
==== Front
Curr Neuropharmacol
Curr Neuropharmacol
CN
Current Neuropharmacology
1570-159X
1875-6190
Bentham Science Publishers

38726788
CN-22-2100
10.2174/1570159X22666240507095700
Medicine, Neurology, Pharmacology, Neuroscience
Long-Term Implicit Epigenetic Stress Information in the Enteric Nervous System and its Contribution to Developing and Perpetuating IBS
Noemi Császár-Nagy 12
Bob Petr 3
Bókkon István 24*
1 National University of Public Services, H-1083 Budapest, Hungary;
2 Psychosomatic Outpatient Clinics, H-1037 Budapest, Hungary;
3 Center for Neuropsychiatric Research of Traumatic Stress, Department of Psychiatry & UHSL, First Faculty of Medicine, and Department of Psychiatry, Faculty of Medicine Pilsen, Charles University, CZ-12108 Prague, Czechia;
4 Neuroscience and Consciousness Research Department, Vision Research Institute, Lowell, MA 01854 USA
* Address correspondence to this author at the Psychosomatic Outpatient Clinics, H-1037 Budapest, Hungary; Neuroscience and Consciousness Research Department, Vision Research Institute, Lowell, MA 01854 USA; Fax: +36 30 208 57 26; E-mail: bokkoni@yahoo.com
09 5 2024
2024
22 13 21002112
23 1 2024
14 4 2024
24 4 2024
© 2024 The Author(s). Published by Bentham Science Publishers
2024
The Author(s)
https://creativecommons.org/licenses/by/4.0/ © 2024 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode.
Psychiatric and mood disorders may play an important role in the development and persistence of irritable bowel syndrome (IBS). Previously, we hypothesized that stress-induced implicit memories may persist throughout life via epigenetic processes in the enteric nervous system (ENS), independent of the central nervous system (CNS). These epigenetic memories in the ENS may contribute to developing and perpetuating IBS. Here, we further elaborate on our earlier hypothesis. That is, during pregnancy, maternal prenatal stresses perturb the HPA axis and increase circulating cortisol levels, which can affect the maternal gut microbiota. Maternal cortisol can cross the placental barrier and increase cortisol-circulating levels in the fetus. This leads to dysregulation of the HPA axis, affecting the gut microbiota, microbial metabolites, and intestinal permeability in the fetus. Microbial metabolites, such as short-chain fatty acids (which also regulate the development of fetal ENS), can modulate a range of diseases by inducing epigenetic changes. These mentioned processes suggest that stress-related, implicit, long-term epigenetic memories may be programmed into the fetal ENS during pregnancy. Subsequently, this implicit epigenetic stress information from the fetal ENS could be conveyed to the CNS through the bidirectional microbiota-gut-brain axis (MGBA), leading to perturbed functional connectivity among various brain networks and the dysregulation of affective and pain processes.

Keywords

ENS
Implicit epigenetic long-term memory
IBS
microbiota-gut-brain axis
stress
short-chain fatty acids
==== Body
pmc1 INTRODUCTION

The exact cause of irritable bowel syndrome (IBS) is still unknown. However, most experts believe that it is related to digestive problems and increased sensitivity of the gastrointestinal tract. There is growing evidence that psychological factors play an important role in the development of IBS [1-3]. Evolution has endowed the gastrointestinal tract (GT) with its dedicated nervous system. The enteric nervous system (ENS) serves as a central control center for regulating the digestive and immune functions of the GT [4]. In mammals, the ENS plays an important role in controlling gut motility and secretion, local blood flow, and the intestinal immune system, among other functions. From an evolutionary standpoint, the ENS predates the development of the central nervous system (CNS) [5, 6]. The ENS developed earlier than and independently of the CNS and, therefore, could be considered the “first brain” [7].

Previously, we hypothesized [8] that stress-induced implicit memories can endure for an individual’s life through epigenetic processes within the ENS. These memories may play important roles in the development and persistence of IBS. This nonconscious (implicit) epigenetic-stress information within the ENS could be transmitted to the CNS via the microbiota-gut-brain axis (MGBA), thereby disrupting functional connectivity among multiple brain networks and dysregulating affective and pain processes, as evidenced by various neuroimaging studies [9-14]. However, the CNS must manage this nonconscious stress information from the ENS, leading to the activation of stress-response systems, such as the hypothalamic-pituitary-adrenal (HPA) axis and the immune system, and affecting gut processes. This creates a self-perpetuating “vicious cycle.”

Herein, we further develop our previous hypothesis [8] and present a possible simple mechanism by which maternal stress may produce stress-induced long-term epigenetic implicit memories (SLEIM) in the ENS of the fetus.

2 MICROBIOTA-GUT-BRAIN AXIS: POSSIBLE RELATIONSHIPS BETWEEN MENTAL DISORDERS AND INFLAMMATORY DISEASES LINKED TO THE GASTROINTESTINAL TRACT

The MGBA is a specific bidirectional communication system between the CNS and the ENS. It connects the emotional and cognitive centers of the brain with peripheral intestinal functions. The MGBA consists of the CNS, the autonomic nervous system (ANS) - which includes the sympathetic nervous system (SNS), the parasympathetic nervous system (PNS), and the ENS - the vagus nerve, the neuroendocrine system, neuroimmune systems, the HPA axis, and the gut microbiota and its metabolites [15, 16]. The bidirectional communication in the MGBA occurs through various pathways, including the vagus nerve, the immune system, neuroendocrine pathways, and bacteria-derived metabolites. Since the gut microbiome is an integral part of the gut-brain axis (GBA), it is more appropriate to use the term microbiota-gut-brain axis (MGBA) than the term gut-brain axis (GBA).

The MGBA, through multiple pathways and microbiota-derived metabolites, potentially influences a variety of functions, including memory, behavior, learning, neurotransmission, synaptic plasticity, stem-cell proliferation, brain development, mental and neurodegenerative disorders, the endocrine system, and the immune system [16, 17-22]. Diverse factors, such as drugs, antibiotics, pathogens, and psychological stress, can disrupt the microbiota, leading to dysbiosis (perturbations in the intestinal microbiota) and impairing communication within the MGBA [23, 24]. The MGBA could contribute to the development of numerous intestinal and extraintestinal diseases, among which are IBS, FM, chronic pain, stroke, lung disease, obesity, type 2 diabetes, insulin resistance, psoriasis, cancer, celiac disease, metabolic syndrome, and nervous system disorders, but the evidence is often limited to animal studies or correlations [25-28]. This axis has been shown to influence neurotransmission and the behaviors that are often associated with neuropsychiatric conditions [29, 30]. There is, in fact, some evidence that the MGBA plays some roles in brain homeostasis and may also influence the pathogenesis of certain disorders, including Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, autism spectrum disorder, and major depressive disorder [31, 32].

In addition, the gut-associated lymphoid tissue (GALT) is the largest immune organ in the body that is located in the gut. GALT is an important component in sensing and responding to the microbial environment and contributes significantly to MGBA processes [33]. In humans, GALT comprises secretory lymphoid aggregates known as Peyer’s patches that sense and fight constant exposure to pathogens and infectious agents. Crucial to the functions of the Peyer’s patches is their communication with the ENS. Crosstalk between these tissues contributes to the MGBA, which influences mood and behavior as well as the homeostasis of neurological development and disease [33].

Psychological stress can impact inflammatory comorbidities and contribute to immune activations [34, 35]. Through the MGBA, mental stress could impact various inflammatory disorders associated with the GT [35, 36]. Recent findings indicate that it is not uncommon for patients with depression, for instance, to have multiple inflammatory comorbidities [37-39]. These processes may have significant implications for the complex relationships between mental disorders and inflammatory diseases associated with the gut [35, 40, 41]. The microbiota in the gut, along with related lymphoid tissue and glial cells, primarily mediates these multidirectional interactions within the MGBA [22, 39, 41].

Intestinal sensitivity, motility, secretion, and permeability are all significantly impacted by psychological stress, and the underlying mechanisms are closely linked to changes in the central nervous system, peripheral neurons, gastrointestinal microbiota, and mucosal immune activation [42]. It seems that MGBA can be the source of the compelling connection between psychological stress and IBS [42]. In addition, MGBA can also have an essential role in inflammatory bowel diseases (IBDs), as it increases the inflammatory response in the CNS and further contributes to anxiety- and depression-like behavioral comorbidities [43].

3 THE VAGUS NERVE: A KEY COMPONENT OF THE MGBA

The vagus nerve (VN) is a part of the autonomic nervous system that regulates numerous involuntary body functions to maintain homeostasis [44]. The VN is the longest cranial nerve, extending from the brain through the thorax to the abdomen, and can regulate blood pressure, heart rate, respiration, digestion, and the immune response [45]. The VN is part of the parasympathetic and sensory nervous systems that have a direct connection between the brain and the ENS and is the main afferent pathway from the abdomen to the brain [46]. The VN can sense alterations in the gastrointestinal lumen through interaction with other cell types. Enteroendocrine cells (EECs) are epithelial cells in the gut that directly interact with the VN [47]. The VN is considered a key component of the MGBA, which connects the gut and the brain bidirectionally [48]. Microorganisms in the gut can activate the VG, and this activation plays a critical role in mediating effects on the brain and behavior. VG plays a key role in the MGBA because vagotomy blocks CNS-related behaviors in rodents [49, 50]. In addition, even in the absence of overt inflammation, the VN can discriminate between non-pathogenic and pathogenic bacteria, and vagal pathways convey signals that can produce both anxiogenic and anxiolytic effects, depending on the nature of the stimulus [46].

4 PHARMACEUTICAL DRUGS COULD INDUCE DYSBIOSIS AND PERTURB MGBA

About 15000 pharmaceutical drugs have been developed so far [51]. A few of these medications are taken for long-term health issues like diabetes, high blood pressure, cancer, and arthritis. The most common drugs used are antidiabetic and cardiovascular drugs, pain relievers, proton pump inhibitors, and antidepressants [51].

