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Gut Feelings: The Surprising Links Between Gut and Your Body’s Vital Organs

the gut organ axis

This article is part two of a four-part series on the microbiome and longevity. In our previous article, we outlined the essential functions of the human gut microbiome (for those who missed it, it can be accessed here). In addition, we alluded to the fact that the gut microbiome has a direct association with several organs, which has been termed the “gut-organ axis.” This phenomenon describes the far-reaching impacts of the gut microbiome on various body systems, including those linked to psoriasis, autism, depression, and obesity. 

Currently, scientific literature has documented nine distinct gut-organ axes. Still, this field of research is constantly evolving as scientists gain a better understanding of the intricate and multifaceted relationships between the gut microbiome and different organs. Herein lies a condensed overview of the most firmly established gut-organ axes, along with the scientific rationale underlying them, encompassing the most cited pathophysiological mechanisms and associations with disease.

In this article, we explore the nine gut-organ axes listed below.

  1. The Gut-Skin Axis
  2. The Gut-Bone Axis
  3. The Gut-Adipose Axis
  4. The Gut-Liver Axis
  5. The Gut-Kidney Axis
  6. The Gut-Heart Axis
  7. The Gut-Muscle Axis
  8. The Gut-Lung Axis
  9. The Gut-Brain Axis

This article is part two of a four-part series on the microbiome and longevity.

  1. From the Gut Up: The Latest Breakthroughs in Microbiome Research
  2. Gut Feelings: The Surprising Links Between Gut and Your Body’s Vital Organs
  3. The Clockwork of Microbiome-Based Aging: Tracing the Lifelong Impact of the Gut Microbiome
  4. Bacterial Botox: Microbiome-Based Interventions for Timeless Health

1. The Gut-Skin Axis: The Link Between Gut Health and Psoriasis, Acne and Skin Aging

The Gut-Skin Axis and its Impact on Skin Health

The skin is the largest organ in direct contact with the external environment, colonized by trillions of bacteria and innervated and vascularized like the gut (O’Neill et al. 2016). The gut microbiome mainly affects skin health by modifying the immune system through the production of short chain fatty acids (SCFAs) (Salem et al. 2018), which slow down the immune response by inhibiting adhesion, migration, proliferation, and cytokine production (Samuelson, Welsh, and Shellito 2015). SCFAs also inhibit (HDACs) which in turn stimulate the proliferation of the regulatory cells in the skin that control various physiological functions, including wound healing and hair follicle stem cell differentiation. 

Impact of Gut Microbiome on Skin-Related Ailments

The gut-skin axis’s revelation has inspired researchers to investigate the impact of the gut microbiome on various skin-related ailments, including atopic dermatitis (AD), psoriasis, acne, and even skin aging. Although AD is mainly due to mutations in the filaggrin gene (Egawa and Kabashima 2016), gut microbiome dysbiosis in adulthood contributes to the progression of the disease. As observed in several studies, the gut of AD patients has elevated levels of Staphylococcus aureus, Escherichia coli, and Clostridium difficile, in conjunction with decreased levels of Faecalibacterium prausnitzii, Bacteroides, Bifidobacterium, and other propionate and butyrate producers (Abrahamsson et al. 2012; S.-Y. Lee et al. 2018; Song et al. 2016). 

Similarly, the disruption of the gut microbiome has been observed in psoriasis patients. In these cases, patients were found to have a less diverse gut microbiota with a reduced number of Coprococcus sp. associated with T immune cells differentiation caused by increased microbial-induced proteins, AMPK, and rapamycin (Omenetti and Pizarro 2015). Finally, patients with acne, which is caused by excess sebum, clogged pores, and inflammation by Propionibacterium acnes bacteria, have fewer Actinobacteria, Bifidobacterium, Butyricicoccus, Coprobacillus, Lactobacillus, and Allobaculum in their gut, and an increase in Proteobacteria (H.-M. Yan et al. 2018). 

A hypothesis proposes that the relationship between the gut microbiome and the mTOR pathway, which governs cell growth and lipid metabolism, can influence the onset of acne (Noureldein and Eid 2018).

Probiotics as Therapy for Skin-Related Ailments

Therapy-wise, probiotics can help treat AD in adult patients, as seen in the reduced Scoring Atopic Dermatitis score and reported improvement of quality of life, but did not show significant differences in other measures like skin severity and itch severity (Umborowati et al. 2022).

Similarly, the effectiveness of probiotic treatment was suggested in a case of severe pustular psoriasis that had been unresponsive to steroids, dapsone, and methotrexate (Vijayashankar and Raghunath 2012). Regarding acne, some studies suggest that probiotic supplements, along with other vitamins and extracts, can improve acne symptoms after 12 weeks of treatment (Tolino et al. 2018; Fabbrocini et al. 2016; Kim et al. 2010). 
Finally, recent studies suggest that oral probiotics could potentially improve various indicators of skin aging, including photodamage, oxidative stress, maintaining an optimal skin pH, and skin barrier dysfunction. Although the exact mechanisms are still being researched, the administration of specific strains of Bifidobacterium and Lactobacillus has been found to have a photoprotective effect that leads to an anti-aging outcome in mice (K. Lee et al. 2021; Ra et al. 2014; Satoh et al. 2015). Moreover, administering Lactobacillus plantarum has also been demonstrated to alleviate symptoms of UV-induced skin photo-aging in humans (K. Lee et al. 2021).

