Digesting the Problem: The Gut-Brain Axis’ Connection to Irritable Bowel Syndrome

Introduction

Approximately 10% of the world’s population is affected by irritable bowel syndrome (IBS), a common gastrointestinal disorder that is notable for abdominal pain and bloating [1-3]. Due to the variation of microbiota amongst individuals and the resulting symptom differences, there is no singular treatment that is superior to the other [3]. Four different subtypes have been identified to describe other symptoms associated with IBS: constipation-predominant (IBS-C), diarrhea-predominant (IBS-D), mixed diarrhea and constipation (IBS-M), and unclassified bowel behavior (INS-U) [3, 4]. The diversity of symptoms likely results from individuals’ unique microbiota and response to psychological stress [1-8]. IBS subtypes vary by the composition of the gut microbiota, which consists of approximately 100 trillion microorganisms of over 1000 different bacterial species [3, 7]. Disruption of the microbiota (dysbiosis) and subsequent dysfunction of signaling pathways between the gut and the brain (gut-brain axis) leads to chemical imbalances associated with IBS symptoms [1]. Current research on IBS is derived from animal models, which may limit our understanding of human metabolites that influence metabolism and inflammation due to a difference in species and physiology from humans [3, 5]. This literature review investigates the factors that lead to IBS and its diverse treatment options. However, due to the different subtypes, further research is necessary to isolate the most effective treatment for improving the state of IBS patients’ gut and brain.

Hormones

IBS can be attributed to a wide variety of causes due to complex interactions between the immune, hormonal, and nervous systems [2]. These interactions are partially influenced by genetics, as shown from family history and twin studies [4]. Additionally, it differs by sex—women are 1.67 more susceptible to IBS than men, suggesting a hormonal relationship [1, 3]. Hormones and neurotransmitters regulate intestinal cellular activity by communicating with the gut microbiota [1]. These signaling factors induce gene expression within the gut microbiome to regulate digestion, production of mucins (proteins that act as a physical barrier to protect cells), and anti-inflammatory responses [1, 4]. Due to dysbiosis and the subsequent reduction of certain hormones, excessive inflammation may occur, leading to bowel discomfort [4]. Inflammation in the gut is also linked to the brain which may lead to neurodegenerative diseases, justifying that the gut-brain axis is bidirectional [5]. Additionally, though IBS patients have an overall lower gut diversity, fluctuations in microbiome diversity cause some bacteria species to increase or decrease, depending on the associated IBS subtype [4]. For example, when compared to healthy individuals, patients with IBS-C have an increased abundance of Methanobacterialles in their gut while patients with IBS-D have a decreased abundance of this microorganism [4]. Identifying different patterns of microbial species abundance may help distinguish IBS subtypes from one another for better diagnosis and treatment. 

A hormone that is highly involved in gut microbiota activity is cortisol. Cortisol is secreted from the adrenal glands when the hypothalamus, a control center in the brain that regulates bodily functions, is stimulated by elevated levels of stress and other hormones [2, 6]. Since IBS patients tend to be more stressed, they also have high cortisol levels [5, 6]. Cortisol has many metabolic effects, including the regulation of the enteric nervous system by moderating absorption and mucus secretion in the gastrointestinal tract [6]. However, consequent disruption of the microbial mucus layer through elevated cortisol levels can affect microbial abundance, leading to a divergence of IBS subtypes [1, 3]. 

Cortisol secretion is also elevated from ghrelin, a hormone secreted from gastrointestinal cells that controls intestinal motility [6]. Ghrelin causes gut microbial metabolites to travel through the gut-brain axis to the hypothalamus which stimulates appetite-inducing hormone secretion [9]. Therefore, ghrelin cell density is elevated in IBS-D while it is reduced in IBS-C patients, impacting metabolite production and subsequent food consumption behaviors: studies hypothesize that IBS-D patients would experience an increased appetite while IBS-C patients would face a decreased appetite [9]. Ghrelin’s role in hormone release makes it a critical factor for distinguishing IBS subtypes, especially due to its role in increasing cortisol secretion [9]. Although most IBS patients have high cortisol levels, differing ghrelin cell densities correlated to IBS subtypes imply that other factors may also elevate cortisol secretion. In particular, more research needs to be conducted to determine cortisol’s effect on IBS-C patients, and whether eating would worsen IBS-C symptoms due to lower ghrelin levels. 