Numerous studies found that pharmaceutical drugs such as antibiotics, antidepressants, statins, non-steroidal anti-inflammatory drugs, and other drugs could induce dysbiosis that influences and perturbs MGBA [51-53]. Antidiabetics, proton pump inhibitors, nonsteroidal anti-inflammatory drugs, and atypical antipsychotics were also associated with perturbations of microbiome composition [54]. Drug-induced dysbiosis may influence brain diseases through MGBA.

The activation of µ-opioid receptors (MORs) by agonists could induce dysbiosis, which is associated with the development of opioid analgesic tolerance, opioid-induced hyperalgesia, and the progression of chronic pain conditions such as neuropathic pain [55]. A recent study by Bernabè et al. [56] reinforced the notion that antibiotic-induced gastrointestinal dysmotility directly correlates with gut dysbiosis as well as structural and functional damage to the ENS. Statins are used to regulate serum cholesterol and reduce the risk of heart disease. Statin therapy produces gut dysbiosis in mice through a pregnane X receptor-dependent mechanism [57].

Individual reactions to a given medication can differ significantly in terms of both toxicity and efficacy. The gut microbiome, the host, and medications interact in a variety of intricate ways. In the future, however, changes in the gut flora should be taken into account when assessing the safety of medications [58].

5 IRRITABLE BOWEL SYNDROME

IBS is a multifactored disease that involves both central and peripheral pathophysiological mechanisms [59]. It is one of the most commonly diagnosed chronic functional gastrointestinal diseases worldwide, affecting 9-23% of the population [60, 61]. IBS is characterized by abdominal pain, bloating, and changes in bowel habits, such as diarrhea, constipation, or alternating constipation and diarrhea [62]. Additionally, IBS patients often experience dyspepsia, dysphagia, non-cardiac chest pain, and nausea [63]. Women are more frequently affected by IBS than are men [64].

Current treatments for IBS span a variety of approaches, including pharmacological interventions, psychotherapy, dietary modifications, microbiota transplantation, and complementary and alternative therapies [65-69]. However, it is important to note that these treatments aim to alleviate symptoms rather than provide a complete cure for IBS. Staudacher et al. [70] reviewed the epidemiology and impact of IBS, depression, and anxiety and considered the shared pathophysiology among these conditions. The authors recommended an integrated (holistic) approach and treatment for IBS. Explicitly, their suggested treatments for managing individuals with IBS and co-occurring symptoms of anxiety or depression are: 1. Medical treatments (low-dose tricyclic antidepressants or selective serotonin reuptake inhibitors (SSRI)); 2. Dietary treatments (Mediterranean diet); 3. Psychological treatments (Brain-gut behavior therapy, such as cognitive behavioral therapy and hypnotherapy).

Although the etiology of IBS is multifaceted and not yet fully understood, various factors, including genetics, epigenetics, stress-related effects on nervous and endocrine systems, immune dysregulation, dysbiosis, altered gastrointestinal motility, visceral hypersensitivity, post-infectious reactivity, food sensitivity, and carbohydrate malabsorption have all been implicated in the pathophysiology of IBS [63, 71-73]. Corticotropin-releasing-hormone-dependent dysregulation of the MGBA is involved in IBS, suggesting that IBS may be a disorder characterized by disturbances in brain-gut interactions and stress response systems, such as the HPA and ANS [74].

There is a growing body of evidence implicating psychiatric and mood disorders, including anxiety, depression, bipolar disorder, suicidal attempts, and eating disorders, in the development and maintenance of IBS [75-81]. Approximately 50-90% of IBS patients have comorbid psychiatric conditions, with anxiety disorders and depression being the most prevalent [82]. Maternal prenatal and postnatal anxiety and depression, maternal separation, and early adverse life events, such as physical and sexual abuse or emotional trauma, have been found to play a role in the development of functional gastrointestinal diseases and IBS [66-71]. Additionally, studies have found familial clusters of IBS, suggesting the possibility of an inherited component across generations [83-88].

6 INFLAMMATION MAY PLAY A PATHOGENIC ROLE IN IBS

Up to now, the underlying pathophysiology of IBS remains incompletely understood [89]. As mentioned in the previous section, the pathogenesis of IBS is multifactorial and complex, involving numerous factors [90, 91]. The digestive tract is a complicated structure that encompasses a single layer of epithelial cells, a mucosal barrier, the host mucosal immune system, and microbes [92]. The invasion and proliferation of pathogenic species, as well as the disruption of the immune system and mucosal barrier homeostasis, can be caused by dysbiosis that is due to harmful biopsychosocial factors [93]. In addition to helping to preserve intestinal homeostasis and reduce inflammation, the gut microbiota collaborates to influence host immunity. The host receives benefits from the gut microbiota in many forms, such as aiding in digesting, producing nutrients, detoxifying the body, defending against infections, and controlling the immune system [94].

Studies suggest that perturbed microbiota by various factors may be a key reason for the development of low-grade inflammation. Ng et al. [95] proposed the role of mucosal inflammation in the disease process of IBS. Recent data have found the pivotal role of intestinal microbiota in mucosal immunity [96]. However, despite the fact that conflicting findings are regularly reported, there is mounting evidence linking IBS patients to low-grade inflammation and innate immune system malfunction [95, 97, 98]. In order to provide a more precise picture of immunological activity, recent research has looked at mucosal samples. These investigations have shown that IBS patients have increased levels of proinflammatory cytokines and immunocytes infiltrating the mucosa [97].

IBS is linked to leaky bowels, in which the integrity of the gut blood barrier is perturbed, causing gut contents such as immune cells and microbiota to enter the bloodstream and produce low-grade systemic inflammation [99]. This increased level of inflammation-associated cytokines in circulation may affect all organs, including the brain. Central inflammation in the brain is associated with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis, as well as with neuropsychiatric disorders, specifically depression and anxiety [100-103].

Numerous research studies have investigated the potential implications of low-grade inflammation in the intestinal mucosa and systemic circulation, as well as the role that disruption of the innate immune response plays in the pathophysiology of IBS. Some evidence supports a primarily inflammatory mechanism that affects the intestinal mucosa locally and possibly systemically [97]. Nevertheless, contradictory findings have emerged from a large number of studies that have concentrated on particular cell types, cytokines, or pathogen recognition receptors. As a result, the precise function of immune cells and mediators is still unknown, and the underlying mechanisms remain obscure.

7 THE ENTERIC NERVOUS SYSTEM: DEVELOPMENT, STRUCTURE AND THE ROLE OF LONG-TERM EPIGENETIC IMPLICIT INFORMATION

As mentioned above, the ANS consists of three main components: the SNS, the PNS, and the ENS. Its primary role is to regulate the body’s unconscious or involuntary processes, including heart rate, blood pressure, respiration, digestion, and sexual arousal [104]. The ENS has a central role as an integrating hub for controlling gastrointestinal physiology [105].

The ENS includes millions of neurons and glial cells derived from neural crest cells (NCCs), which migrate to the gut and then colonize the entire length of the gastrointestinal tract and are organized into interconnected ganglia embedded within the gut wall [106, 107]. There are structural, functional, and chemical similarities between the ENS and the CNS [108]. The development of the ENS requires extensive cell migration, regulated cell proliferation, differentiation, neurite outgrowth, and interconnected neuronal networks [109]. The ENS uses more than 30 neurotransmitters, similar to the brain [110], including serotonin, dopamine, norepinephrine, and epinephrine, as well as amino acid neurotransmitters such as gamma-aminobutyric acid (GABA), glycine, glutamate, histamine, and acetylcholine [111].

The ENS is a highly intricate and independent nervous system that develops before and separately from the CNS [7, 112]. Neural circuits within the ENS are capable of performing localized and autonomous functions. Although the ENS and CNS can communicate bidirectionally through the MGBA, the ENS also possesses the ability to function independently. Moreover, evidence suggests that the ENS may have the capacity for learning and memory [113-115]. The ENS has been proposed to play a role in memorization and implicit learning, functioning akin to a “little brain” or a “second brain” within the gut [114].

7.1 Epigenetic Regulations in the Development and Functioning of the ENS

Epigenetic regulations, such as DNA methylation, histone modification, and microRNA regulation, can play a crucial role in the development and functioning of the ENS [116-120]. Numerous congenital and adult-onset gastrointestinal disorders are caused by defects in the development and function of the ENS, including Hirschsprung disease (HSCR), Esophageal Achalasia, Chronic Constipation, and Gastroesophageal Reflux Disease [121]. Hirschsprung disease (HSCR), which is the most prevalent ENS developmental defect, is brought on by aberrant NCC migration, proliferation, differentiation, or survival, which disrupts ENS development [122].

ENS development has been studied in various embryologic model systems, including zebrafish, avians, and rodents [123]. A relevant model for comprehending the development of vertebrate ENS is the zebrafish [124]. Although having a simpler architecture, the ENS of zebrafish is comparable to that of its mammalian counterpart.

Various genes involved in NCCs differentiation during ENS development have been identified, mostly from animal studies. Early enteric neuron growth from vagal and NCCs during ENS development is regulated by genetic, epigenetic, and signaling processes [118]. For example, in zebrafish experiments, Ganz et al. [125] found that ENS phenotypes detected within double mutants for uhrf1 and dnmt1 are not more severe than those of the single mutants. The authors suggested that Uhrf1 and Dnmt1 cooperate and that DNA methylation as a whole is required for proper ENS development. Thus, uhrf1 and dnmt1 could be potential new Hirschsprung disease candidates.

DNA methylation is also linked to ENS development because enteric progenitor cells (EPCs) have decreased DNA methyltransferases (DNMT catalyzes the transfer of methyl groups to specific CpG sites in DNA) expression in HSCR patients compared to controls, and some HSCR patients have presumed pathogenic missense mutations in Dnmt3b [122].

Polycomb repressive complexes 1 and 2 (PRC1 and PRC2) are key epigenetic regulators through histone modification of gene expression that are involved in almost all developmental stages. Feng and Sun [126] suggested that the rnf2 gene (which encodes Ring1b, the enzymatic component of the PRC1 complex) plays an important role in the migration and differentiation of neural precursor cells, but loss of rnf2 gene function produces abnormal development of the ENS and CNS in zebrafish.