2. The Gut-Bone Axis: How Your Digestive System Impacts Bone Health

The Mechanisms of Gut Microbiome Regulation of Bone Growth

Nutrient absorption, immune system maturation, and the release of metabolic products are some of the mechanisms involved in the gut microbiome regulation of bone growth (Zhang et al. 2018; Villa, Ward, and Comelli 2017). For instance, Bifidobacterium longum and Lactobacillus reuteri promote mineral absorption and increase bone mineral density (Villa, Ward, and Comelli 2017). Additionally, some gut bacteria can synthesize vitamins B and K, which are critical for regulating bone health (Clarke et al. 2014), and gut-derived bile acids can regulate calcium absorption (Rodríguez et al. 2013). SCFAs synthesized from the gut also play a role in regulating bone metabolism, with butyrate and propionate having direct effects on bone marrow. A study on mice found that SCFAs can even move from the gut into the bone tissue as higher levels of butyrate and propionate were observed in the bone marrow of mice given drinking water enriched with SCFAs. (Lucas et al. 2018). 

Links Between Altered Gut Microbiome and Bone Diseases

Research has shown that an altered gut microbiome is linked to bone diseases such as osteoporosis, osteopenia, and osteoarthritis, with antibiotic intervention disrupting gut microbial homeostasis and causing changes to bone mass and biomechanical properties (Rios-Arce et al. 2020; J. Yan et al. 2016). Short-term gut microbial colonization promotes bone turnover and reduces femoral bone mass, while long-term colonization enhances the growth of the femur in adult mice (J. Yan et al. 2016). Finally, selective enrichment of butyrate-producing bacteria through probiotics and berberine supplements was found to enhance gut barrier function and have protective effects on bone in postmenopausal women with estrogenic deficiency (Penoni et al. 2017).

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3. The Gut-Adipose Axis: The Connection Between Gut Health and Obesity

The Gut Microbiome and Obesity

Recent studies have revealed the crucial role of gut microbiota in the onset and progression of obesity and related metabolic disorders, emphasizing a strong association between the gut microbiome and adipose tissue. Evidence of this connection was established through a study where the transplantation of gut communities from obese mice into germ-free mice resulted in the recipient mice developing obesity  (Turnbaugh et al. 2006; 2008). This effect was also observed when germ-free mice were transplanted with the microbiomes of twins, where only one was obese (Ridaura et al. 2013). Interestingly, research has indicated that gut bacteria present in lean individuals have a better ability to ferment SCFAs. (Newgard et al. 2009).

The Role of Specific Gut Microbial Species in Obesity and Related Metabolic Disorders

Despite the fact that some studies have reported a higher Firmicutes/Bacteroidetes ratio in the gut microbiome of obese animals and humans, there is an ongoing debate with regard to the correlation between these phyla and their potential impact on obesity and metabolic health (MetaHIT Consortium et al. 2010; Turnbaugh et al. 2006; 2009). On the other hand, the beneficial effects of Akkermansia muciniphila have gained significant attention in recent years (Cani and de Vos 2017). In preclinical models, the administration of A. muciniphila has demonstrated promising results in mitigating the incidence of obesity and its associated conditions, including insulin resistance, glucose intolerance, gut permeability, and steatosis (Everard et al. 2013; Plovier et al. 2017). 

More recent research has shown that introducing pasteurized A. muciniphila to humans yields improvements in fat mass and body weight, as well as a reduction in markers for liver inflammation and dysfunction, ultimately leading to beneficial effects on obesity, glucose tolerance, and insulin resistance (Depommier et al. 2019). In a nutshell, increasing evidence suggests that the gut microbiome plays a crucial role in influencing lipid metabolism and the formation of fat cells. Giving microbiome-depleted mice sodium butyrate has been found to help break down fats and partially reverse energy impairment (B. Li et al. 2019). Additionally, other studies have suggested that the gut microbiome can affect the expression of a certain protein called angiopoietin-like protein 4, which can stop the activity of enzymes that break down fat into triglycerides. This could potentially explain why germ-free mice tend to have lower levels of body fat, as discovered in an earlier study (Bäckhed et al. 2004).

4. The Gut-Liver Axis: How Your Gut Microbiome Can Affect Liver Function and Liver Disease

Microbial Dysbiosis and Liver Diseases

The liver gets most of its blood supply from the intestine through the portal vein, meaning it is frequently exposed to gut bacteria and their by-products. Researchers have conducted many studies on the gut microbiome to understand the pathophysiology of liver diseases, including non-alcoholic fatty liver disease (NAFLD), steatohepatitis (NASH), hepatocarcinogenesis, alcoholic liver disease (ALD), and cirrhosis. 

