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Introduction
The contribution of gut health towards the overall health and well-being of an individual is a concept that originated several centuries back. However, the discovery of microbes provided new insights not only on their pathological aspects, but also on their role in supporting general health. The scientific research and advancements in the last few decades have expanded the horizon regarding the human microbial ecosystem which continues to scale new heights even in the current times.
The research into the indispensable role of gut bacteria towards wellness as well as the health impacts related to their disruptions are two notions that have emerged side by side. Though the term ‘dysbiosis’ has evolved on a much controversial note, it is being increasingly used to define the disturbances in the microbial ecosystem leading to an altered health status.
In order to elaborate the alterations that occur in the microbial ecosystem in general, dysbiosis is distinguished into three types. They are: 1) Loss of beneficial microbes 2) Overgrowth of potentially harmful microbes 3) Loss of microbial ecosystem diversity. However, these changes do not occur in isolation but rather happen simultaneously.
The microbial dysbiosis not only occurs in the gut, but also in the other organ systems that harbor their own specific microbiota. The bi-directional communication that exists between the gut microbes and those of the other organ systems, influence each other both in states of health and disease.
Reasons explained
On a general note, dysbiosis occurs due to many reasons that are related to the host (humans). Some of the contributing factors include genetics, presence of infections, inflammation, life-style and dietary habits, exposure to xenobiotics and finally the overall level of hygiene.
The concept of ‘genetic dysbiosis’ was introduced to ascertain the relationship between the human genetic makeup and the microbial colonization. It has been hypothesized that the genes present in the cells are programmed in such a way so that they not only influence the human microbial composition, but also in differentiating the friendly bacteria from the harmful ones. Any defects in these genes leads to variations in the microbial ecosystem and an altered health state. Diseases such as cancer, inflammatory bowel disease (IBD), rheumatoid arthritis, psoriasis, bacterial vaginosis and periodontitis are related to this dysbiosis.
The term ‘xenobiotics’ is used to describe chemical substances that are not part of a living organism. The different types of xenobiotics include environmental pollutants, drugs, food additives, pesticides, hydrocarbons (present in fuels), synthetic polymers (nylon, Teflon, poly vinyl chloride) oil mixtures and antioxidants. The gut bacteria play an important role in the metabolism of xenobiotics wherein they are inactivated or undergo bioactivation. The process of bioactivation results in the formation of active metabolites that are either beneficial or harmful. On the other hand, increased exposure to certain environmental toxins have been shown to adversely affect the gut microbial community.
Gut microbial dysbiosis
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The reasons behind the gut bacterial dysbiosis are
Dietary changes
An important factor that modulates gut microbial health, function and composition lies in the type of diet consumed. A diet rich in micronutrients (vitamins, minerals) and fibre along with adequate intake of water and good quality proteins has been found to protect the gut microbes. The plant-based carbohydrates also called as ‘microbiota-accessible carbohydrates’ are crucial for the microbial health. These include the dietary fibres and the polysaccharides that are digested by the gut bacteria to produce short chain fatty acids that has innumerable health benefits.
On the other hand, increased intake of saturated and trans-fats, simple sugars (especially sugars that are added during food processing), refined flour (very low in fibre and nutrients), high-fructose corn syrup (artificial sweetener made from corn), foods containing additives and processed foods can adversely affect the gut microbiota.
High fat diet
Studies have shown that the consumption of a high fat diet causes disruptions in the gut microbial balance leading to a decrease in the health boosting bacteria like Bacteroidetes, Bifidobacterium and Akkermansia. Also, the increase in the number of gram-negative bacteria (a type of bacteria that stain red after a chemical process called gram staining) damages the intestinal barrier leading to the entry of lipopolysaccharides (LPS- a component of the outer membrane of gram-negative bacteria) into the systemic circulation thus initiating an inflammatory response that can damage tissues and organs.
High sugar diet
High intake of refined sugars has been shown to bring about imbalances in the proportion of Proteobacteria and Bacteroidetes. A healthy gut has an abundance of Bacteroidetes and Firmicutes while the Proteobacteria are scarcely populated. These bacteria are well conditioned to the gut environment in such a way that they not only contribute to the gut health, but also to the overall health. The increase in the Proteobacteria (this phylum includes harmful bacteria like Salmonella, Escherichia, Vibrio) damages the mucosal lining of the gut adversely affecting the gut and overall health.
Popular diets
Studies have analyzed the effect of popular diets on the gut microbiome. The Western diet (WD) which is high in saturated fat, animal protein and low in fibre has been shown increase the vulnerability of the gut. In addition to the adverse effects of the high fat diet, the increased production of nitrosamines alters the gut health. These are chemical compounds that are present in processed meat, alcoholic beverages, cigarette smoke and cosmetics that increase the risk of cancers of digestive system, kidneys, bladder, lung, liver and brain.