Restoring the Microbiota’s Diversity

As mentioned previously, fluctuating hormone levels from stress detected in the brain directly impact the gut microbiota, and dysbiosis in the gut leads to neurodegenerative diseases [5]. To explore this connection, various mouse models were conducted to investigate the gut-brain axis’ role in IBS symptoms. Mice grown in germ-free environments or treated with antibiotics have immature enteric and central nervous systems, which results in exaggerated stress responses, memory dysfunction, and anxiety [5, 6]. These psychological symptoms observed in germ-free mice mimic the symptoms observed in human IBS patients, who often suffer from poor sleep, headaches, chronic fatigue, anxiety, and depression [1]. Clinical studies estimate that these impacts on emotional health result in 30% lower productivity, or 13.8 hours lost per 40-hour work week [1]. Additionally, 40-60% of IBS patients have at least one psychiatric disorder, such as Alzheimer’s, Huntington’s, and Parkinson’s disease [2, 5]. These results support the concept of the gut-brain axis; an unhealthy gut and an unhealthy brain go hand in hand. 

Furthermore, mice studies revealed that gut bacterial communities regulated up to 70% of intestinal chemicals [7]. While the relationship between metabolites and IBS symptoms isn’t fully understood, it was found that disrupting gut microbial communities through dysbiosis reduces metabolite production that signals for hormones to regulate bodily processes [3]. Reduced signaling decreases the amount of energy available for intestinal epithelial cells, which impairs their ability to maintain the cellular barrier [3]. As a result, the epithelium is more susceptible to bacterial antigens, provoking inflammatory immune responses [6]. IBS symptoms including abdominal pain and bloating may arise from the disrupted signaling pathways [1, 5]. 

Conversely, increasing microbial diversity would reduce IBS symptoms. A study found that mice fed a diet containing 50% lean ground beef, which is abundant in microbes, exhibited a higher gut diversity than mice fed with standard rodent chow [6]. These mice also experienced an increase in physical activity and memory, as well as a decrease in anxiety [6]. Mice’s enhanced performance was attributed to increased bacterial metabolism, which was quantified by the production of short-chain fatty acids, such as butyric, propionic, and acetic acids, that also stimulate the nervous system [6]. 

Alternatively, microbe abundance can be increased through fecal microbial transplant therapy [1, 2, 4, 5, 7]. However, this is currently not a widespread treatment option due to a lack of knowledge on the benefits and harms to patients.  Although more research is needed to visualize the connection in humans, mice studies have provided insight into the link between the gut and the brain. Current knowledge on IBS, which is limited by the differences between mice and humans, creates the foundation for treatments that promote stress reduction, a healthy diet, and probiotics for a healthy gut [1, 2, 4, 7, 8].

Diet

Numerous IBS studies have found that certain fats and carbohydrates aggravate IBS symptoms; those who consume a Western diet composed of high amounts of processed food and carbohydrates are more susceptible to dysbiosis [1, 8, 9]. Studies have also found that spicy foods aggravate gastrointestinal movement, while coffee and alcohol damage the gut mucosa and soft tissue that lines the digestive system [4]. While these foods may generally lead to gut inflammation, an individual’s unique microbiota may vary in their reaction to different foods [3]. 

To reduce symptoms, IBS diets promote the consumption of water-soluble fibers. Studies on fiber consumption show that soluble fibers significantly decreased IBS symptoms while insoluble fibers either had no effect or worsened the symptoms because they cannot be fully broken down by the digestive system [8, 9]. Although there is no evidence that it alleviates abdominal pain, overall IBS symptoms decreased due to soluble fiber consumption [8]. It was found that soluble fibers are extremely effective for treating constipation, making them especially recommended for IBS-C patients [8]. Soluble fibers likely benefit IBS patients by making foods easier to digest, considering their inflamed bowels [9]. 