Unsurprisingly, liver disorders have been found to be associated with microbial dysbiosis, which has prompted scientists to investigate how the gut microbiome can worsen such conditions by uncovering various underlying mechanisms. For instance, bile acids produced by gut bacteria can disrupt lipid and glucose metabolism, making individuals more susceptible to NAFLD. Additionally, changes in gut microbial composition can lead to “leaky gut” and allow bacteria and their products to enter the liver through the enterohepatic circulation. This triggers a series of events that produce pro-inflammatory cytokines like TNF-a, which contribute to liver damage (Compare et al. 2012; Minemura 2015). 

Butyrate and Liver Cancer

In this context, scientists have focused on microbial butyrate, which is a vital energy source for cells in the colon and can improve the colon’s protective barrier. Additionally, butyrate can help stop the growth of unhealthy cells in the liver by reducing the levels of Sirtuin-1 protein. This makes it an effective inhibitor of liver cancer cells (Pant et al. 2017) 

Gut Microbiome and Hepatic Function

Additionally, the gut microbiome may play a role in the availability of choline and ethanol, which significantly impact hepatic functioning. The gut microbiome can impact choline bioavailability by metabolizing dietary choline from common sources such as milk, eggs, and red meat into trimethylamine (TMA), which can then be further metabolized in the liver into trimethylamine-N-oxide (TMAO). This process has been linked to increased accumulation of hepatic triglycerides, as TMAO affects the synthesis of bile acids, which act as triglyceride emulsifiers. Additionally, even in the absence of external consumption, the fermentation of carbohydrates by Escherichia coli under anaerobic conditions can lead to the production of ethanol, which may influence liver function (Dawes and Foster 1956).

Microbiome-Based Interventions for Liver Diseases

In general, the administration of pro-, pre-, and synbiotics (mixture of probiotics and prebiotics) appears to benefit a range of liver-related indicators in individuals afflicted with NAFLD, ALD, cirrhosis, or hepatic encephalopathy (Schwenger, Clermont-Dejean, and Allard 2019). Similarly, fecal microbiome transplant (FMT), which is a proven therapy for treating antibiotic-resistant Clostridium difficile, has shown promising results in treating liver diseases. 

A pilot study of patients with severe alcoholic hepatitis who received FMT showed marked improvements in liver disease within one week and significantly improved one-year survival rates compared to controls (Philips et al. 2017). Another clinical trial found that FMT improved cognition and dysbiosis in patients with cirrhosis, reducing hospitalization rates and preventing the development of hepatic encephalopathy (Bajaj et al. 2017). Finally, in a pilot study relevant to NAFLD, FMT significantly reduced insulin resistance associated with changes in the microbiome (Vrieze et al. 2012). However, the variable efficacy of microbiome-based interventions across studies necessitates further investigation before validating them as a therapy for liver diseases.

5. The Gut-Kidney Axis: How Your Gut Microbiome Can Influence Kidney Function and Kidney Disease

Impact of Gut Microbiota on Renal Function

The gut microbiota produces many solutes and toxins that worsen renal functions. Undigested proteins or fat from our diet can serve as an energy source for gut bacteria. However, their breakdown in the colon depends on carbohydrates availability (Ramakrishna 2013). When carbohydrate is scarce, Clostridium and Bacteroides ferment proteins into p-cresol, indoles, phenols, and amines, which are then processed into uremic toxins (Sabatino et al. 2015). Upon binding to albumin, these toxins are normally excreted by the kidneys. However, if they build up, they can accelerate the progression of kidney disease. 

Similarly, in a lack of carbohydrates, the gut bacteria can breakdown choline, carnitine, and lecithin from dietary fat, leading to the formation of TMAO through the combined action of hepatic enzymes (Ussher, Lopaschuk, and Arduini 2013). TMAO is released into circulation and eliminated by the kidneys. Disturbance in these pathways can result in severe complications, including chronic kidney disease (CKD), end-stage renal disease (ESRD), and acute kidney injury (AKI). 

Gut Microbiota Composition in Renal Disease

Studies on the gut microbiome have demonstrated significant differences in the bacterial composition of uremic patients compared to healthy individuals (Vaziri, Zhao, and Pahl 2016). It has been observed that 56 members of Clostriadiales, including the families Christensenellaceae, Ruminococcaceae, and Lachnospiraceae are enriched in the gut of patients suffering from early kidney disease (Barrios et al. 2015). Contrarly, individuals with end-stage renal disease (ESRD) have been found to have higher levels of bacteria that produce uricase and urease and bacteria that produce indole and p-cresyl-forming enzymes (Hobby et al. 2019).

Therapeutic Approaches Based on Microbiome

Therapeutic approaches based on the microbiome have been investigated as a potential treatment option for kidney diseases. For example, prebiotics were found beneficial for both adult patients with CKD and pediatric patients with ESRD, as shown by decreases in serum urea nitrogen concentration and improvements in disease status (Bluemel et al. 2016). 
Additionally, dietary fiber supplementation for six weeks resulted in reduced plasma levels of uremic toxins in haemodialysis patients (Sirich et al. 2014). Also, probiotics and synbiotics have been found to improve the levels of uremic toxins in the blood and restore the balance of gut microbiota (Nguyen, Kim, and Kim 2021). Finally, alternative therapies using SCFAs have been shown to improve renal function by reducing inflammation, immune cell infiltration, and apoptotic cells in the kidneys (Magliocca et al. 2022).

