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Last Updated: 12 August 2022

What Causes IBS? We Analyzed Every Potential Cause – Here’s Our Findings

Researched & Written By:
If you've been diagnosed with IBS, you've probably got a lot of questions - key among them, why did this happen to me? Well, in this guide we explore all the potential reasons people can develop IBS during their life. We start out by looking at risk factors outside of your control, such as gender, age and genetics. Then we look at environmental factors such as childhood and gastroenteritis. Plus, overlapping risk factors like epigenetics and mental health. Finally, we spend the rest of the guide explaining how IBS is driven largely by dysfunction in gut-brain interaction. And look: this guide is complex. It is very technical. But if you go through it slowly, we'll take the time to explain it all for you in plain English. By the end, you'll see IBS can be caused by many different factors coming together. And hopefully, you'll begin to understand your IBS origin story.
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Table of Contents

    What Causes IBS? It’s Complicated

    If you’re battling the beast that is IBS, then naturally, you’re probably wondering what caused your IBS in the first place. Chances are, you’ve asked this question before and been met with answers that weren’t all that informative or helpful.

    We know how incredibly frustrating this can be.

    Truth be told, even as people specializing in gut health, sorting out what’s really going on in IBS has left our minds spinning. We’re talking total research burnout, bringing a whole new meaning to the word overwhelmed.

    The good news is we’ve cleared a path along the way through our research, and we’re ready to be your personal tour guides through the ‘basics’ behind what may be causing IBS.

    To do this, we’ll be taking a look at the individual risk factors and underlying mechanisms tied to IBS.

    Our hope is that you’ll come away with a much better understanding of what’s going on behind the scenes of this crazy complex disorder. Most importantly, we want it to be clear that your illness experience is 100% valid and your symptoms are not ‘all in your head’.

    So, take a seat. We’re diving deep into the origins of IBS, and we’re gonna be here for a while.

    Let’s Talk Risk Factors & Mechanisms

    First off, it’s important to know that IBS is well-recognized as a condition of gut-brain interaction. We’ll dive into the nuances of what that entails later, but outside of this broad statement, the truth is, researchers still can’t say for sure what exactly ‘causes’ IBS in all cases.

    But don’t worry! Even though IBS is insanely complicated and it’s very unlikely that we’ll ever pin down a singular cause, we do have some strong ideas as to what is contributing to the condition.

    What we can do is follow an investigative path, looking for clues in those experiencing IBS to get an idea of where it all began. In doing so, we can see that the ‘cause’ of IBS likely comes down to 2 core components of the disorder, including:

    1. Risk factors or traits that seem to increase the risk of developing IBS
    2. The underlying mechanisms in our body that result in IBS symptoms (a.k.a. the pathophysiology)

    Risk Factors

    Fixed Traits
    Overlapping Fixed Traits and Environmental Factors
    Environmental Influences
    • Gender
    • Age
    • Genetics
    • Epigenetics
    • Mental Health
    • Early Adverse Life Events and Trauma

    Underlying Mechanisms

    Dysfunction in Gut-Brain Interaction
    • Altered Central Nervous System Processing
    • Autonomic Nervous System Dysregulation
    • HPA Axis Dysregulation
    • Neurotransmitter Alterations
    • Altered Intestinal Immune Function
    • Altered Gut Microbiome
    • Intestinal Barrier Dysfunction

    Why There’s No Simple Answer

    For starters, the underlying mechanisms and risk factors tied to IBS are wildly complicated and not completely understood in and of themselves. IBS risk factors range from fixed traits that aren’t modifiable, such as age, to environmental influences, like early childhood trauma. These fixed and environmental circumstances often overlap and can affect the interaction between the gut and brain, leading to changes in gastrointestinal (GI) function. Likewise, the underlying mechanisms in IBS also center around dysfunction in gut-brain interaction.

    So the reason why we’ll likely never find a singular cause of IBS is because any combination of risk factors and underlying mechanisms might occur in such a way that provokes IBS symptoms.

    Not to mention, the overlap between risk factors and underlying mechanisms can compound or exacerbate one another, creating a ‘vicious cycle.’ Once this cycle has been triggered, the slew of dysfunction that follows makes it hard to pinpoint what went wrong in the first place, blurring the lines between cause-and-effect relationships. Not to mention, the overlap between risk factors and underlying mechanisms can compound or exacerbate one another, creating a ‘vicious cycle.’ Once this cycle has been triggered, the slew of dysfunction that follows makes it hard to pinpoint what went wrong in the first place, blurring the lines between cause-and-effect relationships1.

    For example, what came first? An altered microbiome or anxiety and depression? What was the straw that broke the camel’s back? Was it your genetics? Childhood trauma? Or maybe the combination of the two?

    The combination of triggering factors and underlying mechanisms that ‘cause’ IBS will differ from one person to the next. That is to say, how and why you developed IBS is unique to you. However, something that may be the tipping point in developing IBS is stress. Stress can affect underlying mechanisms and risk factors and may indeed be what ‘breaks the camel’s back.’

    Key Takeaways

    IBS - A Stress-Sensitive Condition

    Without a doubt, the factors placing someone at risk for IBS are diverse and complex, but at the core is a singular unifying concept found in most IBS risk factors.

    That unifier, you ask?

    Stress.

    When taking a deeper look, we can clearly see that stress in its many forms, in susceptible individuals, often builds the foundation for IBS to occur2.

    What do we mean by stress

    When you hear the word “stress,” the first thing that comes to mind may be some type of psychological stressor. You know what we mean – those stressful work deadlines, unpaid parking tickets, visits with the inlaws, etc.

    But when we say stress, we’re talking about any physical or psychological stressor that can throw your body out of balance.

    Stress can take many forms. Examples might include chronic stress in adulthood from a high-pressure job, abusive relationships, childhood trauma, mood disorders, inflammation, or gastrointestinal infections34.

    Stress–especially chronic stress–can increase your vulnerability to developing IBS.
    Making matters worse, when you throw stress on top of an existing IBS diagnosis, you may experience even worsened symptoms.

    So clearly, stress is an issue, but why do physical and psychological stressors trigger IBS onset and symptoms?

    While this area of research is in its infancy, we know that stress can influence many aspects of gut function. This can include changes to gut motility patterns, intestinal permeability, or the constant cross-talk between the brain and gut, which plays a primary role when it comes to gut symptoms in IBS.

    As we go through the top risk factors and underlying mechanisms of gut-brain interaction in IBS, look out for the stressors at play and how they could trigger or worsen IBS symptoms.

    Key Takeaways

    Fixed Trait Risk Factors

    Gender

    Being female appears to result in greater susceptibility to developing IBS. While this is the case in most studies, the results aren’t consistent and tend to be location-specific.

    For example, women in Western countries are up to twice as likely to develop IBS compared to men. However, in other parts of the world such as Asia, Africa, and South America, men actually have similar, if not higher, odds of being diagnosed with IBS and seeking out healthcare55.

    Why the difference? We don’t know for sure.
    Sex hormones? Probably7. Cultural differences and gender inequality? Also highly likely. Genetics? Always possible, but hasn’t been proven yet26. All of the above? We’ll have to wait and see.

    A Note On Sex Hormones & IBS
    Sex hormones likely play a role in the development of IBS and its presentation. For example, researchers found that estrogen increased pain modulation, whereas testosterone could decrease the sensation of pain. Both estrogen and progesterone increased circulating stress hormones from the HPA axis (corticotropin-releasing hormone and cortisol), whereas testosterone reduced the release of stress hormones (stress-related ACTH)9.

    Other than the overall prevalence of IBS, researchers have found additional gender-specific differences between men and women. Here are a few of the notable ones:

    • When it comes to IBS subtypes, women are more likely to have IBS-C than men, while men experience more IBS-D than women5.
    • There can be differences in the way men and women report and experience IBS. For example, in one Japanese study on IBS-C patients, anxiety was significantly associated with abdominal discomfort and pain in women but not in men10.
    • Gender differences in parts of the brain that are activated in response to pain have been observed in some studies116.
    • For many women, IBS symptoms seem to worsen during menstruation13.

    Key Takeaways

    Age

    Like sex, the impact of age on IBS susceptibility seems to be location-specific.

    In Western countries, a younger age – specifically less than 50 years old – is a risk factor for IBS1415.

    A 2019 review article analyzed multiple studies and determined younger age to be an increased risk factor in 11 of the analyzed studies, with 10 of those studies originating from Western countries.14 In contrast, when looking specifically at those with IBS in Taiwan, this same study actually found older age to put people at increased risk, further illustrating how even fixed traits such as age can be location-specific14.

    Key Takeaways

    Genetics

    Thanks to available data from studies on IBS within families and twins, as well as modern technology that allows us to analyze genes, we now know that genetics can play a role in IBS.

    To what extent? That continues to be debated.