The components of a Mediterranean diet (MD) are high fibre, healthy fats such as mono and polyunsaturated fats, rich in anti-oxidants and lesser amounts of red meat. This diet is regarded as healthy compared to the WD in terms of overall health benefits and gut health. Studies have shown that MD enhances the count of health promoting bacteria such as Prevotella, Bifidobacterium and Lactobacillus and brings about a reduction in the Clostridium.
The vegan and the vegetarian diets which are rich in plant foods and fibre content have been shown to contribute to a balanced gut microbiota. A higher proportion of Bacteroidetes, Lactobacillus and Bifidobacterium with concomitant reduction in the Enterococcus and Clostridium species have been noted with these diets.
A gluten-free diet (GFD) involves eliminating a protein called gluten that is present in wheat and other grains like barley and rye. It is recommended for those diagnosed with coeliac disease (CD), a condition wherein consumption of gluten causes digestive problems and damages the lining of the small intestine. In addition to the imbalances seen in the gut microbes in celiac disease, it has been hypothesized that a gluten free diet itself alters the gut microbial balance significantly. Hence a GFD may not be fully effective in restoring the gut health in those with CD. However, given the fact that a GFD is the only effective therapy, caution should be taken to enhance the nutritional balance in those following GFD. In normal individuals the effects of GFD on gut microbes has not been evaluated.
Food additives
The effect of food additives on the gut microbiota has been an area of recent research. Food additives can be categorized as artificial sweeteners, sugar alcohols, emulsifiers, food colorants, flavor enhancers, thickeners, anticaking agents and preservatives. Though more studies are warranted regarding the effects of artificial sweeteners on gut microbes, available data points that artificial sweeteners like aspartame, saccharin, sucralose, neotame and cyclamate cause dysbiosis of the gut microbes resulting in imbalances in the glucose levels.
The emulsifiers like carboxymethyl cellulose (CMC) and polysorbate 80 (P80) have been shown to affect the gut microbiota in recent studies. But these are in the preliminary stages and need more extensive research. However, the available data reveals that these emulsifiers have a potential to alter the gut microbiome leading to gut inflammation. Also, CMC has been linked to activation of flagellin (a protein present in the flagella of bacteria, which is a thin thread like structure that helps in movement) causing the bacteria to enter the mucosal layer leading to bacterial overgrowth in the gut.
The studies conducted on the effects of two food colorants, silver (E174) and titanium dioxide (E171), have revealed their potential to cause dysbiosis on long term exposure. While imbalances in the healthy bacterial colonies and inflammatory changes were noted, titanium dioxide was found to alter the production of short chain fatty acids by the gut bacteria.
The flavor enhancer monosodium glutamate (MSG) is a popular food additive known for its umami flavor. Apart from the four basic tastes, umami was internationally recognized as a fifth taste in the late 1900, which qualifies as ‘pleasant savory’ taste. MSG is used in canned foods, meat ball mixtures, soups, deli meats (precooked fresh or canned meat), meat bouillon (broth) and many processed foods. Generally regarded as safe, if taken in the recommended amounts (European Union Food Safety Authority recommends 30 mg/kg body weight/day as safe levels), recent studies have provided an insight to the effects of MSG on gut microbes. While a low dose could be beneficial for the gut health in terms of promoting good bacteria, higher doses could lead to gut inflammation and microbial imbalance.
There has been a difference in the outcome of studies conducted on the effect of food additives on gut bacteria. While majority revealed a negative influence, some have shown the potential of food additives towards promoting gut health. However, these findings need further evaluation.
Xenobiotics
The evolution of innumerable compounds in the light of scientific and technological advancements in the last few decades have influenced the human life in many aspects. The constant exposure to chemicals sourced from air, water, soil, food, plants and animals have posed potential threat to the safety and well-being of an individual. The term ‘exposome’ refers to all the external and internal challenges the human body gets exposed in a life time. While the external factors include the environmental, chemical and biological hazards, the internal factors are those relating to the microbiota, disease process, inflammation and oxidative stress.
The evidence behind the contribution of gut microbes towards the metabolism of xenobiotics was put forth about five decades back. However later studies have revealed that the metabolism of xenobiotics is mediated largely by the gut microbes compared to the human cells. The interaction between the gut microbiome and xenobiotics is reciprocal having an influence on each other in states of health and disease.
The exposure to xenobiotics has been shown to bring about changes in the gut microbiome. Some of the changes brought about by the xenobiotics are
Antibiotics
The administration of antibiotics has been shown to have an impact on the types of gut microbes. While it has been hypothesized that there is an actual increase in the bacterial load after antibiotic treatment, it is worth noting that these increases are due to the dominance of antibiotic resistant bacteria. Treatment with antibiotics like amoxicillin-clavulanic acid, vancomycin and gentamycin have been shown to increase the Enterobacteriaceae (E. coli, Salmonella) and reduce the Bifidobacterium species.
