensitivity and responses of all systems in stress-vulnerable individuals to such an extent that the body cannot return to the initial homeostasis. Meanwhile the reaction progresses and transforms into a chronic or recurrent stress response. The symptoms of the disease are characterized by a delayed period. The sufferers of traumatic events are subsequently diagnosed with anxiety, depressive and somatoform disorders are subsequently diagnosed, which determine professional and social maladaptation with stable changes in personality traits. There are no reliable treatments for PTSD until now. In PTSD, as in many other diseases accompanied by inflammation, the main leading or principal link in the chain of disorders arising in the body is systemic sluggish inflammation, which determines the development of other stages of the disease [1]. The functional disorder of organs or systems that arises during the formation of the pathological process usually becomes itself a factor that causes these disorders. Having changed metabolism of the hepatobiliary system and the state of the gut microflora, as well as having activated mast cells, the principal link of the pathological process transforms cause-and-effect relationships, and they swap places. Such a condition in medicine is called a vicious circle, i.e. a closed cycle of pathological processes. The hepatobiliary system, gut microbiota, and mast cells, making up a synergistic trio of metabolic master regulators, shape a vicious circle that sustains the pathological processes in PTSD. The tactics of pharmacological correcting only one component of this vicious circle can only give a temporary positive effect. The authors of this review advance a hypothesis on the necessity of co-targeting all the three components of the metabolic vicious circle.