    Studies assessing the heritability of IBS – that is, the likelihood it gets passed onto us through our genes – report ranges from 0 to 57% Thanks to available data from studies on IBS within families and twins, as well as modern technology that allows us to analyze genes, we now know that genetics can play a role in IBS.

    To what extent? That continues to be debated.

    Studies assessing the heritability of IBS – that is, the likelihood it gets passed onto us through our genes – report ranges from 0 to 57%16. Similarly, while numerous associations have been found between IBS and specific gene variants, results differ depending on which study you look at, and no precise genetic cause has been found17.

    It’s also important to note that it’s unlikely that any particular genetic variant causes IBS; it’s much more likely that it’s caused by the interaction of multiple genes along with environmental risk factors (3).

    With that said, several genes have shown some consistency in being associated with IBS. They include genes that code for various proteins that play key roles in a number of physiological functions161719, such as:

    • Gut motility, secretions, and permeability
    • Neuronal functioning, such as pain sensation
    • Immune system strength and functioning
    • Psychological processing, and the development of mental health disorders

    Key Takeaways

    Environmental Risk Factors

    Early Childhood Adverse Events & Trauma

    Multiple studies have shown a higher rate of early adverse life events (EALs) in people who have IBS. EALs include things like physical violence, sexual abuse, or injury in childhood20.

    A history of EALs were associated with a two-fold higher odds of developing IBS and correlated with the severity of overall IBS symptoms, abdominal pain, poorer daily functioning, and greater health care utilization20.

    Likewise, family history of substance abuse or mental illness and even childhood exposure to war may have physical consequences and possibly affect the development of IBS or other FGID’s. (ch 8)212022

    One study, in particular, showed the following:

    • The greater number of EALs you have increases your odds of having IBS
    • The perceived severity of the trauma significantly increases your odds of having IBS
    • Confiding in others after an EAL showed to be protective against developing IBS, with one study showing that it can reduce your odds of developing it by 17%. This could be because of support resources or a greater ability to cope20

    Tying in gender being a risk factor for IBS, available studies suggest that increased EAL prevalence may be higher in female IBS patients than males. Also, women with EALs are at a higher risk of developing a psychological comorbidity later in life than men2320.

    Trauma of all types has been associated with IBS, such as sexual trauma, being a victim of violence, or experiencing any other major upheaval.20 Another study found that household mental illness, emotional abuse, and having an incarcerated household member were significant predictors of IBS24.

    Early stress from childhood trauma or abuse has been linked to epigenetic (genetic responses due to behaviors and environment) changes4. These changes result in a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system regulation of GI function (e.g., motility, intestinal permeability, sensation)20. This may be why EALs have also been associated with other illnesses besides IBS, like back pain, cancer, chronic fatigue syndrome, and schizophrenia.

    Key Takeaways

    Gastroenteritis & Post-Infectious IBS

    The chances of getting a gastrointestinal infection at some point is pretty high. 25This can be caused by a bacterial infection, viral infection, or protozoal infection. Having a GI infection puts you at a higher risk of developing IBS, or what is sometimes called, ‘post-infectious IBS.’ Rates of PI-IBS vary around the world, but on average, about 1 in 10 people with a GI infection will go on to develop PI-IBS. However, what causes someone to later develop PI-IBS is still unknown25.

    One possible cause is exposure to pathogens that result in alterations to intestinal permeability and inflammation.26 It also involves changes in the intestinal microbiome as well as the epithelial, serotonergic, and immune systems.25 However, these mechanisms are not fully understood yet.

    Risk factors for developing PI-IBS include being female, being younger in age, having psychological distress (like anxiety or depression) during or prior to the acute gastroenteritis, and the severity of the illness.2527 Antibiotic use during illness has shown mixed results for being neutral or a risk factor28.

    Post-Infectious IBS

    2726

    Key Takeaways

    Overlapping Fixed Trait & Environmental Risk Factors

    Epigenetics

    Epigenetics is a fascinating area of scientific research that looks at the molecular modifications that are made to our genes. These modifications determine which genes are being expressed.

    For example, maybe you were unlucky and inherited genes that put you at a higher risk for a certain disease. You can’t change your actual DNA that makes up that gene, or at least not yet, but whether you end up getting that disease somewhat depends on if that gene is ever turned on.

    What causes these epigenetic changes? Some changes may be inherited, but others are likely influenced by environmental factors such as stress, diet, and the microbiome29.

    While the research is still in its early stages, several significant epigenetic changes in certain genes in IBS patients have been observed. These include changes that lead to increased or decreased expression of genes influencing intestinal permeability, motility, and sensitivity2930.

    While we can’t control which genes we inherit, the hope is that with additional research we will someday be able to utilize the power of epigenetics to prevent and cure many disorders including IBS.

    Key Takeaways

    Mental Health

    The sorrow which has no vent in tears may make other organs weep.
    – Henry Maudsley

    There is a huge overlap when it comes to mental health and IBS14. Anxiety and depression are the most common diagnoses, but those with IBS frequently suffer from a number of other psychological disturbances including chronic fatigue syndrome, eating disorders, post-traumatic stress disorder (PTSD), and sleep disorders313233.

    Updated data using the most recent diagnostic criteria for both IBS and anxiety or depression is seriously lacking, but based on previous criteria, the majority of studies have found that somewhere around 40-60% of people who have IBS will also have a mental health disorder of some kind.3434863738 Like other risk factors, these numbers differ somewhat depending on which part of the world the study was done in, but either way, it is clear that a mental health diagnosis is a risk factor regardless of where you call home23935.

    Because of the extremely high numbers of mental health disorders seen alongside IBS, attempts have been made to take the next step and sort out which problem came first. But, IBS being IBS, of course, the results have turned out to be a replay of the chicken vs egg scenario. Diagnosis of IBS is frequently seen both well before or well after a diagnosis of a mental health disorder, making them significant risk factors for each other1540. Leave it to IBS to keep us on our toes.

    Key Takeaways

    IBS - A Disorder Of Gut-Brain Interaction

    “No other organ system is as closely connected to the brain as the GI system, which helps explain the clinical observation of the close relationship between psychosocial features and gut functioning: the gut-brain axis” Rome IV FGIDs41

    Nervous System Basics

    Before we get into the underlying mechanisms of IBS, it’s important to have a basic understanding of nervous system functioning and terminology, as this is the backbone of gut-brain communication. We promise that this quick intro to the nervous system will help you to better understand the mechanisms and pathways that underlie IBS.

    Our bodies are equipped with a very complex nervous system. We can think of this as a communication network and control center that helps to regulate and coordinate the functions of the mind and body. Our nervous system works alongside other bodily systems to keep us in an optimally functioning state (homeostasis).

    The nervous system is broken down into two primary categories:

    • The Central Nervous System (CNS): the brain, brainstem, and spinal cord
    • The Peripheral Nervous System: all the nerves that branch out from the CNS to other parts of the body

    The peripheral nervous system is then further broken down into two subcategories:

    • The Autonomic Nervous System (ANS): takes care of bodily functions that are involuntary or “autonomous” (e.g., breathing, heart rate, blood pressure, and digestion42).
    • The Somatic Nervous System: in charge of voluntary activities that require conscious effort (e.g., walking, reaching, lifting, etc.)

    The ANS is the system we will be focusing on the most. It contains three additional branches:

    • The Sympathetic Nervous System (SNS): promotes the “fight or flight” response
    • The Parasympathetic Nervous System (PNS): promotes “rest and digest” processes
    • The Enteric Nervous System (ENS): controls our digestive processes
    • 4342
    The Nervous system - IBS

    Spotlight on the Enteric Nervous System – The ‘Second Brain’

    The ENS is the nervous system of the gastrointestinal tract. It contains reflex pathways that control digestive functions such as contraction and relaxation, secretion and absorption, and blood flow.42 While the ENS is capable of functioning independently42, its function is influenced by other branches of the ANS, the CNS, and other bodily systems that we’ll explore further below.

    The ENS has been referred to as the ‘second brain’ based on its size, complexity, and similarity to the brain in terms of signaling molecules and neurotransmitters it uses. 43It’s made up of millions of nerve cells (neurons) within the wall of the bowels – 5 times more than are found in our spinal cord69. Most notably, the ENS has close connections with the emotional processing centers of the brain (AKA the limbic system) with some describing the ENS as an extension of the brain’s limbic system in the gut43.

    Key Takeaways

    The Gut-Brain Axis

    We’ve mentioned that IBS is a disorder of gut-brain interaction, but, let’s be real… what does that even mean? For this concept to make sense, we first have to understand the network of communication between the gut and brain called the gut-brain axis (GBA).

    The role of the GBA is to monitor, coordinate, and link the emotional and cognitive centers of the brain with our gut functions. These functions include regulation of immune activation, intestinal reflexes, and intestinal permeability, as well as hormone and neurotransmitter secretion.44 Additionally, gut-brain communication is also known to influence higher cognitive functions, motivation, and mood44.