6. The Gut-Heart Axis: The Role of the Gut-Heart Axis in Heart Disease

Numerous studies have indicated that the gut microbiome significantly influences host physiological processes, suggesting its potential as an extra-genomic contributor to cardiovascular health. There are multiple pathways through which the gut interacts with the heart. 

Gut Bacteria and Blood Pressure

First, it influences blood pressure via the production and release of SCFAs. SCFAs can lower and raise blood pressure by acting on G-protein coupled receptors (GPCR41, GPCR43) or the olfactory receptor 78, respectively (Jose and Raj 2015; Kitai and Tang 2017). Furthermore, SCFAs can interact with peroxisome proliferator-activated receptors (PPARs), which are critical regulators of carbohydrate and lipid metabolism, ultimately leading to reduced lipid levels (Grygiel-Górniak 2014). 

Harmful Effects of Gut Bacteria on Heart Health

Second, uremic toxins produced by the gut bacteria during the fermentation of food can harm the heart by causing enlargement of the heart muscle (hypertrophy) and excess formation of fibrous tissue or scarring (fibrosis). Similarly, the microbial-derived TMA is believed to increase susceptibility to heart failure through increased myocardial fibrosis. Studies have shown that heart failure patients have significantly higher levels of TMAO in their plasma compared to healthy controls (Kamo et al. 2017), and inhibition of the production of microbial TMA has been found to attenuate the development of atherosclerosis in a mouse model (Xue et al. 2017). 

Gut Microbiota and Heart Failure

Finally, the “gut hypothesis of heart failure” has emerged as an explanation for the role of gut microbiota in the pathogenesis of heart failure, an end stage of various cardiovascular diseases. Heart failure causes blood deficiency in the intestinal mucosa, leading to impairment of the barrier function. As a result, gut bacteria and their products, such as endotoxins like LPS, translocate into the bloodstream (Kamo et al. 2017). Once in circulation, the endotoxins bind to receptors (TLR-4) on cardiomyocytes, inducing an inflammatory response that results in structural tissue damage, reduced contractility, and impaired cardiac function (Organ et al. 2016). Additionally, leaking LPS affects lipoprotein metabolism by interacting with low-density lipoprotein (LDL) and favoring the transformation of macrophages into foam cells, contributing to atherosclerosis development and progression (Rogler and Rosano 2014). 

Microbial Compositional Perspective of Cardiovascular Impairments

From a microbial compositional perspective, scientists have found that the abundance of Prevotella genus bacteria is closely associated with hypertension (J. Li et al. 2017). Likewise, in a study of atherosclerotic plaques, the presence of Streptococcus, Veillonella, and Chryseomonas was reported in the plaques and the gut (Calandrini et al. 2014; Xue et al. 2017). Additionally, as previously mentioned, the gut microbiome dysbiosis is a risk factor for a range of diseases, including metabolic syndrome, obesity, and diabetes, which are known to be linked to cardiovascular impairments.

Potential Therapies for Cardiovascular Health

Looking at potential therapies, the administration of Lactobacillus rhamnosus has been shown to improve cardiac functioning (Gan et al. 2014). In the same vein, consuming at least 10 CFU of probiotics per day has effectively reduced blood pressure levels in patients with hypertension (Khalesi et al. 2014). Additionally, antihypertensive drugs have been found to act by regulating gut microbiota. For instance, Captopril, an inhibitor of angiotensin converting enzyme used for the treatment of hypertension, increases the levels of Allobaculum and maintains a sustained anti-hypertensive effect even after withdrawal of the drug (Yang et al. 2019). Similarly, drugs like Irbesartan and Candesartan have been found to prevent disruption of gut microbiota by preserving Lactobacillus levels, thereby normalizing the Firmicutes: Bacteroides ratio and producing anti-hypertensive effects (Yisireyili et al. 2018; D. Wu et al. 2019; R. Wu et al. 2019).

7. The Gut-Muscle Axis: What We’ve Learned from Studies on Bodybuilders & Athletes

Gut-Muscle Pathways

It is widely acknowledged that athletes’ exercise capacity is significantly impacted by the composition and quality of their diet. In recent times, researchers have uncovered that human skeletal muscle is partly affected by the intestinal microbiome.

The gut-muscle pathways that are most well-known include the microbial-derived SCFAs and bile acids. Secondary bile acids have the potential to modulate the activity of the farnesoid X receptor (FXR) (Cerdá et al. 2016), which plays an important role in energy metabolic pathways, lipoprotein, and glucose turnover, thereby contributing to muscle cell energy storage. Similarly, SCFAs contribute to the deposition of proteins in skeletal muscle tissue via the activation of muscular AMP kinase (den Besten et al. 2013). The gut microbiota can also influence muscle performance through other pathways. For example, by influencing the availability of amino acids, vitamins, and glycogen, by participating in digestion and absorption (Lin et al. 2017; LeBlanc et al. 2013; Nay et al. 2019). 