8 METABOLIC COMPOUNDS PRODUCED BY GUT MICROBES

The appropriate composition of the gut microbiota and the metabolic compounds produced by gut microbes are key determinants of human health and disease. Countless metabolic compounds are produced by gut microbes including secondary bile acids; lipids; amino acids (including tyrosine, tryptophan, leucine, valine, and isoleucine); neurotransmitters (including serotonin, γ-aminobutyric acid (GABA), acetylcholine, and noradrenaline); vitamins as C, K, and B-complex; gases (including hydrogen (H2), methane (CH4), carbon dioxide (CO2), hydrogen sulfide (H2S), and nitric oxide (NO)); short-chain fatty acids (SCFAs) (including acetate, propionate, and butyrate) [127-129]. Perturbed production of these metabolites can produce various diseases, including metabolic diseases, cardiovascular diseases, gastrointestinal diseases, neurodegenerative and mental diseases, and cancer [127]. Here, we do not aim to delve into more details to discuss the roles of the metabolites of the gut microbiome. According to Swer et al. [130], “The exact underlying mechanisms of most of these metabolites are not understood; however, evidence of their effects on the brain has been reported in multiple studies”.

9 MATERNAL PRENATAL STRESS

Human and animal studies have demonstrated that maternal prenatal stress can alter the maternal gut microbiota and influence the composition of the microbiome of the offspring [131, 132]. During pregnancy, various factors, such as maternal obesity, diet, maternal stress, depression, infections, antidepressants, and antibiotics, can disrupt the maternal microbiota, affecting the development of fetal MGBA [133, 134].

The prevalence of antenatal depression (also referred to as prenatal or perinatal depression) or anxiety (or both) ranges from 8% to 30% [135]; there is wide variation among estimates, likely due to differences in measurement methods and sociocultural factors in individual studies and cultures [132]. Prenatal exposure to maternal stress is associated with mental and behavioral problems in children and later in life [136, 137].

Maternal psychological stress during pregnancy can perturb the HPA axis, thereby increasing circulating cortisol levels, which can affect the maternal gut microbiota [138]. Maternal cortisol can cross the placental barrier, increase circulating levels in the fetus, and lead to dysregulation of the HPA axis, thereby affecting the gut microbiota, microbial metabolites, and intestinal permeability, among other processes [139-141]. Maternal psychological stress is also associated with intestinal dysbiosis in the offspring and can affect the permeability and integrity of the fetal gut [142]. This stress-induced maternal dysbiotic microbiota in newborns shapes the stress responses of the offspring into adulthood through dysregulation of the HPA axis [137, 143, 144]. SCFAs are the major metabolites produced by the microbiota [145] that can control the cortisol response to psychosocial stress [146].

The metabolites of the gut microbiome can affect various diseases by inducing epigenetic changes through DNA methylation, histone modification, and non-coding RNA-associated gene silencing [145, 146]. SCFAs have pleiotropic effects, play essential roles in numerous molecular biological processes, and can also have effects on tissues and organs beyond the gut through their circulation in the blood [147]. Metabolites of the maternal gut microbiome, such as SCFAs, can regulate the development of the fetal ENS [138]. It has been suggested that epigenetic regulation is a central mechanism by which the environment influences mammalian gene expression in health and disease [148]. SCFAs are essential epigenetic regulators throughout the body and also in the gut [149, 150]. SCFAs, such as butyrate, are inhibitors of histone deacetylases, which, in turn, leads to chromatin changes that are generally associated with increased expression of target genes [151]. Yang et al. [152] proposed that SCFAs may control the formation of the ENS by increasing the growth rate of human neural progenitor cells via influencing the expression of neurogenesis, proliferation, and apoptosis-related genes. Experiments by Kimura et al. [153] suggest that SCFAs such as butyrate and propionate can regulate embryonic development in mice during pregnancy by regulating gene expression of Gpr41 and Gpr43 through epigenetic modifications (Gpr41 and Gpr43 are a pair of mammalian G protein-coupled receptors (GPCRs)).

10 SUMMARY WITH HYPOTHESIS

Various studies support the notion that adult health can be influenced by early-life adversity [154]. The fetal programming hypothesis, also known as Barker’s hypothesis, suggests that prenatal conditions can contribute to an individual’s susceptibility to chronic diseases in adulthood, as well as have an impact on offspring ontogenetic vulnerability and mental health outcomes [155-157].

During pregnancy, both psychological and physiological stressors can have a significant impact on maternal and fetal well-being. These stressors include maternal anxiety, depression, and prenatal malnutrition, as well as life events such as trauma, loss, natural disasters, and pathogenic infections [125, 138-140]. Such stressors can disrupt the HPA stress axis and lead to behavioral or cognitive deficits. Maternal infection, anxiety, or depression are associated with increased levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, not only in the maternal circulation but also in the fetal circulation and CNS [139-141]. In addition, maternal psychological stress can produce dysbiosis and change the microbiota and microbiota-derived metabolites, such as SCFAs, in the offspring, as well as affect the development of fetal MGBA and impair the permeability of the fetal gut [132, 133, 134, 141]. Furthermore, stressors during pregnancy have been widely linked to epigenetic changes that play a crucial role in determining maternal and offspring health, potentially predisposing individuals to psychiatric problems during childhood [158-160].

10.1 Further Developing our Previously Presented Hypothesis

Previously, we presented a novel hypothesis [8] that suggested that during critical developmental periods (e.g., prenatal, perinatal, postnatal, and early childhood stages), epigenetically inherited or psychologically induced stressors like maternal separation, maternal depression, or anxiety have the potential to generate stress-induced long-term epigenetic implicit memories (SLEIM) within the fetal ENS. These stress-induced memories may endure within the ENS throughout an individual’s lifetime.

Eventually, SLEIM from within the ENS can cause mild disruption of the intestinal homeostatic processes and transmit these signals to the brain. Although these signals may not be potent enough to cause organic changes, they can lead to symptoms such as abdominal pain, bloating, and alterations in bowel habits, including diarrhea, constipation, or a combination of both. Additionally, SLEIM from the ENS can be communicated to the CNS via the MGBA, resulting in dysregulation of affective and pain processing within the CNS [9-14]. Consequently, perturbed cortical-limbic circuits contribute to heightened subjective pain sensitivity (somatization) and the experience of negative emotions. Despite the efforts of the CNS to mitigate the impact of the SLEIM signals from the ENS, the ENS continues to transmit these signals to the CNS through the MGBA. The CNS must cope with the influx of SLEIM signals from the gut. In doing so, it activates stress response systems such as the HPA axis and the immune system, thereby influencing intestinal processes. This establishes a self-perpetuating cycle, commonly referred to as a “vicious cycle,” between the ENS and the CNS.

In the present paper, we further develop our previously presented hypothesis and demonstrate how various stresses may produce stress-induced long-term epigenetic memory (SLEIM) in the fetal ENS (Fig. 1). ENS has a fundamental function as an integrating hub for controlling gastrointestinal physiology [105]. In addition, epigenetic regulations also play an essential role in the functioning of the ENS [120, 122].

As we have seen above, maternal prenatal stress induces a dysregulation of the HPA axis that increases circulating cortisol levels, which can affect the maternal gut microbiota [138]. Maternal cortisol can cross the placental barrier, increase circulating levels in the fetus, and lead to dysregulation of the fetal HPA axis, affecting the gut microbiota, microbial metabolites, and intestinal permeability, among others [139, 140]. In addition, cortisol receptors are expressed on various gut cells, including epithelial cells, immune cells, enteroendocrine cells, and enteric neurons, indicating a direct effect of cortisol on both maternal and fetal gut functions [139].

SCFAs are the major metabolites produced by the microbiota [150] that can control the cortisol response to psychosocial stress [151]. SCFAs can regulate several mechanisms along the MGBA through direct and indirect processes and epigenetic signaling [145]. SCFAs can also regulate the development of the fetal ENS [161]. The metabolites of the gut microbiome, including SCFAs, can affect various diseases by inducing epigenetic changes through DNA methylation, histone modification, and non-coding RNA-associated gene silencing [145, 162, 163].

Finally, one could argue that we are born germ-free. However, studies support the evidence in utero transmission of microbes from mother to infant [163-166]. In addition, maternal metabolites pass from the gut lumen to the circulation, access the fetus through the placenta, reach fetal circulation, and provide the nutrients required for fetal growth and development [167]. So, regardless of the microbiota that could be present in the uterus, the metabolites of the mother's gut microbiota give energy, nutrients, vitamins, folate, choline, betaine, and SCFAs that provide nutritional programming for fetal growth and development through neurotransmitters and epigenetic mechanisms [138].

These mentioned processes suggest that during pregnancy, SLEIM may be programmed into the ENS of the fetus and could persist throughout life, which may play an important role in the development and persistence of IBS.

If our outlined hypothesis can be further confirmed, it may lead to the development of new neuropharmacological and other therapeutic strategies in the future concerning IBS.

ACKNOWLEDGEMENTS

Declared none.

AUTHORS’ CONTRIBUTIONS

I.B. developed the concept. N.Cs-N.; P.B. and I.B. contributed to the writing of the manuscript.