    Crosstalk between the gut and brain through the GBA is bi-directional, with the brain altering the function of the gut (top-down regulation) and the gut altering the function of the brain (bottom-up regulation).

    How does the GBA do all of this?

    This complicated network of interaction relies on several interwoven components, including:

    • The Central Nervous System
    • The Autonomic Nervous System
    • The Hypothalamic-pituitary-adrenal (HPA) axis
    • The Immune System
    • The Gut Microbiome
    • The Intestinal Barrier

    Each of the above components have been found to be dysfunctional in subsets of IBS patients and comprise many of the underlying mechanisms tied to IBS.

    We’ll be exploring the underlying mechanisms below, but it’s important to know that each of these GBA components can influence each other in direct or indirect ways. This means that even just one of these systems being out of balance may provoke abnormalities in gut-brain functioning and communication.

    But take heart, even though this may sound overwhelming, the good news is these sites of dysfunction may also be therapeutic windows through which IBS symptoms can be managed. But that’s a story for a different module. For now, let’s dig into each of the pieces in this GBA puzzle: what they are, how they interact, and the dysfunction identified in IBS populations.

    Gut-Brain Axis IBS

    Key Takeaways

    Underlying Mechanisms

    Altered Central Nervous System Processing

    One of the reasons IBS is so poorly understood is because much of what we think is going on involves body systems that are not well understood themselves. This is especially true when it comes to studying our central nervous system (CNS), which includes the brain, brainstem, and spinal cord.

    Only in recent years with the development of modern brain imaging tools, such as fMRI and PET scans, have neuroscientists been able to start to get an idea of what’s really going on under the hood. These amazing machines allow us to start making much-needed progress in understanding the neural networks that process all the data in the form of electrical signals that neurons are sending and receiving.

    Getting a deeper understanding of how the brain works is incredibly important because it shifts the way in which we think about our thoughts and emotions, and how deeply intertwined these mental experiences are to the physical. It also means we can develop and utilize effective treatments based on this interconnected, bi-directional brain-gut relationship to reprogram our brains and overcome debilitating disorders such as IBS.

    The CNS & IBS

    How our brain circuits are mapped is highly complex and individualized, but researchers have noticed that there are some significant ways in which the brains of people with IBS are different compared to those without IBS. This includes everything from the physical brain composition (grey vs white matter), all the way to exactly which areas are being used to process information, how the different areas are connected to each other, and the strength of those connections4546.

    Along the same lines is the issue of visceral sensitization. This is when nerves in the gut are activated and/or altered in a way that results in increased stimulation in the CNS, leading to some of the common symptoms of IBS such as pain. Those with IBS have been found to have lower pain thresholds, which means they start to experience pain at lower levels of stimulation compared to those without IBS. There are a number of legitimate reasons for this, including an increased immune response, significant stress, injury, and even genetics474849.

    The good news is that several effective therapies already exist that can decrease correct altered processing and reduce visceral sensitivity.

    Key Takeaways

    Autonomic Nervous System Dysregulation

    The Autonomic Nervous System (ANS) contains the sympathetic and parasympathetic systems, which participate in communication between the gut and the brain– this includes both top-down (brain-to-gut) and bottom-up (gut-to-brain) communication44.

    The Sympathetic Nervous System

    Stimulation of the sympathetic nervous system (SNS) by some perceived sort of stress causes increased attention and activity: the “fight or flight” response. This response is characterized by increases in blood pressure and heart rate, increased blood sugar levels, a halting of gastrointestinal movement, and a decline in GI secretions4250.

    The SNS connects to the nerve cells of the ENS and can alter their activity. For example, the SNS can alter the release of neurotransmitters which regulate and influence ENS function.51 It also influences intestinal immune system activity through a network of intestinal immune cells, known as gut-associated lymphoid tissue5251.

    Generally, the stimulation of the SNS results in increased inflammation48, but in some cases, it may be protective against inflammation.48 The SNS can also alter the intestinal microbiome, potentially increasing the growth of certain damaging microbes53.

    Parasympathetic Nervous System

    The parasympathetic nervous system (PNS) promotes the “rest and digest” processes in the body. PNS activation results in a decrease in heart rate and blood pressure and promotes gastrointestinal movement and digestion42.

    Parasympathetic connections to the GI tract are supplied by the vagus nerve.51 The vagus nerve is our fastest and most direct route connecting the brain and gut and provides bi-directional communication between the gut and CNS.54 The activity of the PNS is anti-inflammatory and may help to lessen intestinal tissue injury4848.

    Parasympathetic Nervous System - IBS

    The Parasympathetic and Sympathetic Nervous Systems & IBS

    People with IBS have been found to have hyperfunction of the SNS and reduced function of the PNS. 50This pattern of dysfunction is also seen in mood and anxiety disorders,50 which are known IBS risk factors.

    Increased SNS activity has been shown to enhance visceral sensitivity,50 and decreased PNS activity has been hypothesized to be the culprit behind some of the overlapping chronic pain disorders in IBS such as headaches, chronic pelvic pain, fibromyalgia, and psychiatric conditions50.

    Key Takeaways

    HPA Axis Dysregulation

    The hypothalamic-pituitary-adrenal (HPA) axis is an important neuroendocrine system in the body that is one of our main stress response output systems. The term “neuroendocrine” refers to interactions between our nervous system and hormones secreted by endocrine glands in the body.

    The HPA axis involves 3 populations of hormone-releasing cells located in the hypothalamus, pituitary gland, and adrenal cortex55. Hormonal signals sent out from each of these cell populations drives the interaction of the HPA axis and its influence on bodily functions and systems. These hormones include:

    • Corticotropin-releasing factor (CRF)
    • Adrenocorticotropic hormone (ACTH)
    • Cortisol

    We do not have direct control over HPA axis activity, but it can be activated by life experiences and other environmental stressors, as well as increased inflammation in general.4455 When stressors or inflammatory molecules activate the system, the following neuroendocrine cascade of ensues:

    • CRF is released from the hypothalamus
    • CRF binds to the anterior pituitary
    • ACTH is then secreted by the pituitary gland
    • ACTH enters into circulation, prompting the release of cortisol from the adrenal cortex
    • Cortisol provides negative feedback to halt CRF production and to switch off the HPA axis so the body can return to a balanced state (homeostasis)

    48So why do we care so much about the HPA Axis when it comes to gut function? Well turns out hormones released as part of the HPA axis can influence intestinal motility, secretion, and sensitivity.56 Likewise, HPA axis hormones have downstream effects on the immune system, autonomic nervous system, intestinal neurotransmitters, and the gut microbiome. 57Hormones such as CRF can also alter function in regions of the brain that process fear and pain. 56Therefore, the HPA axis influences gut-brain functioning and communication through multiple interconnected mechanisms.

    HPA Axis

    HPA Axis & IBS

    Evidence suggests that subsets of IBS patients may have an excessive HPA axis response to stress. For instance, administering the hormone CRF to IBS patients – the hormone that initiates the HPA axis cascade – can result in an exaggerated release of a downstream hormone, ACTH, which suggests that some people with IBS might have a hyperactive HPA axis48. Moreover, HPA axis dysfunction is a hallmark characteristic of certain risk factors for IBS, such as in those who’ve gone through early adverse life events48.

    Key Takeaways

    Neurotransmitter Alterations

    As you know by now, the gut-brain axis communication involves several key players, including the ANS, CNS, ENS, HPA axis, microbiome, and the intestinal barrier. One of the ways all these systems communicate is through chemical messengers called neurotransmitters53.

    Neurotransmitters form a primary link between intestinal functioning and the emotional and cognitive centers of the brain,59 influencing our thoughts, feelings, memories, and pain regulation59.

    In the intestines, various neurotransmitters help regulate motility, secretion, visceral sensitivity, immune system regulation, and even microbiome activity and composition53.

    Sadly, there’s evidence that these key players in intestinal and cognitive functioning may be altered in some people with IBS. Evidence for this includes the presence of certain IBS risk factors where neurotransmitters are known to be involved – i.e., anxiety, stress, and depression.53 Hints of this neurotransmitter dysfunction can also be seen in the central nervous systems of IBS patients where significant alterations in neural processing have been found53.

    Just for a glance-over, neurotransmitters that have been proposed to play a role in IBS include:

    • Serotonin
    • Norepinephrine
    • Epinephrine
    • Glutamate
    • Gamma-Aminobutyric Acid (GABA)
    • Acetylcholine (ACh)
    • Histamine

    53
    Of these, we’ll be highlighting serotonin, as this is the most well-researched neurotransmitter in IBS, and because common IBS therapies often target serotonin dysfunction through medications.

    Serotonin

    Serotonin (also known as 5-hydroxytryptamine, or 5-HT) is a neurotransmitter that plays an important role in the CNS and in the GI tract. It is released from specialized cells in the gut called enterochromaffin cells (ECCs), as well as from serotonergic neurons in the ENS.60 It’s involved in controlling behavior, vomiting, temperature, and other neurological functions in the CNS.53 In the gut, it’s an important signaling molecule that regulates intestinal motility, secretion, and pain perception.61 Gut-derived serotonin may also impact inflammation, neuron development, maintenance of the ENS, and bone development61.