Studies On Athletes

To corroborate the influence of the gut microbiome on muscle and sports performance, several studies examined the gut microbiome of athletes. A now classical result, researchers from Harvard found that after completing the Boston Marathon, athletes exhibited an enrichment of the Veillonella genus. The researchers then extracted the strain of Veillonella from the athletes’ fecal samples and administered it to mice. Using a treadmill test, they discovered that the mice given the Veillonella bacteria performed 13% better than those who did not. This improvement was attributed to Veillonella‘s ability to break down lactate and produce propionate, which enhances the body’s ability to handle exercise-induced stress (Scheiman et al. 2019). 

Similarly, research conducted on cyclists has shown a correlation between the frequency of exercise and higher activity levels of carbohydrate-metabolizing bacteria, such as Prevotella (Petersen et al. 2017). Finally, a pilot study conducted on male bodybuilders has suggested that common patterns of gut microbiota and circulating metabolome across participants may have contributed to bodybuilding outcomes (Philips et al. 2017).

Excessive Training and Microbiome Imbalances

In terms of the impact on the body, changes in the microbial community promoted by training appear to be advantageous to host health. However, excessive training may lead to microbiome imbalances due to factors such as elevated oxidative stress and increased permeability of the intestinal barrier. These imbalances can exacerbate inflammatory responses, resulting in increased muscle catabolism and a decline in muscle function (Karl et al. 2017). 

Gut Health and Aging Muscles

To conclude, it is critical to highlight the relationship between the composition of the gut microbiome and muscle function in the development of age-related sarcopenia. Research has linked sarcopenia and systemic weakness among older adults with intestinal dysbiosis, which contributes to increased intestinal barrier permeability, elevated levels of lipopolysaccharides (LPS) in the blood, immune system activation, and a decrease in insulin sensitivity (Ni Lochlainn, Bowyer, and Steves 2018). Interestingly, 13-week supplementation of a mixture of Lactobacillus and Bifidobacterium probiotics in older individuals has been shown to improve endurance and muscular strength (Buigues et al. 2016).

8. The Gut-Lung Axis: The Connection Between Your Digestive System and Respiratory Health

The Importance of Gut Microbiota in Regulating Respiratory Tract Health

While the lungs do possess their own microbiome, the intestinal microbiome may play a more critical role in regulating the health of the respiratory tract. The lung microbiota is significantly smaller in size than the gut microbiota, and its composition is influenced by the colonization of microorganisms from the upper respiratory tract. Starting from birth and throughout a person’s life, there is a strong correlation between the composition of the gut microbiota and the lung microbiota.

Immune Effects of Gut Microbiome on the Pulmonary Immune System

In addition to regulating the immune system at its specific site, it is now acknowledged that the gut microbiome has a broader immune effect, particularly on the pulmonary immune system. It was found that intact bacteria, as well as their fragments or metabolites like SCFAs, may move across the intestinal barrier, enter the systemic circulation, and influence the immune response in the lungs. 

One example is the impact that SCFAs have as signaling molecules on suppressing inflammatory and allergic responses in lung cells (Cait et al. 2018). Another crucial factor contributing to this far-reaching immune effect is a group of commensal bacteria known as gut-segmented filamentous bacteria, which reside in the ileum and play a role in regulating the development of the immune system (Yin et al. 2013). As a result, the gut microbiota plays a vital role in the response to bacterial infections in the lungs. For example, the use of broad-spectrum antibiotics to disrupt the gut microbiota in mouse models of lung infection leads to worse outcomes (Robak et al. 2018). Functionally, pulmonary immune cells in mice lacking gut microbiota due to antibiotic treatment exhibit reduced responsiveness to stimulation. Additionally, the communication between the gut and lungs is a two-way process. Indeed, a pre-clinical model has demonstrated that influenza infection results in an increased proportion of Enterobacteriaceae and reduced levels of Lactobacilli and Lactococci in the gut (Looft and Allen 2012). 

The Gut-Lung Axis and Respiratory Diseases

Proof of the gut-lung axis can be found in the pathogenesis of respiratory diseases. For instance, increased permeability of the gastrointestinal tract has been observed in patients admitted with chronic obstructive pulmonary disease, and the level of circulating gut microbes has been linked to mortality (Ottiger et al. 2018). Perturbations in bacterial gut colonization during early life, such as low microbial diversity after C-section or neonatal antibiotic use, are critical in inducing the development of childhood asthma. Causality has been demonstrated in murine models where inoculation with bacteria absent from the microbiota of asthmatic patients leads to a decrease in airway inflammation (Arrieta et al. 2015). Additionally, in patients with cystic fibrosis, the gut and lung microbiota differ from those of healthy individuals, and disease progression is linked to microbiota alterations (Stokell et al. 2015). Patients with documented intestinal inflammation in cystic fibrosis have a higher abundance of Streptococcus in the gut (Enaud et al. 2019), suggesting the involvement of the gut-lung axis in intestinal inflammation.