LIST OF ABBREVIATIONS

ANS Autonomic Nervous System

CH4 Methane

CNS Central Nervous System

CO2 Carbon Dioxide

CpG sites Cytosine-phosphate-guanine Sites

DNA Deoxyribonucleic Acid

DNMT DNA Methyltransferase

Dnmt1 DNA Methyltransferase 1

dnmt1 Dnmt1 Protein Coding Gene

EECs Enteroendocrine Cells

ENS Enteric Nervous System

EPC Enteric Progenitor Cell

GABA Gamma-aminobutyric Acid

GALT Tut-associated Lymphoid Tissue

GT Gastrointestinal Tract

H2 Hydrogen

H2S Hydrogen Sulfide

HPA axis Hypothalamic-Pituitary-Adrenal Axis

HSCR Hirschsprung Disease

IBD Inflammatory Bowel Diseases

IBS Irritable Bowel Syndrome

IL-1β Interleukin-1 Beta

IL-6 Interleukin 6

MGBA Microbiota-gut-brain Axis

MORs µ-opioid Receptors

NCC Neural Crest Cell

NO Nitric Oxide

PNS Parasympathetic Nervous System

PRC1 Polycomb Repressive Complex 1

PRC2 Polycomb Repressive Complex 2

Ring1b Enzymatic Component of the PRC1 Complex

rnf2 Ring Finger Protein 2 Protein Coding Gene

SCFAs Short-chain Fatty Acids

SLEIM Stress-induced Long-term Epigenetic Memory

SNS Sympathetic Nervous System

SSRI Selective Serotonin Reuptake Inhibitors

TNF-α Tumour Necrosis Factor-alpha

Uhrf1 Ubiquitin-like Protein Containing PHD and RING Finger Domains 1

uhrf1 Uhrf1 Protein Coding Gene

VN Vagus Nerve

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

None.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

Fig. (1) The parts and lines marked in red represent our simplified hypothesis about how stress-induced long-term epigenetic memory (SLEIM) may be programmed into the fetal ENS during pregnancy. The other processes in Figure 1 indicate complex processes of the intestine that could also play various roles in these processes. See a more detailed description in Section 10.1. This figure is adapted with multiple modifications from our open access paper: Császár-Nagy N, Bókkon I. Hypnotherapy and IBS: Implicit and simple stress memory in ENS? Heliyon 2023; 9(1): e12751.
==== Refs
REFERENCES