    The functions of serotonin are carried out through the binding of serotonin to its various receptors throughout the body.53 The body comprises 14 different types of serotonin receptors, with 3 main receptor types located in the intestines: 5-HT1, 5-HT3, and 5-HT453.

    After performing functions in the intestine to stimulate intestinal motility, secretion, and other GI reflexes, serotonin is taken up by serotonin transporters (SERT) from cells situated along the intestinal lining. 53The uptake of serotonin by SERT prevents serotonin overstimulation53.

    Serotonin signaling in the gut can be altered by the intestinal microbiota through the production of microbial byproducts, often referred to as metabolites.60 These metabolites bind to receptors on ECCs, and can increase serotonin production. Serotonin then goes on to regulate gut motility by activating neurons of the ENS.60 Serotonin release can also be regulated by a variety of other stimuli, including the parasympathetic and sympathetic nervous systems53.

    Serotonin & IBS

    A number of research findings point to serotonin’s involvement in the altered motility and bowel transit times found in IBS60.

    For example, after-meal serotonin blood plasma levels have been found to be higher in patients with IBS-D and correlate to faster transit times in the colon60.

    In patients with IBS-C, the mechanisms responsible for serotonin release are also thought to be impaired. For instance, IBS-C patients have been found to have higher serotonin concentrations inside ECCs, and low after-meal serotonin blood plasma levels60, indicating impaired release of serotonin from ECCs.

    Moreover, IBS symptoms including hypersensitivity, altered motility, or diarrhea might be explained by changes in serotonin transporter (SERT) function through changes in gene expression. 53A decrease of SERT function in IBS-D patients has been tied to an increased quantity of intestinal immune cells, such as intraepithelial lymphocytes and mast cells,53 which link SERT function to potential alterations in intestinal immune activity. Changes to SERT function in IBS populations are not consistent, with variance seen depending on gender, psychological conditions, genetics, and ethnicity53.

    The serotonin receptor, 5-HT3, plays a role in regulating intestinal movement, is involved in gut-brain communication via vagus nerve connections, and can alter pain signaling pathways. Genetic variations of 5-HT3 receptors may be associated with IBS-D risk53.

    The significance of serotonin in IBS has also been supported by the use of serotonergic drugs which have shown to be effective in treating some patients with IBS-C and IBS-D60.

    Key Takeaways

    Altered Intestinal Immune Function

    As you may already know, the immune system is our body’s way of protecting us by responding to perceived threats. Not surprisingly, the largest interface between our immune system and the environment is in the GI tract.62 This makes a lot of sense, given that our intestines are constantly exposed to potentially harmful byproducts from our gut microbiota and food antigens62.

    In order to tolerate these exposures, our immune system has to appropriately regulate a balance between pro-inflammatory or anti-inflammatory responses. 63To pull this off, our GI tract is equipped with a complex monitoring system to help orchestrate appropriate patterns of movement, secretion, and blood flow. 48This signals the bowels to either digest and absorb when everything seems safe and clear, or to dilute and expel if there’s a perceived threat48.

    These GI sensory mechanisms play an important role in triggering intestinal reflexes by communicating information to the ENS and also through pathways of communication to our CNS48.

    The Immune System & IBS

    Research has yet to reveal exactly what role the immune system is playing in the dysregulated brain-gut pathways, but safe to say something seems fishy.

    For example, studies have shown that people with IBS often have increased numbers of certain types of white blood cells, such as mast cells, in specific areas of their gut64. Like other white blood cells, mast cells help protect our bodies from foreign invaders, such as bacteria and allergens, but can also be activated by non-physical stressors too65. They function by releasing various types of molecules, such as cytokines, neurotransmitters, and enzymes that break down proteins, known as proteases65.

    Why is this especially interesting in the context of IBS? Well, turns out, these molecules are known to cause a whole host of effects including, inflammation, visceral hypersensitivity, increased intestinal permeability, and dysmotility67, all key symptoms in IBS. On top of this, studies have also found that the presence of mast cells hanging out close to enteric nerves correlated with symptoms of abdominal pain68. Coincidence? We think not.

    Besides this whole suspicious mast cell business, results from genetic studies also support the theory that the immune system is playing a big role in IBS for some people. Several of these studies have shown that having certain variations in genes that code for pro-inflammatory molecules, such as IL-6 and TNFS15, increase the risk of IBS, whereas having certain variations in genes for anti-inflammatory molecules, such as IL-10, decreases IBS risk.6970 Again, these are just association studies and don’t prove cause and effect, but they do point to inflammation as a potential factor in IBS.

    Lastly, there is a lot of evidence to suggest that an altered immune response may be underlying the development of post infectious-IBS (PI-IBS). Those who acquire PI-IBS seem to have a stronger immune response during a gastrointestinal infection, as evidenced by increased expression of pro-inflammatory molecules such as IL-1β.71 Not only was IL-1β beta elevated during the course of the actual infection, but also long afterwards. All this extra inflammation may be damaging tissue and sensitizing nerves, leading to increased pain lasting long after a bout of gastroenteritis7273.

    Key Takeaways

    Altered Gut Microbiome

    The human microbiome is a diverse and complex ecosystem inhabited by thousands of microbial species known to play a role in health and disease74.

    When we start to talk about the microbiome, it is important to note that our bodies consist of many microbiomes. It may not be too comforting to think about, but the truth is that every surface of our body exposed to the environment is covered with bacteria and other microorganisms. Your skin, nasal passage, mouth, everything.

    With that said, usually when we are talking about the “microbiome”, especially in the context of IBS, we are actually referring to the microbiota of the small and large intestines in the gastrointestinal system.

    Most of the time these microorganisms live in peace and harmony with our own bodies, thriving off of the cozy home we offer them, and in return, providing us with a long list of goods and services. This includes proper immune system development and regulation, production of vitamins, prevention of infections, regulation of our genes, and it even plays a role in brain and nervous system functioning7576777879.

    However, sometimes people can find themselves in a state of dysbiosis that can lead to many different types of illnesses.

    Defining dysbiosis can be a bit tricky since the scientific community has not yet been able to identify what exactly a healthy, normal microbial profile even is80. But in general, dysbiosis refers to an imbalance in the microbiota composition and activity that results in disease promotion81.

    The Gut Microbiome & IBS

    So, how do we know that dysbiosis or disturbances of the microbiota play a role in IBS specifically?

    One clue is that the amounts of certain bacteria and the overall diversity of microbes in IBS patients differ significantly from healthy controls in research studies82. For example, several studies have found decreased amounts of the genera Bifidobacterium and Lactobacillus in IBS subjects, with increased Firmicutes to Bacteroidetes ratios at the phylum level83.

    Another clue is that many of those with IBS have a previous history of some sort of intestinal infection, referred to as gastroenteritis84. Results vary (as usual), but studies show that at least 10% of those who get gastroenteritis will go on to then develop IBS85. IBS diagnosed after a bout of gastroenteritis is referred to as post-infectious IBS, or PI-IBS.

    Another strong piece of evidence that supports the role of the microbiome in IBS is that certain antibiotics have been shown to be helpful in treating IBS in some cases. 8687The positive effects don’t always last with these medications, but for a subset of people they do seem to help to some extent.

    Still not convinced? Well then get this: Scientists have shown that they are able to induce IBS symptoms in rats, such as hypersensitivity, anxiety, and increased gut motility, by simply transferring fecal material from IBS patients into the intestines of previously healthy rats, a process known as a fecal transplant.8889 These amazing studies not only tie the microbiome to IBS specifically, but also to the bigger gut-brain picture in general.

    Key Takeaways

    Intestinal Barrier Dysfunction

    The intestinal barrier is the part of our gut that separates fecal content moving through our intestines from the rest of our body. It is made up of multiple layers, including an outer mucus layer colonized by bacteria, an inner mucus layer, the epithelial cell layer, and then finally the lamina propria, a layer which contains immune cells that help the body respond to unwanted invaders and other threats90.

    Although all these layers play a significant role in protecting us against the outside environment, most of the time concerns regarding the intestinal barrier integrity are referring to dysfunction in the permeability of the epithelial cell layer, a condition often referred to as ‘leaky gut’.

    Intestinal permeability in general refers to the ability of ions, molecules, and other particles to pass through the intestinal epithelial cells. This happens either directly through the cells (transcellular route) or in-between them (paracellular route)91. Epithelial cells are held together by junction complexes, which regulate the flow of particles through the paracellular route.

    Because these cells that make up our intestinal barrier are also responsible for absorbing nutrients from the food we eat, some permeability is totally normal and healthy. However, too much permeability may be leading to unwanted particles getting through that are wreaking havoc on our bodies and causing illness.