The Gut-Lung Axis and COVID-19

The gut-lung axis has recently been implicated in COVID-19. Many COVID-19 patients experience gastrointestinal symptoms such as diarrhea and nausea, which can precede respiratory symptoms. A recent study identified 20 proteomic biomarkers that may be linked to disease severity for predicting COVID-19 progression (Gou et al. 2020). Using a machine learning model, the study also linked the gut microbiota to COVID-19 severity and identified a core group of bacteria that are associated with inflammation, including Ruminococcus and Blautia (positively associated), and Bacteroides and Clostridiales (negatively associated). Furthermore, it is well-established that both the gut and lung microbiomes experience a decline in diversity as individuals age, which can contribute to a weakened and imbalanced immune system (Nagpal et al. 2018). This decline in microbiome diversity may also be linked to the increased susceptibility and severity of COVID-19 in older individuals. 

To combat these issues, the administration of specific probiotic strains such as Lactobacillus spp. in the respiratory and digestive tracts could potentially provide protective benefits against certain pathologies such as cystic fibrosis or nosocomial pneumonitis (Alexandre et al. 2014). Recent research has shown that recombinant Lactobacillus plantarum has antiviral effects against coronavirus infection in the intestinal epithelial cells of animal models (Y. Liu et al. 2020). Despite these promising findings, the effects of probiotics in reducing the mortality and severity of COVID-19 have not been definitively established.

9. The Gut-Brain Axis: Its Impact on Depression, Autism, Aging, and Beyond

The Gut-Brain Axis and Emotional State

The idiomatic expressions of ‘gut feeling’ and ‘butterflies in the stomach’ are not mere linguistic tropes. They reflect the remarkable connection between the gut and the central nervous system (CNS), supported by an intricate network of approximately 100 million nerve cells lining the gastrointestinal tract, known as the enteric nervous system (ENS) (Fleming et al. 2020). This “second brain,” housed within the digestive system and microbiome, profoundly influences our moods, decision-making, and even behavior. When the gut microbiome is imbalanced and causes digestive discomfort, it is no coincidence that our overall emotional state is adversely impacted.

The Role of the Vagus Nerve in Gut-Brain Communication

The fundamental pathways of the gut-brain axis include the vagus nerve, immune and neuroendocrine systems, neurotransmitters, microbial metabolites, and gut bacteria. 

The tenth cranial nerve, known as the vagus nerve, courses from the brain to the abdominal region, acting as a regulator of numerous internal organ functions such as digestion, heart rate, and respiratory rate. 
Functioning as a highway of signals between the brain and vital organs, including the cells of the intestines, the vagus nerve is highly susceptible to the effects of the gut microbiota. This intricate interplay allows the brain to detect and interpret the complex and ever-changing conditions within the gastrointestinal tract, providing a means for the central nervous system to ‘sense’ the microenvironment of the gut (Furness et al. 2014).

Immune System Signaling between the Gut and Brain

At a second level, the immune system plays a pivotal role in the signaling between the gut and brain. Many neurological disorders, ranging from autism spectrum disorders and epilepsy to Alzheimer’s disease, Parkinson’s disease, and cerebrovascular diseases, demonstrate low-grade systemic inflammation, which is suggestive of a maladaptive immune response and dysbiosis of the microbiome. Various microbe-associated molecular patterns, including lipopolysaccharide (LPS), flagellin, and bacterial lipoprotein, activate different immune cell types within the gut. Once activated, these gut-associated immune cells produce proinflammatory cytokines such as interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor α that can reach the brain by crossing the blood-brain barrier via diffusion or cytokine transporters. Once in the brain, these cytokines can interact with microglial receptors, stimulating further cytokine release and modifying neuronal function (Fung 2020; Ceppa, Mancini, and Tuohy 2019). 

Gut-Derived Metabolites and Neurotransmitters

In addition, a vital channel for inter-organ signaling involves gut-derived metabolites, including hormones, neurotransmitters, and bile acids, as has been extensively described by my own work (Monteiro-Cardoso and Corlianò 2020). Notably, recent findings indicate that the gut microbiota can trigger the activation of the hypothalamic–pituitary–adrenal (HPA) axis, a major neuroendocrine system responsible for regulating stress responses, mood and emotions, and the immune system (Farzi, Fröhlich, and Holzer 2018; Bao and Swaab 2019). 