1 Chen J. Barandouzi Z.A. Lee J. Xu W. Feng B. Starkweather A. Cong X. Psychosocial and sensory factors contribute to self-reported pain and quality of life in young adults with irritable bowel syndrome. Pain Manag. Nurs. 2022 23 5 646 654 10.1016/j.pmn.2021.12.004 35074280
2 Tripathi R. Mehrotra S. Irritable bowel syndrome and its psychological management. Ind. Psychiatry J. 2015 24 1 91 93 10.4103/0972-6748.160947 26257492
3 van Tilburg M.A.L. Palsson O.S. Whitehead W.E. Which psychological factors exacerbate irritable bowel syndrome? Development of a comprehensive model. J. Psychosom. Res. 2013 74 6 486 492 10.1016/j.jpsychores.2013.03.004 23731745
4 Sharkey K.A. Mawe G.M. The enteric nervous system. Physiol. Rev. 2023 103 2 1487 1564 10.1152/physrev.00018.2022 36521049
5 Furness J.B. Comparative and evolutionary aspects of the digestive system and its enteric nervous system control. Adv. Exp. Med. Biol. 2022 1383 165 177 10.1007/978-3-031-05843-1_16 36587156
6 Green S.A. Uy B.R. Bronner M.E. Ancient evolutionary origin of vertebrate enteric neurons from trunk-derived neural crest. Nature 2017 544 7648 88 91 10.1038/nature21679 28321127
7 Furness J.B. Stebbing M.J. The first brain: Species comparisons and evolutionary implications for the enteric and central nervous systems. Neurogastroenterol. Motil. 2018 30 2 e13234 10.1111/nmo.13234 29024273
8 Császár-Nagy N. Bókkon I. Hypnotherapy and IBS: Implicit, long-term stress memory in the ENS? Heliyon 2023 9 1 e12751 10.1016/j.heliyon.2022.e12751 36685398
9 Mao C.P. Chen F.R. Huo J.H. Zhang L. Zhang G.R. Zhang B. Zhou X.Q. Altered resting‐state functional connectivity and effective connectivity of the habenula in irritable bowel syndrome: A cross‐sectional and machine learning study. Hum. Brain Mapp. 2020 41 13 3655 3666 10.1002/hbm.25038 32488929
10 Weng Y. Qi R. Liu C. Ke J. Xu Q. Wang F. Zhang L.J. Lu G.M. Disrupted functional connectivity density in irritable bowel syndrome patients. Brain Imaging Behav. 2017 11 6 1812 1822 10.1007/s11682-016-9653-z 27848148
11 Bhatt R.R. Gupta A. Labus J.S. Zeltzer L.K. Tsao J.C. Shulman R.J. Tillisch K. Altered brain structure and functional connectivity and its relation to pain perception in girls with irritable bowel syndrome. Psychosom. Med. 2019 81 2 146 154 10.1097/PSY.0000000000000655 30615602
12 Nisticò V. Rossi R.E. D’Arrigo A.M. Priori A. Gambini O. Demartini B. Functional neuroimaging in irritable bowel syndrome: A systematic review highlights common brain alterations with functional movement disorders. J. Neurogastroenterol. Motil. 2022 28 2 185 203 10.5056/jnm21079 35189600
13 Qi R. Liu C. Weng Y. Xu Q. Chen L. Wang F. Zhang L.J. Lu G.M. Disturbed interhemispheric functional connectivity rather than structural connectivity in irritable bowel syndrome. Front. Mol. Neurosci. 2016 9 141 10.3389/fnmol.2016.00141 27999530
14 Li J. He P. Lu X. Guo Y. Liu M. Li G. Ding J. A resting-state functional magnetic resonance imaging study of whole-brain functional connectivity of voxel levels in patients with irritable bowel syndrome with depressive symptoms. J. Neurogastroenterol. Motil. 2021 27 2 248 256 10.5056/jnm20209 33795543
15 Martinou E. Stefanova I. Iosif E. Angelidi A.M. Neurohormonal changes in the gut-brain axis and underlying neuroendocrine mechanisms following bariatric surgery. Int. J. Mol. Sci. 2022 23 6 3339 10.3390/ijms23063339 35328759
16 Carabotti M. Scirocco A. Maselli M.A. Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann. Gastroenterol. 2015 28 2 203 209 25830558
17 Muhammad F. Fan B. Wang R. Ren J. Jia S. Wang L. Chen Z. Liu X.A. The molecular gut-brain axis in early brain development. Int. J. Mol. Sci. 2022 23 23 15389 10.3390/ijms232315389 36499716
18 Sarubbo F. Cavallucci V. Pani G. The influence of gut microbiota on neurogenesis: Evidence and hopes. Cells 2022 11 3 382 10.3390/cells11030382 35159192
19 Song J.G. Yu M.S. Lee B. Lee J. Hwang S.H. Na D. Kim H.W. Analysis methods for the gut microbiome in neuropsychiatric and neurodegenerative disorders. Comput. Struct. Biotechnol. J. 2022 20 1097 1110 10.1016/j.csbj.2022.02.024 35317228
20 Wachsmuth H.R. Weninger S.N. Duca F.A. Role of the gut–brain axis in energy and glucose metabolism. Exp. Mol. Med. 2022 54 4 377 392 10.1038/s12276-021-00677-w 35474341
21 Chakrabarti A. Geurts L. Hoyles L. Iozzo P. Kraneveld A.D. La Fata G. Miani M. Patterson E. Pot B. Shortt C. Vauzour D. The microbiota-gut-brain axis: Pathways to better brain health. Perspectives on what we know, what we need to investigate and how to put knowledge into practice. Cell. Mol. Life Sci. 2022 79 2 80 10.1007/s00018-021-04060-w 35044528
22 Rutsch A. Kantsjö J.B. Ronchi F. The gut-brain axis: How microbiota and host inflammasome influence brain physiology and pathology. Front. Immunol. 2020 11 604179 10.3389/fimmu.2020.604179 33362788
23 Karl J.P. Hatch A.M. Arcidiacono S.M. Pearce S.C. Feliciano P.I.G. Doherty L.A. Soares J.W. Effects of psychological, environmental and physical stressors on the gut microbiota. Front. Microbiol. 2018 9 2013 10.3389/fmicb.2018.02013 30258412
24 Gebrayel P. Nicco C. Al Khodor S. Bilinski J. Caselli E. Comelli E.M. Egert M. Giaroni C. Karpinski T.M. Loniewski I. Mulak A. Reygner J. Samczuk P. Serino M. Sikora M. Terranegra A. Ufnal M. Villeger R. Pichon C. Konturek P. Edeas M. Microbiota medicine: Towards clinical revolution. J. Transl. Med. 2022 20 1 111 10.1186/s12967-022-03296-9 35255932
25 Afzaal M. Saeed F. Shah Y.A. Hussain M. Rabail R. Socol C.T. Hassoun A. Pateiro M. Lorenzo J.M. Rusu A.V. Aadil R.M. Human gut microbiota in health and disease: Unveiling the relationship. Front. Microbiol. 2022 13 999001 10.3389/fmicb.2022.999001 36225386
26 Chidambaram S.B. Essa M.M. Rathipriya A.G. Bishir M. Ray B. Mahalakshmi A.M. Tousif A.H. Sakharkar M.K. Kashyap R.S. Friedland R.P. Monaghan T.M. Gut dysbiosis, defective autophagy and altered immune responses in neurodegenerative diseases: Tales of a vicious cycle. Pharmacol. Ther. 2022 231 107988 10.1016/j.pharmthera.2021.107988 34536490
27 Carding S. Verbeke K. Vipond D.T. Corfe B.M. Owen L.J. Dysbiosis of the gut microbiota in disease. Microb. Ecol. Health Dis. 2015 26 26191 25651997
28 Scriven M. Dinan T. Cryan J. Wall M. Neuropsychiatric disorders: Influence of gut microbe to brain signalling. Diseases 2018 6 3 78 10.3390/diseases6030078 30200574
29 Sandhu K.V. Sherwin E. Schellekens H. Stanton C. Dinan T.G. Cryan J.F. Feeding the microbiota-gut-brain axis: Diet, microbiome, and neuropsychiatry. Transl. Res. 2017 179 223 244 10.1016/j.trsl.2016.10.002 27832936
30 Socała K. Doboszewska U. Szopa A. Serefko A. Włodarczyk M. Zielińska A. Poleszak E. Fichna J. Wlaź P. The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacol. Res. 2021 172 105840 10.1016/j.phrs.2021.105840 34450312
31 Zang Y. Lai X. Li C. Ding D. Wang Y. Zhu Y. The role of gut microbiota in various neurological and psychiatric disorders-an evidence mapping based on quantified evidence. Mediators Inflamm. 2023 2023 1 16 10.1155/2023/5127157 36816743
32 Suganya K. Koo B.S. Gut-brain axis: Role of gut microbiota on neurological disorders and how probiotics/prebiotics beneficially modulate microbial and immune pathways to improve brain functions. Int. J. Mol. Sci. 2020 21 20 7551 10.3390/ijms21207551 33066156
33 Abo-Shaban T. Sharna S.S. Hosie S. Lee C.Y.Q. Balasuriya G.K. McKeown S.J. Franks A.E. Yardin H.E.L. Issues for patchy tissues: Defining roles for gut-associated lymphoid tissue in neurodevelopment and disease. J. Neural Transm. 2023 130 3 269 280 10.1007/s00702-022-02561-x 36309872
34 Agustí A. Pardo G.M.P. Almela L.I. Campillo I. Maes M. Pérez R.M. Sanz Y. Interplay between the gut-brain axis, obesity and cognitive function. Front. Neurosci. 2018 12 155 10.3389/fnins.2018.00155 29615850
35 Rudzki L. Maes M. The microbiota-gut-immune-glia (MGIG) axis in major depression. Mol. Neurobiol. 2020 57 10 4269 4295 10.1007/s12035-020-01961-y 32700250
36 Clapp M. Aurora N. Herrera L. Bhatia M. Wilen E. Wakefield S. Gut microbiota’s effect on mental health: The gut-brain axis. Clin. Pract. 2017 7 4 987 10.4081/cp.2017.987 29071061
37 Berk M. Williams L.J. Jacka F.N. O’Neil A. Pasco J.A. Moylan S. Allen N.B. Stuart A.L. Hayley A.C. Byrne M.L. Maes M. So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 11 1 200 10.1186/1741-7015-11-200 24228900
38 Maes M. Vasupanrajit A. Jirakran K. Klomkliew P. Chanchaem P. Tunvirachaisakul C. Plaimas K. Suratanee A. Payungporn S. Adverse childhood experiences and reoccurrence of illness impact the gut microbiome, which affects suicidal behaviours and the phenome of major depression: Towards enterotypic phenotypes. Acta Neuropsychiatr. 2023 35 6 328 345 10.1017/neu.2023.21 37052305
39 Maes M. Yirmyia R. Noraberg J. Brene S. Hibbeln J. Perini G. Kubera M. Bob P. Lerer B. Maj M. The inflammatory & neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab. Brain Dis. 2009 24 1 27 53 10.1007/s11011-008-9118-1 19085093
40 Rudzki L. Maes M. From “Leaky Gut” to impaired glia-neuron communication in depression. Adv. Exp. Med. Biol. 2021 1305 129 155 10.1007/978-981-33-6044-0_9 33834399
41 Martínez R.S. Real S.L. García G.A.P. Cruz T.E. Jonapa C.L.A. Amedei A. García A.M.M. Neuroinflammation, microbiota-gut-brain axis, and depression: The vicious circle. J. Integr. Neurosci. 2023 22 3 65 10.31083/j.jin2203065 37258450
42 Qin H.Y. Cheng C.W. Tang X.D. Bian Z.X. Impact of psychological stress on irritable bowel syndrome. World J. Gastroenterol. 2014 20 39 14126 14131 10.3748/wjg.v20.i39.14126 25339801