    Intestinal Barrier Dysfunction
    Created with BioRender.com

    The Intestinal Barrier & IBS

    Woven into the pathophysiological hairball that is IBS is the issue of intestinal barrier dysfunction. Much of the research surrounding intestinal barrier dysfunction in IBS has been focused on increased permeability via the paracellular route. Several of the proteins that make up the junction complexes have been shown to be altered in IBS patients, resulting in increased permeability9293.

    What’s causing all of this? Well, it turns out the list of factors that have been shown to affect intestinal permeability is almost as long as the list for IBS itself. They include:

    • Food94
    • Gastrointestinal infections95
    • Environmental factors such as smoke, pollution, and pesticides18
    • Medications, such as proton pump inhibitors (PPIs) and non-steroidal antiinflammatory drugs (NSAIDs)18
    • Stress and other psychological factors 12
    • Immune system activation858
    • Microbiota97
    • Genetics17

    Determining the prevalence of increased permeability in IBS is complicated due to the lack of test standardization and normal values90. However, a recent systematic review looking at the studies that have been done so far found that 37-62% of patients with IBS-D and 16-50% of patients with PI-IBS had increased permeability93. Most studies on IBS-C did not find that patients had increased permeability, as well as the one study on IBS-M93, so barrier dysfunction may not be as big of a factor in these IBS subtypes.

    Like every other potential cause of IBS, there is still a lot to be learned when it comes to intestinal permeability and overall barrier dysfunction, including how to test for it and treat it. Stay tuned!

    Key Takeaways

    Summary

    Stress - IBS
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    1. Elizabeth J. Videlock, Lin Chang. Chapter: Latest Insights on the Pathogenesis of Irritable Bowel Syndrome. Editors: William D. Chey, Alan L. Buchman. Irritable Bowel Syndrome, An Issue of Gastroenterology Clinics of North America. Volume 50, Number 3. Philadelphia, Pennsylvania: Elsevier inc. 2021, pg.516

       

    2. Christopher J. Black & Alexander C. Ford. Global burden of irritable bowel syndrome: trends, predictions and risk factors. Nature Reviews Gastroenterology & Hepatology volume 17, pages473–486 (2020)

    3. En X S Low,1 Maimouna N K Al Mandhari,2 Charles C Herndon,3 Evelyn X L Loo,4,5 Elizabeth H Tham,5,7 and Kewin T H Siah. Parental, Perinatal, and Childhood Risk Factors for Development of Irritable Bowel Syndrome: A Systematic Review. J Neurogastroenterol Motil. 2020 Sep 30; 26(4): 437–446

    4. Swapna Mahurkar-Joshi and Lin Chang*. Epigenetic Mechanisms in Irritable Bowel Syndrome. Front. Psychiatry, 14 August 2020
      Sec. Psychological Therapy and Psychosomatics

    5. Lovell, Rebecca M MBChB1; Ford, Alexander C MBChB, MD, MRCP1, 2. Effect of Gender on Prevalence of Irritable Bowel Syndrome in the Community: Systematic Review and Meta-Analysis. American Journal of Gastroenterology: July 2012 – Volume 107 – Issue 7 – p 991-1000 doi: 10.1038/ajg.2012.131

    6. Camilleri M. Sex as a biological variable in irritable bowel syndrome. Neurogastroenterol Motil. 2020 Jul;32(7):e13802. doi: 10.1111/nmo.13802. Epub 2020 Jan 13. PMID: 31943595; PMCID: PMC7319890.

    7. Dulantha Ulluwishewa 1, Rachel C Anderson, Warren C McNabb, Paul J Moughan, Jerry M Wells, Nicole C Roy. Regulation of tight junction permeability by intestinal bacteria and dietary components. J Nutr.2011 May;141(5):769-76. doi: 10.3945/jn.110.135657. Epub 2011 Mar 23

    8. J Matricon, M Meleine, A Gelot, T Piche, M Dapoigny, E Muller, D Ardid. Review article: Associations between immune activation, intestinal permeability and the irritable bowel syndrome. Aliment Pharmacol Ther. 2012 Dec;36(11-12):1009-31. doi: 10.1111/apt.12080. Epub 2012 Oct 15.

    9. Sweta Ghosh 1, Caleb Samuel Whitley 1, Bodduluri Haribabu 1, Venkatakrishna Rao Jala 2. Regulation of Intestinal Barrier Function by Microbial Metabolites. Cell Mol Gastroenterol Hepatol. 2021;11(5):1463-1482. doi: 10.1016/j.jcmgh.2021.02.007. Epub 2021 Feb 18.

    10. Masanori Kosako,corresponding author1 Hiraku Akiho,2 Hiroto Miwa,3 Motoyori Kanazawa,4 and Shin Fukudo4. Impact of symptoms by gender and age in Japanese subjects with irritable bowel syndrome with constipation (IBS-C): a large population-based internet survey. Biopsychosoc Med. 2018; 12: 12. Published online 2018 Sep 4. doi: 10.1186/s13030-018-0131-2

    11. Mathieu Meleine and Julien Matricon. Gender-related differences in irritable bowel syndrome: Potential mechanisms of sex hormones. World J Gastroenterol. 2014 Jun 14; 20(22): 6725–6743. Published online 2014 Jun 14. doi: 10.3748/wjg.v20.i22.6725

    12. Carmen Alonso, Mar Guilarte, Maria Vicario, Laura Ramos, Ziad Ramadan, Maria Antolín, Cristina Martínez, Serge Rezzi, Esteban Saperas, Sunil Kochhar, Javier Santos, Juan Ramón Malagelada. Maladaptive intestinal epithelial responses to life stress may predispose healthy women to gut mucosal inflammation. Gastroenterology. 2008 Jul;135(1):163-172.e1. doi: 10.1053/j.gastro.2008.03.036. Epub 2008 Mar 22.

    13. Agata Mulak1,2 and Yvette Taché1. Sex difference in irritable bowel syndrome: do gonadal hormones play a role? Gastroenterol Pol. Author manuscript; available in PMC 2014 Nov 26. Published in final edited form as: Gastroenterol Pol. 2010; 17(2): 89–97.

    14. Francis Creed. Review article: the incidence and risk factors for irritable bowel syndrome in population-based studies. 17 July 2019 https://doi.org/10.1111/apt.15396

    15. Rebecca M Lovell 1, Alexander C Ford. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol. 2012 Jul;10(7):712-721.e4. doi: 10.1016/j.cgh.2012.02.029. Epub 2012 Mar 15.

    16. Saito YA. The role of genetics in IBS. Gastroenterol Clin North Am. 2011 Mar;40(1):45-67. doi: 10.1016/j.gtc.2010.12.011. PMID: 21333900; PMCID: PMC3056499.

    17. Maria Gazouli 1, Mira M Wouters 2, Lejla Kapur-Pojskić 3, May-Bente Bengtson 4, Eitan Friedman 5, Gordana Nikčević 6, Christiana A Demetriou 7, Agata Mulak 8, Javier Santos 9, Beate Niesler 10. Lessons learned–resolving the enigma of genetic factors in IBS. Nat Rev Gastroenterol Hepatol. 2016 Feb;13(2):77-87. doi: 10.1038/nrgastro.2015.206. Epub 2016 Jan 4.

    18. Di Tommaso N, Gasbarrini A, Ponziani FR. Intestinal Barrier in Human Health and Disease. Int J Environ Res Public Health. 2021 Dec 6;18(23):12836. doi: 10.3390/ijerph182312836. PMID: 34886561; PMCID: PMC8657205.

    19. 3. Rome IV FGIDs: Disordered of Gut-Brain Interaction – Rome IV FGIDs – Chapter 1: Functional Gastrointestinal Disorders and the Rome IV Process – Biopsychosocial Overview of Functional GI Disorders

    20. Tiffany Ju, BA,1 Bruce D. Naliboff, PhD,1 Wendy Shih, DrPH,1,2 Angela P. Presson, PhD,3 Cathy Liu, BA,1 Arpana Gupta, PhD,1 Emeran A. Mayer, MD, PhD,1 and Lin Chang, MD1. Risk and Protective Factors Related to Early Adverse Life Events in Irritable Bowel Syndrome. J Clin Gastroenterol. 2020 Jan; 54(1): 63–69. doi: 10.1097/MCG.0000000000001153

    21. Paul Enck 1, Qasim Aziz 2, Giovanni Barbara 3, Adam D Farmer 2, Shin Fukudo 4, Emeran A Mayer 5, Beate Niesler 6, Eamonn M M Quigley 7, Mirjana Rajilić-Stojanović 8, Michael Schemann 9, Juliane Schwille-Kiuntke 1, Magnus Simren 10, Stephan Zipfel 1, Robin C Spiller 11. Irritable bowel syndrome. Nat Rev Dis Primers. 2016 Mar 24;2:16014. doi: 10.1038/nrdp.2016.14.