Furthermore, neurotransmitters, including dopamine, serotonin, noradrenaline, and gamma-aminobutyric acid (GABA), neuroactive amino acids such as tyramine and tryptophan, as well as short-chain fatty acids (SCFAs), and bile acids are directly synthesized by gut bacteria

Briefly, GABA is known to modulate behavior, cognition, and stress and anxiety responses, and its deficiency has been linked to psychiatric disorders such as depression, autism, and schizophrenia. Interestingly, some strains of Lactobacilli and Bifidobacterium can produce GABA (Zheng et al. 2020; Duranti et al. 2020). Serotonin plays a critical role in mood, cognition, sleep, and appetite control. The amino acid tryptophan is considered the sole precursor to serotonin, and gut microbiota may influence up to 90% of serotonin synthesis by affecting tryptophan uptake (Jenkins et al. 2016). Dopamine is a key neurotransmitter involved in the brain’s reward system, and its deficiency has been implicated in conditions such as Parkinson’s disease, schizophrenia, and addiction (Strandwitz 2018). 

Finally, research indicates that SCFAs play a significant role in gut-brain communication and are involved in maintaining the integrity of the blood-brain barrier (BBB). Studies have revealed that butyrate, for instance, has links to memory, cognition, mood, and metabolism, while acetate is associated with appetite regulation, and propionate may be involved in protecting against type 2 diabetes and obesity as well as reducing stress behaviors (Hoyles et al. 2018; Frost et al. 2014; De Vadder et al. 2014).

Microbes and the Central Nervous System

Remarkably, signals originating from microbes can be transmitted to the central nervous system (CNS) either directly through the systemic circulation or indirectly by engaging receptors on the cells of the intestinal lining. Upon activation, these cells secrete molecules that stimulate receptors on the synaptically connected vagal and spinal nerves. This sensory information is relayed to the CNS, which responds by modulating activity via the sympathetic and parasympathetic branches of the autonomic nervous system (ANS) as well as the HPA axis (Walsh and Zemper 2019).

Gut Microbiota and Neurological Disorders

The scientific investigation into the effects of gut microbiota on neurological disorders has rapidly expanded, with the current pace of approximately 30 new studies being published each day. Of particular interest are recent findings suggesting that certain strains of intestinal microorganisms may be linked to cognitive functions such as memory and learning, as well as emotional states including stress and mood, and may play a role in the development of neurological conditions ranging from neurodevelopmental disorders to neurodegeneration.

Microbes and Depression

The mechanisms by which microbes influence CNS functions and contribute to mental illness remain controversial; evidence indicates that patients with minor and major depressive disorders experience a shift in gut microbiota composition associated with an increase in the level of proinflammatory cytokines (P. Liu et al. 2022). To corroborate the data, probiotics have been shown to normalize depression and anxiety-like behaviors in CNS disorders (Chao et al. 2020). A wealth of research has also examined the association between gut microbiota and memory acquisition and learning during childhood. 

Gut Microbiota and Learning

In animal models, changes in gut microbiota have been shown to significantly impact visual-spatial learning and memory (D’Amato et al. 2020). Although human studies remain limited, one investigation found that microbial diversity was linked to cognitive performance in infancy (Callaghan 2020). 

Gut Microbiota and Autism Spectrum Disorder (ASD)

On another angle, there is mounting evidence of the significant role played by the microbiota in autism spectrum disorder (ASD). Transplantation of microbes from individuals with ASD has been shown to induce ASD-like behavior in mice (Sharon et al. 2019). In addition, children diagnosed with ASD are four times more likely to experience gastrointestinal (GI) symptoms, such as inflammation and abdominal pain (Roussin et al. 2020).  Finally, fecal transplantation has shown long-term positive effects on intestinal and behavioral symptoms in individuals with ASD (Kang et al. 2019). 

Gut Microbiota and Multiple Sclerosis (MS)

Similarly, a growing body of evidence suggests that the gut microbiome undergoes changes in individuals with multiple sclerosis (MS). Specifically, studies have shown that MS patients exhibit a distinct gut microbial profile compared to healthy individuals. These microbial changes appear to increase the levels of regulatory immune cells, which in turn decrease the activation of proinflammatory cells (Chen et al. 2016). In contrast, the elevated levels of circulatory T immune cells seem to increase the permeability of the blood-brain barrier, ultimately resulting in inflammation in the central nervous system. Additionally, studies have demonstrated that fecal microbiota transplantation from MS patients into mice can lead to a higher incidence of autoimmune encephalomyelitis (EAE), underscoring the potential role of the gut microbiome in MS pathogenesis (Berer et al. 2017). 

Gut Microbiota and Amyotrophic Lateral Sclerosis (ALS)

Emerging evidence has linked gut dysbiosis and altered bacterial composition to the etiology and progression of amyotrophic lateral sclerosis (ALS). A recent longitudinal study investigated the microbiota composition in ALS patients, revealing an imbalance between protective microbial groups such as Bacteroidetes and neurotoxic/proinflammatory groups such as Cyanobacteria (Di Gioia et al. 2020). Moreover, differences in microbial biodiversity were observed between ALS patients and controls, with pathways related to amino acid, nucleotide, and carbohydrate metabolism being lower in the ALS group (Zeng et al. 2020). Notably, supplementation with Akkermansia muciniphila improved ALS symptoms, while Parabacteroides distasonis and Ruminococcus torques exacerbated symptoms in mice (Blacher et al. 2019). 