43 Belei O. Basaca D.G. Olariu L. Pantea M. Bozgan D. Nanu A. Sîrbu I. Mărginean O. Enătescu I. The interaction between stress and inflammatory bowel disease in pediatric and adult patients. J. Clin. Med. 2024 13 5 1361 10.3390/jcm13051361 38592680
44 Howland R.H. Vagus nerve stimulation. Curr. Behav. Neurosci. Rep. 2014 1 2 64 73 10.1007/s40473-014-0010-5 24834378
45 Berthoud H.R. Neuhuber W.L. Functional and chemical anatomy of the afferent vagal system. Auton. Neurosci. 2000 85 1-3 1 17 10.1016/S1566-0702(00)00215-0 11189015
46 Forsythe P. Bienenstock J. Kunze W.A. Vagal pathways for microbiome-brain-gut axis communication. Adv. Exp. Med. Biol. 2014 817 115 133 10.1007/978-1-4939-0897-4_5 24997031
47 Latorre R. Sternini C. Giorgio D.R. Meerveld G.V.B. Enteroendocrine cells: A review of their role in brain–gut communication. Neurogastroenterol. Motil. 2016 28 5 620 630 10.1111/nmo.12754 26691223
48 Kanai T. Teratani T. Role of the vagus nerve in the gut-brain axis: Development and maintenance of gut regulatory T cells via the liver-brain-gut vago-vagal reflex. Brain Nerve 2022 74 8 971 977 35941793
49 Han Y. Wang B. Gao H. He C. Hua R. Liang C. Zhang S. Wang Y. Xin S. Xu J. Vagus nerve and underlying impact on the gut microbiota-brain axis in behavior and neurodegenerative diseases. J. Inflamm. Res. 2022 15 6213 6230 10.2147/JIR.S384949 36386584
50 Chang L. Wei Y. Hashimoto K. Brain–gut–microbiota axis in depression: A historical overview and future directions. Brain Res. Bull. 2022 182 44 56 10.1016/j.brainresbull.2022.02.004 35151796
51 Garg K. Mohajeri M.H. Potential effects of the most prescribed drugs on the microbiota-gut-brain-axis: A review. Brain Res. Bull. 2024 207 110883 10.1016/j.brainresbull.2024.110883 38244807
52 Vich Vila A. Collij V. Sanna S. Sinha T. Imhann F. Bourgonje A.R. Mujagic Z. Jonkers D.M.A.E. Masclee A.A.M. Fu J. Kurilshikov A. Wijmenga C. Zhernakova A. Weersma R.K. Impact of commonly used drugs on the composition and metabolic function of the gut microbiota. Nat. Commun. 2020 11 1 362 10.1038/s41467-019-14177-z 31953381
53 Karakan T. Ozkul C. Akkol K.E. Bilici S. Sánchez S.E. Capasso R. Gut-brain-microbiota axis: Antibiotics and functional gastrointestinal disorders. Nutrients 2021 13 2 389 10.3390/nu13020389 33513791
54 Maier L. Pruteanu M. Kuhn M. Zeller G. Telzerow A. Anderson E.E. Brochado A.R. Fernandez K.C. Dose H. Mori H. Patil K.R. Bork P. Typas A. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 2018 555 7698 623 628 10.1038/nature25979 29555994
55 Essmat N. Karádi D.Á. Zádor F. Király K. Fürst S. Khrasani A.M. Insights into the current and possible future use of opioid antagonists in relation to opioid-induced constipation and dysbiosis. Molecules 2023 28 23 7766 10.3390/molecules28237766 38067494
56 Bernabè G. Shalata M.E.M. Zatta V. Bellato M. Porzionato A. Castagliuolo I. Brun P. Antibiotic treatment induces long-lasting effects on gut microbiota and the enteric nervous system in mice. Antibiotics 2023 12 6 1000 10.3390/antibiotics12061000 37370319
57 Caparrós-Martín J.A. Lareu R.R. Ramsay J.P. Peplies J. Reen F.J. Headlam H.A. Ward N.C. Croft K.D. Newsholme P. Hughes J.D. O’Gara F. Statin therapy causes gut dysbiosis in mice through a PXR-dependent mechanism. Microbiome 2017 5 1 95 10.1186/s40168-017-0312-4 28793934
58 Doestzada M. Vila A.V. Zhernakova A. Koonen D.P.Y. Weersma R.K. Touw D.J. Kuipers F. Wijmenga C. Fu J. Pharmacomicrobiomics: A novel route towards personalized medicine? Protein Cell 2018 9 5 432 445 10.1007/s13238-018-0547-2 29705929
59 Crişan I.M. Dumitraşcu D.L. Irritable bowel syndrome: Peripheral mechanisms and therapeutic implications. Clujul Med. 2014 87 2 73 79 26528001
60 Saha L. Irritable bowel syndrome: Pathogenesis, diagnosis, treatment, and evidence-based medicine. World J. Gastroenterol. 2014 20 22 6759 6773 10.3748/wjg.v20.i22.6759 24944467
61 Weaver K.R. Melkus G.D.E. Henderson W.A. Irritable bowel syndrome. Am. J. Nurs. 2017 117 6 48 55 10.1097/01.NAJ.0000520253.57459.01 28541989
62 Lee Y.J. Park K.S. Irritable bowel syndrome: Emerging paradigm in pathophysiology. World J. Gastroenterol. 2014 20 10 2456 2469 10.3748/wjg.v20.i10.2456 24627583
63 Chong P.P. Chin V.K. Looi C.Y. Wong W.F. Madhavan P. Yong V.C. The microbiome and irritable bowel syndrome - A review on the pathophysiology, current research and future therapy. Front. Microbiol. 2019 10 1136 10.3389/fmicb.2019.01136 31244784
64 Oka P. Parr H. Barberio B. Black C.J. Savarino E.V. Ford A.C. Global prevalence of irritable bowel syndrome according to Rome III or IV criteria: A systematic review and meta-analysis. Lancet Gastroenterol. Hepatol. 2020 5 10 908 917 10.1016/S2468-1253(20)30217-X 32702295
65 Camilleri M. Diagnosis and treatment of irritable bowel syndrome: A review. JAMA 2021 325 9 865 877 10.1001/jama.2020.22532 33651094
66 Dinic R.B. Rajkovic T.S. Grgov S. Petrovic G. Zivkovic V. Irritable bowel syndrome - From etiopathogenesis to therapy. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech Repub. 2018 162 1 1 9 10.5507/bp.2017.057 29358788
67 Rodiño-Janeiro B.K. Vicario M. Cotoner A.C. García P.R. Santos J. A review of microbiota and irritable bowel syndrome: Future in therapies. Adv. Ther. 2018 35 3 289 310 10.1007/s12325-018-0673-5 29498019
68 Black C.J. Thakur E.R. Houghton L.A. Quigley E.M.M. Moayyedi P. Ford A.C. Efficacy of psychological therapies for irritable bowel syndrome: Systematic review and network meta-analysis. Gut 2020 69 8 1441 1451 10.1136/gutjnl-2020-321191 32276950
69 Grundmann O. Yoon S.L. Irritable bowel syndrome: Epidemiology, diagnosis and treatment: An update for health‐care practitioners. J. Gastroenterol. Hepatol. 2010 25 4 691 699 10.1111/j.1440-1746.2009.06120.x 20074154
70 Staudacher H.M. Walus M.A. Ford A.C. Common mental disorders in irritable bowel syndrome: pathophysiology, management, and considerations for future randomised controlled trials. Lancet Gastroenterol. Hepatol. 2021 6 5 401 410 10.1016/S2468-1253(20)30363-0 33587890
71 Juruena M.F. Eror F. Cleare A.J. Young A.H. The role of early life stress in HPA axis and anxiety. Adv. Exp. Med. Biol. 2020 1191 141 153 10.1007/978-981-32-9705-0_9 32002927
72 Distrutti E. Monaldi L. Ricci P. Fiorucci S. Gut microbiota role in irritable bowel syndrome: New therapeutic strategies. World J. Gastroenterol. 2016 22 7 2219 2241 10.3748/wjg.v22.i7.2219 26900286
73 Occhipinti K. Smith J. Irritable bowel syndrome: A review and update. Clin. Colon Rectal Surg. 2012 25 1 046 052 10.1055/s-0032-1301759 23449495
74 Kano M. Muratsubaki T. Van Oudenhove L. Morishita J. Yoshizawa M. Kohno K. Yagihashi M. Tanaka Y. Mugikura S. Dupont P. Ly H.G. Takase K. Kanazawa M. Fukudo S. Altered brain and gut responses to corticotropin-releasing hormone (CRH) in patients with irritable bowel syndrome. Sci. Rep. 2017 7 1 12425 10.1038/s41598-017-09635-x 28963545
75 Tarar Z.I. Farooq U. Zafar Y. Gandhi M. Raza S. Kamal F. Tarar M.F. Ghouri Y.A. Burden of anxiety and depression among hospitalized patients with irritable bowel syndrome: A nationwide analysis. Ir. J. Med. Sci. 2023 192 5 2159 2166 10.1007/s11845-022-03258-6 36593438
76 Eijsbouts C. Zheng T. Kennedy N.A. Bonfiglio F. Anderson C.A. Moutsianas L. Holliday J. Shi J. Shringarpure S. Agee M. Aslibekyan S. Auton A. Bell R.K. Bryc K. Clark S.K. Elson S.L. Brant K. Fontanillas P. Furlotte N.A. Gandhi P.M. Heilbron K. Hicks B. Hinds D.A. Huber K.E. Jewett E.M. Jiang Y. Kleinman A. Lin K-H. Litterman N.K. Luff M.K. McCreight J.C. McIntyre M.H. McManus K.F. Mountain J.L. Mozaffari S.V. Nandakumar P. Noblin E.S. Northover C.A.M. O’Connell J. Petrakovitz A.A. Pitts S.J. Poznik G.D. Sathirapongsasuti J.F. Shastri A.J. Shelton J.F. Tian C. Tung J.Y. Tunney R.J. Vacic V. Wang X. Zare A.S. Voda A-I. Kashyap P. Chang L. Mayer E. Heitkemper M. Sayuk G.S. Kulka R.T. Ringel Y. Chey W.D. Eswaran S. Merchant J.L. Shulman R.J. Bujanda L. Etxebarria G.K. Dlugosz A. Lindberg G. Schmidt P.T. Karling P. Ohlsson B. Walter S. Faresjö Å.O. Simren M. Halfvarson J. Portincasa P. Barbara G. Satta U.P. Neri M. Nardone G. Cuomo R. Galeazzi F. Bellini M. Latiano A. Houghton L. Jonkers D. Kurilshikov A. Weersma R.K. Netea M. Tesarz J. Gauss A. Stengel G.M. Andresen V. Frieling T. Pehl C. Schaefert R. Niesler B. Lieb W. Hanevik K. Langeland N. Wensaas K-A. Litleskare S. Gabrielsen M.E. Thomas L. Thijs V. Lemmens R. Van Oudenhove L. Wouters M. Farrugia G. Franke A. Hübenthal M. Abecasis G. Zawistowski M. Skogholt A.H. Jensen N.E. Hveem K. Esko T. Laving T.M. Zhernakova A. Camilleri M. Boeckxstaens G. Whorwell P.J. Spiller R. McVean G. D’Amato M. Jostins L. Parkes M. Genome-wide analysis of 53,400 people with irritable bowel syndrome highlights shared genetic pathways with mood and anxiety disorders. Nat. Genet. 2021 53 11 1543 1552 10.1038/s41588-021-00950-8 34741163
77 Aziz M. Kumar J. Nawawi M.K. Ali R.R. Mokhtar N. Irritable bowel syndrome, depression, and neurodegeneration: A bidirectional communication from gut to brain. Nutrients 2021 13 9 3061 10.3390/nu13093061 34578939
78 Midenfjord I. Polster A. Sjövall H. Törnblom H. Simrén M. Anxiety and depression in irritable bowel syndrome: Exploring the interaction with other symptoms and pathophysiology using multivariate analyses. Neurogastroenterol. Motil. 2019 31 8 e13619 10.1111/nmo.13619 31056802
79 Ng Q.X. Soh A.Y.S. Loke W. Venkatanarayanan N. Lim D.Y. Yeo W.S. Systematic review with meta‐analysis: The association between post‐traumatic stress disorder and irritable bowel syndrome. J. Gastroenterol. Hepatol. 2019 34 1 68 73 10.1111/jgh.14446 30144372