    22. Sabrina Berens a b 1, Philine Banzhaf a 1, David Baumeister a, Annika Gauss c, Wolfgang Eich a, Rainer Schaefert a d e 2, Jonas Tesarza 2. Relationship between adverse childhood experiences and illness anxiety in irritable bowel syndrome – The impact of gender. Journal of Psychosomatic Research. Volume 128, January 2020, 109846

    23. Sabrina Berens a b 1, Philine Banzhaf a 1, David Baumeister a, Annika Gauss c, Wolfgang Eich a, Rainer Schaefert a d e 2, Jonas Tesarza 2. Relationship between adverse childhood experiences and illness anxiety in irritable bowel syndrome – The impact of gender. Journal of Psychosomatic Research. Volume 128, January 2020, 109846

    24. S. H. Park,E. J. Videlock,W. Shih,A. P. Presson,E. A. Mayer,L. Chang. Adverse childhood experiences are associated with irritable bowel syndrome and gastrointestinal symptom severity. 08 April 2016 https://doi.org/10.1111/nmo.12826

    25. Giovanni Barbara,1 Madhusudan Grover,2 Premysl Bercik,3 Maura Corsetti,4 Uday C. Ghoshal,5 Lena Ohman,6 and Mirjana Rajilić-Stojanović7. ROME FOUNDATION WORKING TEAM REPORT ON POST-INFECTION IRRITABLE BOWEL SYNDROME Gastroenterology. 2019 Jan; 156(1): 46–58.e7. Published online 2018 Nov 28. doi: 10.1053/j.gastro.2018.07.011

    26. Prof Gerald J Holtmann, MD, Prof Alexander C Ford, MD , Prof Nicholas J Talley, MD. Pathophysiology of irritable bowel syndrome. VOLUME 1, ISSUE 2, P133-146, OCTOBER 01, 2016, DOI:https://doi.org/10.1016/S2468-1253(16)30023-1

    27. Fabiane Klem, Akhilesh Wadhwa, Larry J. Prokop, Michael Camilleri, Siddharth Singh, Madhusudan Grover. Prevalence, Risk Factors, and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: A Systematic Review and Meta-analysis. VOLUME 152, ISSUE 5, P1042-1054.E1, APRIL 01, 2017. DOI:https://doi.org/10.1053/j.gastro.2016.12.039

    28. Antonio Berumen, Ryan Lennon, Margaret Breen-Lyles, Jayne Griffith, Robin Patel||David Boxrud, Marijke Decuir, GianricoFarrugia, KirkSmith, MadhusudanGrover. Characteristics and Risk Factors of Post-Infection Irritable Bowel Syndrome After Campylobacter Enteritis. Clinical Gastroenterology and Hepatology Volume 19, Issue 9, September 2021, Pages 1855-1863.e1

    29. Swapna Mahurkar-Joshi and Lin Chang*. Epigenetic Mechanisms in Irritable Bowel Syndrome. Front Psychiatry. 2020; 11: 805.Published online 2020 Aug 14. doi: 10.3389/fpsyt.2020.00805

    30. Paul Enck,1 Qasim Aziz,2 Giovanni Barbara,3 Adam D. Farmer,2 Shin Fukudo,4 Emeran A. Mayer,5 Beate Niesler,6 Eamonn M. M. Quigley,7 Mirjana Rajilić-Stojanović,8 Michael Schemann,9 Juliane Schwille-Kiuntke,1 Magnus Simren,10 Stephan Zipfel,1 and Robin C. Spiller11. Irritable bowel syndrome. Nat Rev Dis Primers. 2016; 2: 16014. Published online 2016 Mar 24. doi: 10.1038/nrdp.2016.14

    31. William E.WhiteheadOlafurPalssonKenneth R.Jones. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: What are the causes and implications? Gastroenterology Volume 122, Issue 4, April 2002, Pages 1140-1156

    32. Andrea Riedl, Marco Schmidtmann, Andreas Stengel, Miriam Goebel, Anna-Sophi Wisser, Burghard F. Klapp, Hubert Mönnikes. Somatic comorbidities of irritable bowel syndrome: A systematic analysis. Journal of Psychosomatic Research Volume 64, Issue 6, June 2008, Pages 573-582

    33. Qin Xiang Ng, Alex Yu Sen Soh, Wayren Loke, Nandini Venkatanarayanan, Donovan Yutong Lim, Wee-Song Yeo. Systematic review with meta-analysis: The association between post-traumatic stress disorder and irritable bowel syndrome. 25 August 2018 https://doi.org/10.1111/jgh.14446

    34. Guillaume Fond 1, Anderson Loundou, Nora Hamdani, Wahid Boukouaci, Aroldo Dargel, José Oliveira, Matthieu Roger, Ryad Tamouza, Marion Leboyer, Laurent Boyer. Anxiety and depression comorbidities in irritable bowel syndrome (IBS): a systematic review and meta-analysis. Eur Arch Psychiatry Clin Neurosci. 2014 Dec;264(8):651-60. doi: 10.1007/s00406-014-0502-z. Epub 2014 Apr 6.

    35. Hyun Sun Cho 1, Jae Myung Park, Chul Hyun Lim, Yu Kyung Cho, In Seok Lee, Sang Woo Kim, Myung-Gyu Choi, In-Sik Chung, Yun Kyung Chung. Anxiety, depression and quality of life in patients with irritable bowel syndrome. Gut Liver. 2011 Mar;5(1):29-36. doi: 10.5009/gnl.2011.5.1.29. Epub 2011 Mar 16.

    36. B B Toner 1, P E Garfinkel, K N Jeejeebhoy. Psychological factors in irritable bowel syndrome. Can J Psychiatry. 1990 Mar;35(2):158-61. doi: 10.1177/070674379003500210.

    37. Constanze Hausteiner-Wiehle and Peter Henningsen. Irritable bowel syndrome: Relations with functional, mental, and somatoform disorders. World J Gastroenterol. 2014 May 28; 20(20): 6024–6030. Published online 2014 May 28. doi: 10.3748/wjg.v20.i20.6024

    38. Zhichao Hu 1, Meixuan Li 2, Liang Yao 3, Yinshu Wang 4, Enkang Wang 4, Jianye Yuan 4, Fengyun Wang 5, Kehu Yang 2, Zhaoxiang Bian 6, Linda L D Zhong 7. The level and prevalence of depression and anxiety among patients with different subtypes of irritable bowel syndrome: a network meta-analysis. BMC Gastroenterol. 2021 Jan 7;21(1):23. doi: 10.1186/s12876-020-01593-5.

    39. Yuman Kawoos1, Zaid A Wani1, Showkat A Kadla2, Irfan A Shah3, Arshad Hussain1, M Maqbool Dar1, Mushtaq A Margoob1, and Kouser Sideeq4. Psychiatric Co-morbidity in Patients With Irritable Bowel Syndrome at a Tertiary Care Center in Northern India. Journal of Neurogastroenterology and Motility 2017; 23(4): 555-560 https://doi.org/10.5056/jnm16166

    40. Michael P Jones 1, Jan Tack 2, Lukas Van Oudenhove 3, Marjorie M Walker 4, Gerald Holtmann 5, Natasha A Koloski 6, Nicholas J Talley 4. Mood and Anxiety Disorders Precede Development of Functional Gastrointestinal Disorders in Patients but Not in the Population. Clin Gastroenterol Hepatol. 2017 Jul;15(7):1014-1020.e4. doi: 10.1016/j.cgh.2016.12.032. Epub 2017 Jan 10.

    41. Rome IV FGIDs: Disorders of Gut-Brain Interaction | ROME IV FGIDs | Chapter 19: History of FGI Symptoms and Disorders and Chronicle of the Rome Foundation

    42. Waxenbaum, Reddy, Varacallo. Anatomy, Autonomic Nervous System. StatPearls Publishing, Treasure Island (FL), 11 Apr 2019

    43. Emeran A. Mayer. Gut feelings: the emerging biology of gut–brain communication. Nat Rev Neurosci. Author manuscript; available in PMC 2013 Dec 2.

    44. Marilia Carabotti,a Annunziata Scirocco,a Maria Antonietta Maselli,b and Carola Severia. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol. 2015 Apr-Jun; 28(2): 203–209.

    45. Kirsten Tillisch, Data analysis and interpretation, manuscript draft and revision, Emeran A. Mayer, Data interpretation, revision of the manuscript, and Jennifer S. Labus, Study design, data analysis and interpretation, manuscript draft and revision. Quantitative Meta-Analysis Identifies Brain Regions Activated during Rectal Distension in Irritable Bowel Syndrome. Gastroenterology. 2011 Jan; 140(1): 91–100. Published online 2010 Aug 7. doi: 10.1053/j.gastro.2010.07.053

    46. https://0-gut-bmj-com.catalog.llu.edu/content/68/9/1701

    47. Emeran A Mayer 1, Jennifer S Labus 1, Kirsten Tillisch 2, Steven W Cole 1, Pierre Baldi 3. Towards a systems view of IBS. Nat Rev Gastroenterol Hepatol. 2015 Oct;12(10):592-605. doi: 10.1038/nrgastro.2015.121. Epub 2015 Aug 25.