Gut Microbiota and Huntington’s Disease (HD)

Another neuronal disease linked to the gut is Huntington’s disease (HD), primarily caused by the expansion and instability of trinucleotide (CAG) repeats in the huntingtin (HTT) gene, which is expressed throughout the brain. Recent studies have shed light on possible gut dysbiosis in HD. Gastrointestinal dysfunction has been shown to induce unintended weight loss, which is a hallmark clinical feature of HD in mice models (van der Burg et al. 2011). The gut microbiota composition in individuals with HD was found to be significantly different in the microbial communities. It displayed lower alpha-diversity (richness and evenness) compared to healthy controls (Wasser et al. 2020). 

Microbial Diversity and Healthy Aging

Finally, increasing evidence suggests that microbial diversity is closely related to healthy aging and longevity. In mice, studies have demonstrated that fecal microbiota transplantation can improve age-related immune function defects (Parker et al. 2022). In contrast, a similar transplant from aged to young mice has been found to impact critical CNS functions negatively (D’Amato et al. 2020). Moreover, neurological research indicates that the microbiota plays a crucial role in neurodegenerative disorders, suggesting that an aging gut microbiota may be linked to immune and neuronal dysfunction in conditions such as Parkinson’s and Alzheimer’s disease. 

Indeed, several human studies have reported microbial dysbiosis in patients with neurodegenerative diseases, characterized by a lower abundance of SCFA-producing bacteria (e.g., Clostridium sp. strain SY8519, Butyrivibrio, Roseburia hominis, Eubacterium, and F. prausnitzii) and a higher proportion of taxa associated with neurological disorders (Odoribacter splanchnicus) and proinflammatory states (e.g., Bacteroides vulgatus, B. fragilis, Eggerthella lenta, and Gammaproteobacteria) (Haran et al. 2019; Nakahara et al. 2023). In line with this, studies of faecal microbiota transplantation in transgenic mouse models indicate a causal relationship between intestinal microbiota, protein aggregation, and cognitive impairments (Radde et al. 2006; Sun et al. 2019).

Psychobiotics and Mental Health

From a therapeutic perspective, various meta-analyses have demonstrated the advantages of psychobiotics in treating anxiety, schizophrenia, and cognitive functions. Psychobiotics are a particular class of probiotics that when ingested in appropriate quantities are thought to improve mental health by impacting the microbiota of the host organism. Bifdobacteria, Lactobacilli, Streptococci, Escherichia, and Enterococci are the most typical psychobiotic bacteria (Sharma et al. 2021). In clinical trials on humans, ingestion of a psychobiotic suspension resulted in a significant reduction in anxiety parameters in individuals with depressive symptoms (Gualtieri et al. 2020). 

In another study, psychosocial behaviour improved in subjects who had excess fat mass and underwent weight loss dietary treatments after consuming psychobiotics (Colica et al. 2017). Psychobiotics have also been shown to be helpful in treating insomnia, as demonstrated by studies that showed improved NREM sleep (Non-Rapid Eye Movement sleep) during the resting phase, as well as significant improvement in sleep efficiency and wakening episodes of the subjects (Yamamura et al. 2009; Higo-Yamamoto et al. 2019). Despite the significant progress made in psychobiotic research, there is still much to learn. Certain parts of the mechanism pathway remain unclear, and many properties are strain-specific, so safety and efficacy associated with specific formulations should not be extrapolated to other probiotic products.

The Gut-Organ Axis: How the Microbiome Affects the Whole Body

In summary, it is becoming increasingly clear that the gut microbiome plays a significant role in overall health and well-being. The intricate relationships between the gut and various organs have been documented through the identification of several gut-organ axes. Although this field of research is still evolving, the use of probiotics, prebiotics, and synbiotics has shown promise in promoting gut health and supporting some of these gut-organ axes. As we age, maintaining a healthy gut-organ axis becomes even more critical, as it can have significant impacts on vital organs such as the brain, skin, and muscles. By continuing to investigate the role of the microbiome in the aging process, we can develop targeted interventions to promote longevity, healthy aging and improve the quality of life in older adults.

The first two articles of this series delved into the fascinating world of the microbiome, examining its intricacies and the various gut-organ axes that affect everything from mental health, hypertension, diabetes, cancer, and more. Our next article will focus on how the gut microbiome evolves throughout our lifespan and its implications for the aging process. Our final article will cover the cutting-edge microbiome-based therapies that are revolutionizing the field of medicine.

Maria Corlianò, Ph.D.

Dr. Maria Corlianò is an Italian biologist with 8 years of experience in biomedical research at top-ranked laboratories across Europe and Asia. At the age of 23, she was awarded the Singapore International Graduate Award by A*STAR/National University of Singapore, a merit-based Ph.D. scholarship investing in young aspiring scientific talents. During this time, she investigated the role of the gut microbiome in human health and disease, leading to groundbreaking results in the field, as showcased by her publications and her presence at international conferences. 

Dr. Maria Corlianò is now the Co-founder and CTO of OSbiome, an AI-driven precision recommendation platform that helps people improve their lives through the gut microbiome.


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