80 Creed F. Risk factors for self-reported irritable bowel syndrome with prior psychiatric disorder: The lifelines cohort study. J. Neurogastroenterol. Motil. 2022 28 3 442 453 10.5056/jnm21041 35799238
81 Fadgyas-Stanculete M. Buga A.M. Popa-Wagner A. Dumitrascu D.L. The relationship between irritable bowel syndrome and psychiatric disorders: From molecular changes to clinical manifestations. J. Mol. Psychiatry 2014 2 1 4 10.1186/2049-9256-2-4 25408914
82 Lydiard R.B. Falsetti S.A. Experience with anxiety and depression treatment studies: implications for designing irritable bowel syndrome clinical trials. Am. J. Med. 1999 107 5 65 73 10.1016/S0002-9343(99)00082-0 10588175
83 Tao E. Long G. Yang T. Chen B. Guo R. Ye D. Fang M. Jiang M. Maternal separation induced visceral hypersensitivity evaluated via novel and small size distention balloon in post-weaning mice. Front. Neurosci. 2022 15 803957 10.3389/fnins.2021.803957 35153662
84 Ge L. Liu S. Li S. Yang J. Hu G. Xu C. Song W. Psychological stress in inflammatory bowel disease: Psychoneuroimmunological insights into bidirectional gut–brain communications. Front. Immunol. 2022 13 1016578 10.3389/fimmu.2022.1016578 36275694
85 Sun Y. Xie R. Li L. Jin G. Zhou B. Huang H. Li M. Yang Y. Liu X. Cao X. Wang B. Liu W. Jiang K. Cao H. Prenatal maternal stress exacerbates experimental colitis of offspring in adulthood. Front. Immunol. 2021 12 700995 10.3389/fimmu.2021.700995 34804005
86 Császár-Nagy N. Bókkon I. Mother-newborn separation at birth in hospitals: A possible risk for neurodevelopmental disorders? Neurosci. Biobehav. Rev. 2018 84 337 351 10.1016/j.neubiorev.2017.08.013 28851575
87 Bradford K. Shih W. Videlock E.J. Presson A.P. Naliboff B.D. Mayer E.A. Chang L. Association between early adverse life events and irritable bowel syndrome. Clin. Gastroenterol. Hepatol. 2012 10 4 385 390.e1 10.1016/j.cgh.2011.12.018 22178460
88 Chitkara D.K. van Tilburg M.A.L. Martin B.N. Whitehead W.E. Early life risk factors that contribute to irritable bowel syndrome in adults: A systematic review. Am. J. Gastroenterol. 2008 103 3 765 774 10.1111/j.1572-0241.2007.01722.x 18177446
89 Videlock E.J. Chang L. Latest insights on the pathogenesis of irritable bowel syndrome. Gastroenterol. Clin. North Am. 2021 50 3 505 522 10.1016/j.gtc.2021.04.002 34304785
90 Tang H.Y. Jiang A.J. Wang X.Y. Wang H. Guan Y.Y. Li F. Shen G.M. Uncovering the pathophysiology of irritable bowel syndrome by exploring the gut-brain axis: A narrative review. Ann. Transl. Med. 2021 9 14 1187 10.21037/atm-21-2779 34430628
91 Salhy E.M. Irritable bowel syndrome: Diagnosis and pathogenesis. World J. Gastroenterol. 2012 18 37 5151 5163 10.3748/wjg.v18.i37.5151 23066308
92 Gieryńska M. Szulc-Dąbrowska L. Struzik J. Mielcarska M.B. Zboroch G.K.P. Integrity of the intestinal barrier: the involvement of epithelial cells and microbiota-a mutual relationship. Animals 2022 12 2 145 10.3390/ani12020145 35049768
93 Gritz E.C. Bhandari V. The human neonatal gut microbiome: A brief review. Front Pediatr. 2015 3 17 25798435
94 Wu H.J. Wu E. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes 2012 3 1 4 14 10.4161/gmic.19320 22356853
95 Ng Q.X. Soh A.Y.S. Loke W. Lim D.Y. Yeo W.S. The role of inflammation in irritable bowel syndrome (IBS). J. Inflamm. Res. 2018 11 345 349 10.2147/JIR.S174982 30288077
96 Shi N. Li N. Duan X. Niu H. Interaction between the gut microbiome and mucosal immune system. Mil. Med. Res. 2017 4 1 14 10.1186/s40779-017-0122-9 28465831
97 Lazaridis N. Germanidis G. Current insights into the innate immune system dysfunction in irritable bowel syndrome. Ann. Gastroenterol. 2018 31 2 171 187 10.20524/aog.2018.0229 29507464
98 Akiho H. Ihara E. Nakamura K. Low-grade inflammation plays a pivotal role in gastrointestinal dysfunction in irritable bowel syndrome. World J. Gastrointest. Pathophysiol. 2010 1 3 97 105 10.4291/wjgp.v1.i3.97 21607147
99 El-Hakim Y. Bake S. Mani K.K. Sohrabji F. Impact of intestinal disorders on central and peripheral nervous system diseases. Neurobiol. Dis. 2022 165 105627 10.1016/j.nbd.2022.105627 35032636
100 Lu S. Jiang H. Shi Y. Association between irritable bowel syndrome and Parkinson’s disease: A systematic review and meta‐analysis. Acta Neurol. Scand. 2022 145 4 442 448 10.1111/ane.13570 34908158
101 Yoon S.Y. Shin J. Heo S.J. Chang J.S. Sunwoo M.K. Kim Y.W. Irritable bowel syndrome and subsequent risk of Parkinson’s disease: A nationwide population-based matched-cohort study. J. Neurol. 2022 269 3 1404 1412 10.1007/s00415-021-10688-2 34255181
102 Alvino B. Arianna F. Assunta B. Antonio C. Emanuele D. Giorgia M. Leonardo S. Daniele S. Renato D. Buscarinu M.C. Massimiliano M. Crisafulli S.G. Aurora Z. Nicoletti G.C. Marco S. Viola B. Francesco P. Marfia A.G. Grazia S. Valentina S. Davide O. Giovanni S. Gioacchino T. Gallo A. Prevalence and predictors of bowel dysfunction in a large multiple sclerosis outpatient population: An Italian multicenter study. J. Neurol. 2022 269 3 1610 1617 [Erratum in: Prevalence and predictors of bowel dysfunction in a large multiple sclerosis outpatient population: An Italian multicenter study. J. Neurol., 2022; 269(5): 2824-2825. 34347149
103 Lee Y.T. Hu L.Y. Shen C.C. Huang M.W. Tsai S.J. Yang A.C. Hu C.K. Perng C.L. Huang Y.S. Hung J.H. Risk of psychiatric disorders following irritable bowel syndrome: A nationwide population-based cohort study. PLoS One 2015 10 7 e0133283 10.1371/journal.pone.0133283 26222511
104 Meade E. Garvey M. The Role of neuro-immune interaction in chronic pain conditions; Functional somatic syndrome, neurogenic inflammation, and peripheral neuropathy. Int. J. Mol. Sci. 2022 23 15 8574 10.3390/ijms23158574 35955708
105 Frauches B.A.C. Boesmans W. The enteric nervous system: The hub in a star network. Nat. Rev. Gastroenterol. Hepatol. 2020 17 12 717 718 10.1038/s41575-020-00377-2 33087897
106 Holland A.M. Frauches B.A.C. Keszthelyi D. Melotte V. Boesmans W. The enteric nervous system in gastrointestinal disease etiology. Cell. Mol. Life Sci. 2021 78 10 4713 4733 10.1007/s00018-021-03812-y 33770200
107 Nagy N. Goldstein A.M. Enteric nervous system development: A crest cell’s journey from neural tube to colon. Semin. Cell Dev. Biol. 2017 66 94 106 10.1016/j.semcdb.2017.01.006 28087321
108 Gershon M.D. Ratcliffe E.M. Developmental biology of the enteric nervous system: Pathogenesis of Hirschsprung’s disease and other congenital dysmotilities. Semin. Pediatr. Surg. 2004 13 4 224 235 10.1053/j.sempedsurg.2004.10.019 15660316
109 Torroglosa A. Alves M.M. Fernández R.M. Antiñolo G. Hofstra R.M. Borrego S. Epigenetics in ENS development and Hirschsprung disease. Dev. Biol. 2016 417 2 209 216 10.1016/j.ydbio.2016.06.017 27321561
110 de Jonge W.J. The gut’s little brain in control of intestinal immunity. ISRN Gastroenterol. 2013 2013 1 17 10.1155/2013/630159 23691339
111 Yang X. Lou J. Shan W. Ding J. Jin Z. Hu Y. Du Q. Liao Q. Xie R. Xu J. Pathophysiologic role of neurotransmitters in digestive diseases. Front. Physiol. 2021 12 567650 10.3389/fphys.2021.567650 34194334
112 Spencer N.J. Travis L. Wiklendt L. Costa M. Hibberd T.J. Brookes S.J. Dinning P. Hu H. Wattchow D.A. Sorensen J. Long range synchronization within the enteric nervous system underlies propulsion along the large intestine in mice. Commun. Biol. 2021 4 1 955 10.1038/s42003-021-02485-4 34376798
113 Annahazi A. Schemann M. The enteric nervous system: “A little brain in the gut”. Neuroforum 2020 26 1 31 42 10.1515/nf-2019-0027
114 Schemann M. Frieling T. Enck P. To learn, to remember, to forget—How smart is the gut? Acta Physiol. 2020 228 1 e13296 10.1111/apha.13296 31063665
115 Furness J.B. Clerc N. Kunze W.A. Memory in the enteric nervous system. Gut 2000 47 S4 60 62 10.1136/gut.47.suppl_4.iv60
116 Cheng L. Progress on the regulation of DNA methylation in the development of the enteric nervous system. Int. J. Pediatr. 2018 6 756 760
117 Jaroy E.G. Acosta-Jimenez L. Hotta R. Goldstein A.M. Emblem R. Klungland A. Ougland R. “Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease — A review. Clin. Epigenetics 2019 11 1 135 10.1186/s13148-019-0718-x 31519213
118 Uribe R.A. Genetic regulation of enteric nervous system development in zebrafish. Biochem. Soc. Trans. 2024 52 1 177 190 10.1042/BST20230343 38174765
119 Kenny S.E. Tam P.K.H. Barcelo G.M. Hirschsprung’s disease. Semin. Pediatr. Surg. 2010 19 3 194 200 10.1053/j.sempedsurg.2010.03.004 20610192
120 Diposarosa R. Bustam N.A. Sahiratmadja E. Susanto P.S. Sribudiani Y. Literature review: Enteric nervous system development, genetic and epigenetic regulation in the etiology of Hirschsprung’s disease. Heliyon 2021 7 6 e07308 10.1016/j.heliyon.2021.e07308 34195419
121 Brosens E. Burns A.J. Brooks A.S. Matera I. Borrego S. Ceccherini I. Tam P.K. Barceló G.M.M. Thapar N. Benninga M.A. Hofstra R.M.W. Alves M.M. Genetics of enteric neuropathies. Dev. Biol. 2016 417 2 198 208 10.1016/j.ydbio.2016.07.008 27426273
122 Torroglosa A. Villalba-Benito L. Toro L.B. Fernández R.M. Antiñolo G. Borrego S. Epigenetic mechanisms in hirschsprung disease. Int. J. Mol. Sci. 2019 20 13 3123 10.3390/ijms20133123 31247956
123 Heanue T.A. Shepherd I.T. Burns A.J. Enteric nervous system development in avian and zebrafish models. Dev. Biol. 2016 417 2 129 138 10.1016/j.ydbio.2016.05.017 27235814
124 Kuil L.E. Chauhan R.K. Cheng W.W. Hofstra R.M.W. Alves M.M. Zebrafish: A model organism for studying enteric nervous system development and disease. Front. Cell Dev. Biol. 2021 8 629073 10.3389/fcell.2020.629073 33553169
125 Ganz J. Melancon E. Wilson C. Amores A. Batzel P. Strader M. Braasch I. Diba P. Kuhlman J.A. Postlethwait J.H. Eisen J.S. Epigenetic factors Dnmt1 and Uhrf1 coordinate intestinal development. Dev. Biol. 2019 455 2 473 484 10.1016/j.ydbio.2019.08.002 31394080