    48. Rome IV FGIDs: Disorders of Gut-Brain Interaction | ROME IV FGIDs | Chapter 2: Fundamentals of Neurogastroenterology: Basic Science

    49. Elizabeth J Videlock 1, Lin Chang 2. Latest Insights on the Pathogenesis of Irritable Bowel Syndrome. Gastroenterol Clin North Am. 2021 Sep;50(3):505-522. doi: 10.1016/j.gtc.2021.04.002.

    50. Maria Rosaria A Muscatello, Antonio Bruno, Giuseppe Scimeca, Gianluca Pandolfo, and Rocco A Zoccali. Role of negative affects in pathophysiology and clinical expression of irritable bowel syndrome. World J Gastroenterol. 2014 Jun 28; 20(24): 7570–7586. Published online 2014 Jun 28. doi: 10.3748/wjg.v20.i24.7570

    51. Kirsteen N. Browning1 and R. Alberto Travagli1. Central Nervous System Control of Gastrointestinal Motility and Secretion and Modulation of Gastrointestinal Functions. Compr Physiol. 2014 Oct; 4(4): 1339–1368. doi: 10.1002/cphy.c130055

    52. Emanuele Rinninella,1,2,* Marco Cintoni,3 Pauline Raoul,2 Loris Riccardo Lopetuso,2,4 Franco Scaldaferri,2,4 Gabriele Pulcini,3 Giacinto Abele Donato Miggiano,1,2 Antonio Gasbarrini,2,4 and Maria Cristina Mele1,2. Food Components and Dietary Habits: Keys for a Healthy Gut Microbiota Composition. Nutrients. 2019 Oct; 11(10): 2393. Published online 2019 Oct 7. doi: 10.3390/nu11102393

    53. Mónica Gros, Belén Gros, José Emilio Mesonero, Eva Latorre. Neurotransmitter Dysfunction in Irritable Bowel Syndrome: Emerging Approaches for Management. J. Clin. Med. 2021, 10(15), 3429; https://doi.org/10.3390/jcm10153429

    54. John F. Cryan, Kenneth J. O’Riordan, Caitlin S. M. Cowan, Kiran V. Sandhu, Thomaz F. S. Bastiaanssen, Marcus Boehme, Martin G. Codagnone, Sofia Cussotto, Christine Fulling, Anna V. Golubeva, Katherine E. Guzzetta, Minal Jaggar, Caitriona M. Long-Smith, Joshua M. Lyte, Jason A. Martin, Alicia Molinero-Perez, Gerard Moloney, Emanuela Morelli, Enrique Morillas, Rory O’Connor, Joana S. Cruz-Pereira, Veronica L. Peterson, Kieran Rea, Nathaniel L. Ritz, Eoin Sherwin, Simon Spichak, Emily M. Teichman, Marcel van de Wouw, Ana Paula Ventura-Silva, Shauna E. Wallace-Fitzsimons, Niall Hyland, Gerard Clarke, and Timothy G. Dinan. The Microbiota-Gut-Brain Axis. 28 AUG 2019 https://doi.org/10.1152/physrev.00018.2018

    55. Robert L Spencera and Terrence Deakb. A USERS GUIDE TO HPA AXIS RESEARCH. Physiol Behav. 2017 Sep 1; 178: 43–65. Published online 2016 Nov 18. doi: 10.1016/j.physbeh.2016.11.014

    56. Philip C Keightley, Natasha A Koloski and Nicholas J Talley. Pathways in gut-brain communication: Evidence for distinct gut-to-brain and brain-to-gut syndromes. Australian & New Zealand Journal of Psychiatry 2015, Vol. 49(3) 207–214 DOI: 10.1177/0004867415569801

    57. Hong-Yan Qin, Chung-Wah Cheng, Xu-Dong Tang, and Zhao-Xiang Bian. Impact of psychological stress on irritable bowel syndrome. World J Gastroenterol. 2014 Oct 21; 20(39): 14126-14131. Published online 2014 Oct 21. doi: 10.3748/wjg.v20.i39.14126

    58. Takuya Suzuki. Regulation of intestinal epithelial permeability by tight junctions. Cell Mol Life Sci. 2013 Feb;70(4):631-59. doi: 10.1007/s00018-012-1070-x. Epub 2012 Jul 11.

    59. Rome IV FGIDs: Disorders of Gut-Brain Interaction | ROME IV FGIDs | Chapter 1: Functional Gastrointestinal Disorders and the Rome IV Process

    60. Elizabeth J. Videlock, Lin Chang. Latest Insights on the Pathogenesis of Irritable Bowel Syndrome. Editors: William D. Chey, Alan L. Buchman. Irritable Bowel Syndrome, An Issue of Gastroenterology Clinics of North America. Volume 50, Number 3. Philadelphia, Pennsylvania: Elsevier inc. 2021 pg.514

    61. Susan Mills,1 Catherine Stanton,2 Jonathan A. Lane,3 Graeme J. Smith,3,* and R. Paul Ross1. Precision Nutrition and the Microbiome, Part I: Current State of the Science. Nutrients. 2019 Apr; 11(4): 923. Published online 2019 Apr 24. doi: 10.3390/nu11040923

    62. M Sun, C He, Y Cong, Z Liu. Regulatory immune cells in regulation of intestinal inflammatory response to microbiota. Mucosal Immunol. 2015 Sep; 8(5): 969–978. Published online 2015 Jun 17. doi: 10.1038/mi.2015.49

    63. Martin Beukema, Marijke M. Faas & Paul de Vos. The effects of different dietary fiber pectin structures on the gastrointestinal immune barrier: impact via gut microbiota and direct effects on immune cells. Experimental & Molecular Medicine volume 52, pages1364–1376 (2020)

    64. M Bashashati 1, S Moossavi 2 3, C Cremon 4, M R Barbaro 4, S Moraveji 1, G Talmon 5 6, N Rezaei 7, P A Hughes 8, Z X Bian 9, C H Choi 10, O Y Lee 11, M Coëffier 12, L Chang 13, L Ohman 14, M J Schmulson 15, R W McCallum 1, M Simren 16 17, K A Sharkey 18, G Barbara 4. Colonic immune cells in irritable bowel syndrome: A systematic review and meta-analysis. Neurogastroenterol Motil. 2018 Jan;30(1). doi: 10.1111/nmo.13192. Epub 2017 Aug 29.

    65. Cristina Stasi 1, Massimo Rosselli, Massimo Bellini, Giacomo Laffi, Stefano Milani. Altered neuro-endocrine-immune pathways in the irritable bowel syndrome: the top-down and the bottom-up model. J Gastroenterol. 2012 Nov;47(11):1177-85. doi: 10.1007/s00535-012-0627-7. Epub 2012 Jul 6.

    66. José Antonio Uranga, Vicente Martínez, Raquel Abalo. Mast Cell Regulation and Irritable Bowel Syndrome: Effects of Food Components with Potential Nutraceutical Use. Molecules. 2020 Sep; 25(18): 4314. Published online 2020 Sep 20. doi: 10.3390/molecules25184314

    67. Kang Nyeong Lee, Oh Young Lee. The Role of Mast Cells in Irritable Bowel Syndrome. Gastroenterol Res Pract. 2016; 2016: 2031480. Published online 2016 Dec 28. doi: 10.1155/2016/2031480

    68. Giovanni Barbara, Vincenzo Stanghellini, Roberto De Giorgio, Cesare Cremon, Graeme S Cottrell, Donatella Santini, Gianandrea Pasquinelli, Antonio M Morselli-Labate, Eileen F Grady, Nigel W Bunnett, Stephen M Collins, Roberto Corinaldesi. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004 Mar;126(3):693-702. doi: 10.1053/j.gastro.2003.11.055.

    69. Shiwei Zhu, Ben Wang, Qiong Jia, and Liping Duancorresponding. Candidate single nucleotide polymorphisms of irritable bowel syndrome: a systemic review and meta-analysis. BMC Gastroenterol. 2019; 19: 165. Published online 2019 Oct 15. doi: 10.1186/s12876-019-1084-z

    70. Elham Barkhordari, Nima Rezaei, Bita Ansaripour, Pegah Larki, Maryam Alighardashi, Hamid Reza Ahmadi-Ashtiani, Mahdi Mahmoudi, Mohammad-Reza Keramati, Peiman Habibollahi, Mohammad Bashashati, Naser Ebrahimi-Daryani, Ali Akbar Amirzargar. Proinflammatory cytokine gene polymorphisms in irritable bowel syndrome. J Clin Immunol. 2010 Jan;30(1):74-9. doi: 10.1007/s10875-009-9342-4. Epub 2009 Oct 21.