In addition, foods that are part of the fermentable oligo-, di-, monosaccharide and polyols (FODMAP) group, such as milk, wheat, cabbage, beans, onions, and peas, should be avoided because they are difficult for the body to digest [4, 9]. FODMAPs and insoluble fiber enter the distal small intestine and colon [9]. Because they are only partially digested, they osmotically cause the large intestines to have increased water content which allows fermentable bacteria to proliferate [9]. Consequent gas production leads to abdominal pain, a common symptom in IBS patients [9]. As a result, the low FODMAP diet was developed to reduce the intake of polyols that the human intestine has difficulty absorbing. These include fructans, galactans, lactose, fructose, sorbitol, xylitol, and mannitol [8]. 

Although the low FODMAP diet is not the perfect solution to IBS, it can provide short-term benefits by reducing abdominal pain and gastrointestinal motility [9]. However, due to individuals’ differences in microbiota, only 50-70% of IBS patients who change their diet experience a reduction of symptoms such as bloating, abdominal pain, and diarrhea [1, 4]. Additionally, low FODMAP diets are relatively imbalanced and negatively impact the gut microbiota long-term because they lead to vitamin, mineral, and antioxidant deficiencies [4]. If this diet is practiced long-term, patients could experience malnutrition and inappropriate weight loss [1]. Therefore, IBS patients should not solely rely on the low FODMAP diet to alleviate their symptoms.

Anti-inflammatory probiotics (supplements containing live microorganisms to balance a healthy gut) including Lactobacilli, Bifidobacteria, and Saccharomyces boulardii have been found to reduce abdominal pain and bloating [8]. Although Lactobacilli products are a commercially available source of probiotics, most clinical trials cannot establish any significant benefit to IBS patients due to conflicting results [8]. Currently, only the probiotic strain Bifido bacterium infantis 35624 has shown significant benefits for improving IBS symptoms across all subtypes [8]. Even though no other probiotic species show a significant impact on abdominal issues, all of the probiotics tested were beneficial for reducing inflammation [8]. 

It is recommended to consume probiotics and perform regular exercises in combination with the low FODMAP diet to improve IBS patients’ quality of life [9]. Probiotics are useful for increasing the tolerance of consuming FODMAP-rich foods, while regular exercise improves the benefits of the low FODMAP diet [9]. Although diet is useful for reducing the severity of IBS symptoms, it should be moderated carefully to prevent unforeseen health declines. 

Conclusion

The impacts of disrupted gut microbiota on cognitive function are evident in both mouse models and human IBS patients, but the multifactorial nature of IBS makes it difficult to diagnose and treat [3-6]. There’s currently no explanation for why IBS has so many subtypes, but investigating hormone-induced gene expression associated with producing pro-inflammatory metabolites may provide some insight. Future studies are necessary to understand the pathways leading to human metabolite production, as well as how metabolites relate to IBS. 

Treatments that improve the state of the gut have shown to alleviate IBS symptoms. At the moment, diet changes appear to be the most effective way of altering the gut microbiome. However, the most popular diet, low FODMAP, is not sustainable long-term because it leads to nutrient deficiency. Within the sectors of diet and psychological treatment, targeted therapy may promote a good balance of pro- and anti-inflammatory metabolites to restore the microbiome and prevent neurodegenerative diseases. Introducing beneficial bacteria species through probiotics to address dysbiosis can also reduce inflammation. Although varying symptoms may make IBS difficult to address, opportunities for addressing IBS symptoms are plentiful due to the wide range of targets for treatment.

About the Author: Abigail Lin

Abigail is a class of 2024 Biological Sciences major and a Communications minor. She was a senior editor at the Aggie Transcript, a BioLaunch mentor, and an undergraduate researcher at the Harmer Lab studying genes related to plants’ circadian clock. She plans on pursuing a career related to environmental science after graduating. Besides being a member of the Aggie Transcript, Abigail enjoys taking pictures of birds, crocheting, and playing with her esports team.

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