126 Feng G. Sun Y. The Polycomb group gene rnf2 is essential for central and enteric neural system development in zebrafish. Front. Neurosci. 2022 16 960149 10.3389/fnins.2022.960149 36117635
127 Liu J. Tan Y. Cheng H. Zhang D. Feng W. Peng C. Functions of gut microbiota metabolites, current status and future perspectives. Aging Dis. 2022 13 4 1106 1126 10.14336/AD.2022.0104 35855347
128 Fujisaka S. Watanabe Y. Tobe K. The gut microbiome: A core regulator of metabolism. J. Endocrinol. 2023 256 3 e220111 10.1530/JOE-22-0111 36458804
129 Ansari M.H.R. Saher S. Parveen R. Khan W. Khan I.A. Ahmad S. Role of gut microbiota metabolism and biotransformation on dietary natural products to human health implications with special reference to biochemoinformatics approach. J. Tradit. Complement. Med. 2023 13 2 150 160 10.1016/j.jtcme.2022.03.005 36970455
130 Swer N.M. Venkidesh B.S. Murali T.S. Mumbrekar K.D. Gut microbiota-derived metabolites and their importance in neurological disorders. Mol. Biol. Rep. 2023 50 2 1663 1675 10.1007/s11033-022-08038-0 36399245
131 Yeramilli V. Cheddadi R. Shah J. Brawner K. Martin C. A Review of the impact of maternal prenatal stress on offspring microbiota and metabolites. Metabolites 2023 13 4 535 10.3390/metabo13040535 37110193
132 Mepham J. McGee N.T. Andrews K. Gonzalez A. Exploring the effect of prenatal maternal stress on the microbiomes of mothers and infants: A systematic review. Dev. Psychobiol. 2023 65 7 e22424 10.1002/dev.22424 37860905
133 Yang H. Guo R. Li S. Liang F. Tian C. Zhao X. Long Y. Liu F. Jiang M. Zhang Y. Ma J. Peng M. Zhang S. Ye W. Gan Q. Zeng F. Mao S. Liang Q. Ma X. Han M. Gao F. Yang R. Zhang C. Xiao L. Qin J. Li S. Zhu C. Systematic analysis of gut microbiota in pregnant women and its correlations with individual heterogeneity. NPJ Biofilms Microbiomes 2020 6 1 32 10.1038/s41522-020-00142-y 32917878
134 Gorczyca K. Obuchowska A. Trojnar K.Ż. Opoka W.M. Gorzelak L.B. Changes in the gut microbiome and pathologies in pregnancy. Int. J. Environ. Res. Public Health 2022 19 16 9961 10.3390/ijerph19169961 36011603
135 Srinivasan K. Satyanarayana V.A. Lukose A. Maternal mental health in pregnancy and child behavior. Indian J. Psychiatry 2011 53 4 351 361 10.4103/0019-5545.91911 22303046
136 Tuovinen S. Pulkkinen L.M. Girchenko P. Heinonen K. Lahti J. Reynolds R.M. Hämäläinen E. Villa P.M. Kajantie E. Laivuori H. Raikkonen K. Maternal antenatal stress and mental and behavioral disorders in their children. J. Affect. Disord. 2021 278 57 65 10.1016/j.jad.2020.09.063 32950844
137 Van den Bergh B.R.H. van den Heuvel M.I. Lahti M. Braeken M. de Rooij S.R. Entringer S. Hoyer D. Roseboom T. Räikkönen K. King S. Schwab M. Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy. Neurosci. Biobehav. Rev. 2020 117 26 64 10.1016/j.neubiorev.2017.07.003 28757456
138 Sulkowska S.E.M. The impact of maternal gut microbiota during pregnancy on fetal gut-brain axis development and life-long health outcomes. Microorganisms 2023 11 9 2199 10.3390/microorganisms11092199 37764043
139 Rusch J.A. Layden B.T. Dugas L.R. Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis. Front. Endocrinol. 2023 14 1130689 10.3389/fendo.2023.1130689 37404311
140 Misiak B. Łoniewski I. Marlicz W. Frydecka D. Szulc A. Rudzki L. Samochowiec J. The HPA axis dysregulation in severe mental illness: Can we shift the blame to gut microbiota? Prog. Neuropsychopharmacol. Biol. Psychiatry 2020 102 109951 10.1016/j.pnpbp.2020.109951 32335265
141 Turroni F. Rizzo S.M. Ventura M. Bernasconi S. Cross-talk between the infant/maternal gut microbiota and the endocrine system: A promising topic of research. Microbiome Res Rep. 2022 1 2 14 10.20517/mrr.2021.14 38045647
142 Garzoni L. Faure C. Frasch M.G. Fetal cholinergic anti-inflammatory pathway and necrotizing enterocolitis: The brain-gut connection begins in utero. Front. Integr. Nuerosci. 2013 7 57 10.3389/fnint.2013.00057 23964209
143 Zijlmans M.A.C. Korpela K. Walraven R.J.M. de Vos W.M. de Weerth C. Maternal prenatal stress is associated with the infant intestinal microbiota. Psychoneuroendocrinology 2015 53 233 245 10.1016/j.psyneuen.2015.01.006 25638481
144 Gur T.L. Palkar A.V. Rajasekera T. Allen J. Niraula A. Godbout J. Bailey M.T. Prenatal stress disrupts social behavior, cortical neurobiology and commensal microbes in adult male offspring. Behav. Brain Res. 2019 359 886 894 10.1016/j.bbr.2018.06.025 29949734
145 Silva Y.P. Bernardi A. Frozza R.L. The role of short-chain fatty acids from gut microbiota in gut-brain communication. Front. Endocrinol. 2020 11 25 10.3389/fendo.2020.00025 32082260
146 Dalile B. Vervliet B. Bergonzelli G. Verbeke K. Oudenhove V.L. Colon-delivered short-chain fatty acids attenuate the cortisol response to psychosocial stress in healthy men: A randomized, placebo-controlled trial. Neuropsychopharmacology 2020 45 13 2257 2266 10.1038/s41386-020-0732-x 32521538
147 Zhang D. Jian Y.P. Zhang Y.N. Li Y. Gu L.T. Sun H.H. Liu M.D. Zhou H.L. Wang Y.S. Xu Z.X. Short-chain fatty acids in diseases. Cell Commun. Signal. 2023 21 1 212 10.1186/s12964-023-01219-9 37596634
148 Chen B. Sun L. Zhang X. Integration of microbiome and epigenome to decipher the pathogenesis of autoimmune diseases. J. Autoimmun. 2017 83 31 42 10.1016/j.jaut.2017.03.009 28342734
149 Li L. Zhao S. Xiang T. Feng H. Ma L. Fu P. Epigenetic connection between gut microbiota-derived short-chain fatty acids and chromatin histone modification in kidney diseases. Chin. Med. J. 2022 135 14 1692 1694 10.1097/CM9.0000000000002295 36193977
150 Stein R.A. Riber L. Epigenetic effects of short-chain fatty acids from the large intestine on host cells. Microlife 2023 4 uqad032 37441522
151 Woo V. Alenghat T. Epigenetic regulation by gut microbiota. Gut Microbes 2022 14 1 2022407 10.1080/19490976.2021.2022407 35000562
152 Yang L.L. Millischer V. Rodin S. MacFabe D.F. Villaescusa J.C. Lavebratt C. Enteric short‐chain fatty acids promote proliferation of human neural progenitor cells. J. Neurochem. 2020 154 6 635 646 10.1111/jnc.14928 31784978
153 Kimura I. Miyamoto J. Kitano O.R. Watanabe K. Yamada T. Onuki M. Aoki R. Isobe Y. Kashihara D. Inoue D. Inaba A. Takamura Y. Taira S. Kumaki S. Watanabe M. Ito M. Nakagawa F. Irie J. Kakuta H. Shinohara M. Iwatsuki K. Tsujimoto G. Ohno H. Arita M. Itoh H. Hase K. Maternal gut microbiota in pregnancy influences offspring metabolic phenotype in mice. Science 2020 367 6481 eaaw8429 10.1126/science.aaw8429 32108090
154 Liu R.T. Childhood adversities and depression in adulthood: Current findings and future directions. Clin. Psychol. Sci. Pract. 2017 24 2 140 153 10.1111/cpsp.12190 28924333
155 Garcia-Rizo C. Bitanihirwe B.K.Y. Implications of early life stress on fetal metabolic programming of schizophrenia: A focus on epiphenomena underlying morbidity and early mortality. Prog. Neuropsychopharmacol. Biol. Psychiatry 2020 101 109910 10.1016/j.pnpbp.2020.109910 32142745
156 Kwon E.J. Kim Y.J. What is fetal programming?: A lifetime health is under the control of in utero health. Obstet. Gynecol. Sci. 2017 60 6 506 519 10.5468/ogs.2017.60.6.506 29184858
157 Gluckma P.D. Hanson M.A. Predictive adaptive responses and human disease. The fetal matrix. Evolution, development and disease Cambridge. UK Cambridge Universiy Press 2005 78 102
158 Zietlow A.L. Nonnenmacher N. Reck C. Ditzen B. Müller M. Emotional stress during pregnancy - Associations with maternal anxiety disorders, infant cortisol reactivity, and mother-child interaction at pre-school age. Front. Psychol. 2019 10 2179 10.3389/fpsyg.2019.02179 31607996
159 Howerton C.L. Bale T.L. Prenatal programing: At the intersection of maternal stress and immune activation. Horm. Behav. 2012 62 3 237 242 10.1016/j.yhbeh.2012.03.007 22465455
160 Van den Bergh B.R.H. Van Calster B. Smits T. Van Huffel S. Lagae L. Antenatal maternal anxiety is related to HPA-axis dysregulation and self-reported depressive symptoms in adolescence: A prospective study on the fetal origins of depressed mood. Neuropsychopharmacology 2008 33 3 536 545 10.1038/sj.npp.1301450 17507916
161 Begum N. Mandhare A. Tryphena K.P. Srivastava S. Shaikh M.F. Singh S.B. Khatri D.K. Epigenetics in depression and gut-brain axis: A molecular crosstalk. Front. Aging Neurosci. 2022 14 1048333 10.3389/fnagi.2022.1048333 36583185
162 Li D. Li Y. Yang S. Lu J. Jin X. Wu M. Diet-gut microbiota-epigenetics in metabolic diseases: From mechanisms to therapeutics. Biomed. Pharmacother. 2022 153 113290 10.1016/j.biopha.2022.113290 35724509
163 O’Riordan K.J. Collins M.K. Moloney G.M. Knox E.G. Aburto M.R. Fülling C. Morley S.J. Clarke G. Schellekens H. Cryan J.F. Short chain fatty acids: Microbial metabolites for gut-brain axis signalling. Mol. Cell. Endocrinol. 2022 546 111572 10.1016/j.mce.2022.111572 35066114
164 Walker R.W. Clemente J.C. Peter I. Loos R.J.F. The prenatal gut microbiome: Are we colonized with bacteria in utero? Pediatr. Obes. 2017 2017 12 (S1) 3 17 10.1111/ijpo.12217
165 Nuriel-Ohayon M. Neuman H. Koren O. Microbial changes during pregnancy, birth, and infancy. Front. Microbiol. 2016 7 1031 10.3389/fmicb.2016.01031 27471494
166 Aagaard K. Ma J. Antony K.M. Ganu R. Petrosino J. Versalovic J. The placenta harbors a unique microbiome. Sci. Transl. Med. 2014 6 237 237ra65 10.1126/scitranslmed.3008599 24848255
167 Miko E. Csaszar A. Bodis J. Kovacs K. The maternal-fetal gut microbiota axis: Physiological changes, dietary influence, and modulation possibilities. Life 2022 12 3 424 10.3390/life12030424 35330175