    71. K-A Gwee, S M Collins, N W Read, A Rajnakova, Y Deng, J C Graham, M W McKendrick, S M Moochhala. Increased rectal mucosal expression of interleukin 1β in recently acquired post-infectious irritable bowel syndrome. Gut. 2003 Apr; 52(4): 523–526. doi: 10.1136/gut.52.4.523

    72. Yeong Yeh Lee, Chandramouli Annamalai, Satish S C Rao. Post-Infectious Irritable Bowel Syndrome. Curr Gastroenterol Rep. 2017 Sep 25;19(11):56. doi: 10.1007/s11894-017-0595-4.

    73. D. Balemans, S. U. Mondelaers, V. Cibert-Goton, N. Stakenborg, J. Aguilera-Lizarraga, J. Dooley, A. Liston, D. C. Bulmer, P. Vanden Berghe, G. E. Boeckxstaens, M. M. Wouters. Evidence for long-term sensitization of the bowel in patients with post-infectious-IBS. Sci Rep. 2017; 7: 13606. Published online 2017 Oct 19. doi: 10.1038/s41598-017-12618-7

    74. Fassarella, Marina, Blaak, Ellen E., Penders, John, Nauta, Arjen, Smidt, Hauke et al. Gut microbiome stability and resilience : Elucidating the response to perturbationsin order to modulate gut health. https://doi.org/10.1136/gutjnl-2020-321747

    75. Michael I McBurney, Cindy Davis, Claire M Fraser, Barbara O Schneeman, Curtis Huttenhower, Kristin Verbeke, Jens Walter, Marie E Latulippe. Establishing What Constitutes a Healthy Human Gut Microbiome: State of the Science, Regulatory Considerations, and Future Directions. The Journal of Nutrition, Volume 149, Issue 11, November 2019, Pages 1882–1895, https://doi.org/10.1093/jn/nxz154

    76. Pamela Vernocchi, Federica Del Chierico, Lorenza Putignani. Gut Microbiota Profiling: Metabolomics Based Approach to Unravel Compounds Affecting Human Health. Front. Microbiol., 26 July 2016 Sec. Systems Microbiology https://doi.org/10.3389/fmicb.2016.01144

    77. Sabrina Duranti, Lorena Ruiz, Gabriele Andrea Lugli, Héctor Tames, Christian Milani, Leonardo Mancabelli, Walter Mancino, Giulia Longhi, Luca Carnevali, Andrea Sgoifo, Abelardo Margolles, Marco Ventura, Patricia Ruas-Madiedo, Francesca Turroni. Bifidobacterium adolescentis as a key member of the human gut microbiota in the production of GABA. Scientific Reports volume 10, Article number: 14112 (2020)

    78. Claire Immediato Daïen, Gabriela Veronica Pinget, Jian Kai Tan, Laurence Macia. Detrimental Impact of Microbiota-Accessible Carbohydrate-Deprived Diet on Gut and Immune Homeostasis: An Overview. Front Immunol. 2017; 8: 548. Published online 2017 May 12. doi: 10.3389/fimmu.2017.00548

    79. Mirjana Rajilić-Stojanović. Function of the microbiota. Best Pract Res Clin Gastroenterol. 2013 Feb;27(1):5-16. doi: 10.1016/j.bpg.2013.03.006.

    80. Fergus Shanahan. The colonic microbiota in health and disease. Curr Opin Gastroenterol. 2013 Jan;29(1):49-54. doi: 10.1097/MOG.0b013e32835a3493.

    81. Stephen M Collins. A role for the gut microbiota in IBS. Nat Rev Gastroenterol Hepatol. 2014 Aug;11(8):497-505. doi: 10.1038/nrgastro.2014.40. Epub 2014 Apr 22.

    82. Mark Pimentel, Anthony Lembo. Microbiome and Its Role in Irritable Bowel Syndrome. Dig Dis Sci. 2020 Mar;65(3):829-839. doi: 10.1007/s10620-020-06109-5.

    83. Emeran A. Mayer, Tor Savidge, Robert J. Shulman. Brain Gut Microbiome Interactions and Functional Bowel Disorders. Gastroenterology. 2014 May; 146(6): 1500–1512. Published online 2014 Feb 28. doi: 10.1053/j.gastro.2014.02.037

    84. Yoo Jin Lee, Kyung Sik Park. Irritable bowel syndrome: Emerging paradigm in pathophysiology. World J Gastroenterol. 2014 Mar 14; 20(10): 2456–2469. Published online 2014 Mar 14. doi: 10.3748/wjg.v20.i10.2456

    85. Fabiane Klem, Akhilesh Wadhwa, Larry J Prokop, Wendy J Sundt, Gianrico Farrugia, Michael Camilleri, Siddharth Singh, Madhusudan Grover. Prevalence, Risk Factors, and Outcomes of Irritable Bowel Syndrome After Infectious Enteritis: A Systematic Review and Meta-analysis. Gastroenterology. 2017 Apr;152(5):1042-1054.e1. doi: 10.1053/j.gastro.2016.12.039. Epub 2017 Jan 6.

    86. Stacy B Menees, Monthira Maneerattannaporn, Hyungjin Myra Kim, William D Chey. The efficacy and safety of rifaximin for the irritable bowel syndrome: a systematic review and meta-analysis. Am J Gastroenterol. 2012 Jan;107(1):28-35; quiz 36. doi: 10.1038/ajg.2011.355. Epub 2011 Nov 1.

    87. Mark Pimentel, Anthony Lembo, William D Chey, Salam Zakko, Yehuda Ringel, Jing Yu, Shadreck M Mareya, Audrey L Shaw, Enoch Bortey, William P Forbes, TARGET Study Group. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med. 2011 Jan 6;364(1):22-32. doi: 10.1056/NEJMoa1004409.

    88. Giada De Palma 1, Michael D J Lynch 2, Jun Lu 1, Vi T Dang 3, Yikang Deng 1, Jennifer Jury 1, Genevieve Umeh 1, Pedro M Miranda 1, Marc Pigrau Pastor 1, Sacha Sidani 1, Maria Ines Pinto-Sanchez 1, Vivek Philip 1, Peter G McLean 4, Moreno-Gabriel Hagelsieb 5, Michael G Surette 1, Gabriela E Bergonzelli 4, Elena F Verdu 1, Philip Britz-McKibbin 3, Josh D Neufeld 2, Stephen M Collins 1, Premysl Bercik 6. Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice. Sci Transl Med. 2017 Mar 1;9(379):eaaf6397. doi: 10.1126/scitranslmed.aaf6397.

    89. L Crouzet, E Gaultier, C Del’Homme, C Cartier, E Delmas, M Dapoigny, J Fioramonti, A Bernalier-Donadille. The hypersensitivity to colonic distension of IBS patients can be transferred to rats through their fecal microbiota. Neurogastroenterol Motil. 2013 Apr;25(4):e272-82. doi: 10.1111/nmo.12103. Epub 2013 Feb 25.

    90. Michael Camilleri. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019 Aug;68(8):1516-1526. doi: 10.1136/gutjnl-2019-318427. Epub 2019 May 10.

    91. S Ménard, N Cerf-Bensussan, M Heyman. Multiple facets of intestinal permeability and epithelial handling of dietary antigens. Mucosal Immunol. 2010 May;3(3):247-59. doi: 10.1038/mi.2010.5. Epub 2010 Mar 10.

    92. Nathalie Bertiaux-Vandaële, Stéphanie Beutheu Youmba, Liliana Belmonte, Stéphane Lecleire, Michel Antonietti, Guillaume Gourcerol, Anne-Marie Leroi, Pierre Déchelotte, Jean-François Ménard, Philippe Ducrotté, Moïse Coëffier. The expression and the cellular distribution of the tight junction proteins are altered in irritable bowel syndrome patients with differences according to the disease subtype. Am J Gastroenterol. 2011 Dec;106(12):2165-73. doi: 10.1038/ajg.2011.257. Epub 2011 Oct 18.

    93. Nikita Hanning, Adam L. Edwinson, Hannah Ceuleers, Stephanie A. Peters, Joris G. De Man, Leslie C. Hassett, Benedicte Y. De Winter, Madhusudan Grover. Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review. Therap Adv Gastroenterol. 2021; 14: 1756284821993586. Published online 2021 Feb 24. doi: 10.1177/1756284821993586

    94. Katayoun Khoshbin, Michael Camilleri. Effects of dietary components on intestinal permeability in health and disease. Am J Physiol Gastrointest Liver Physiol. 2020 Nov 1;319(5):G589-G608. doi: 10.1152/ajpgi.00245.2020. Epub 2020 Sep 9.

    95. J K Marshall, M Thabane, A X Garg, W Clark, J Meddings, S M Collins, WEL Investigators. Intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario. Aliment Pharmacol Ther. 2004 Dec;20(11-12):1317-22. doi: 10.1111/j.1365-2036.2004.02284.x.

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