Also, the eradication of the healthy gut bacteria together with the damage to the mucus (inner lining) layer of the intestine results in so called antibiotic- associated diarrhea (AAD). Exposure to antibiotics early in life leads to dysbiosis increasing the risk of intestinal and systemic diseases such as inflammatory bowel disease (IBD), asthma and allergies.
Pesticides
Pesticides can be classified into three types namely; insecticides (control insects), herbicides (weed killers) and fungicides (destroys fungus). In addition to the occupational exposure, consuming contaminated food especially fruits and vegetables and drinking water makes an individual susceptible to its harmful effects.
The herbicides 2,4-dichlorophenoxyacetic acid (2,4-D) and glyphosate are usually mixed and used as a compound not only as an herbicide, but also drying of crops such as cereals, beans and seeds before harvesting. Occupational exposure to these herbicides has been shown to cause a reduction in the Firmicutes and Bacteroidetes in animal studies. In humans, the exposure to glyphosate negatively affects the human microbiome. With regard to the gut bacteria, it has been shown that 54% of the bacterial species are sensitive to this herbicide.
The insecticide chlorpyrifos (CPF) is one of the widely used organophosphorus pesticide and is commonly found in fruits and vegetables. The effect of the insecticide chlorpyrifos (CPF) on the gut microbiota has been studied in animal models. These have revealed that a chronic, low-dose exposure to this chemical brings about a reduction in the Lactobacillus and Bifidobacterium species. Also, changes induced in the metabolism of nutrients by the gut bacteria by CPF led to gut inflammation.
Fungicides are used to protect fruits, vegetables and the postharvest crops from getting spoilt. The studies conducted on the effects of fungicides carbendazim (CBZ), imazalil (IMZ), propamocarb (PM) and Epoxiconazole in animal models have revealed their adversities on the composition of the gut microbiota, lipid metabolism, production of short chain fatty acids and bile acid metabolism in addition to promoting gut inflammation.
Air pollutants
The effects of the air pollutants on the gut microbiota have been investigated in recent years. But these are still in the preliminary stages and needs further evaluation. However, available evidence suggests that continuous inhalation or ingestion of air pollutants brings about imbalances in the gut microbiota in terms of composition and diversity. Also, air pollutants have been shown to alter the production of metabolites like short chain fatty acids, lipids, amino acids and bile acids by the gut bacteria. These changes have been linked to obesity and type 2 diabetes.
Heavy metals
Exposure to high mercury levels sourced from contaminated fish has become a major environmental and health hazard. The sources of contamination can be either natural or man-made. Mercury sulfide or cinnabar is a natural source of mercury present in volcanic rocks and can be released into the air or water during the weathering (breaking down) of rocks. In addition to this, human activities such as burning of fossil fuels and industrialization are the other sources. The mercury which enters the water bodies from these sources is converted into methylmercury (Me Hg), a toxic form, which is easily taken up by the marine animals. This compound readily crosses the blood brain barrier and the placental barrier affecting the functioning of the brain.
There are only a few studies that have evaluated the effects of mercury on the gut microbiota. The alterations caused in the gut microbiota relates to the increase in the number of mercury resistant bacteria and significant reductions in the Bacteroidetes and increase in the Proteobacteria species (eg. Salmonella, Vibrio). In addition to this, mercury also has been shown to interfere with the production of neurotransmitters in the intestine. On the other hand, studies conducted in the pregnant woman have revealed that increasing the intake of probiotics can counter the adverse effects of mercury.
The exposure to cadmium and lead have been associated with negative health consequences such as anaemia, increased cancer risk, neurological and kidney disorders. The sources of these metals include agricultural fertilizers, mining, batteries, paint and electronic waste. Though more clarity is needed regarding the effects of these metals on the gut microbiota, some studies have revealed that cadmium has the potential to disrupt the gut microbiota by reducing the Bacteroidetes numbers. Also, a deceased production of short chain fatty acid especially butyrate, increases the vulnerability of the gut to inflammation.
Both short- and long-term exposure to lead have been shown to affect the gut microbiota in terms of health promoting bacterial imbalances and production of metabolites. However, more clarity is needed to ascertain the specific changes related to the gut microbiota.
Synthetic polymers
On a global note, the production of plastics has drastically increased in the last few decades. Having taken a prominent place in everyday life, its negative effects on the environment and health have been much propagated. On the other hand, concerns have also been raised about microplastics and nano plastics and their impact on environment and health.
Microplastics are defined as the tiny particles of plastic whose size is less than 5mm. They are of two types: primary and secondary microplastics. Some of the sources of primary microplastics are personal care products, textiles and various industries using plastic pellets for manufacturing process. Secondary microplastics are the remains from the broken bits of larger pieces of plastic. Nano plastics are derived from the disintegration of microplastics and their size range varies between 1-100nm.
The dangers of these plastics are that they remain in the environment indefinitely posing a threat to the environment as well as the terrestrial and aquatic life. In addition to this, the additives and chemicals present in these particles are released and further contaminate the eco system.
The effects of microplastics on gut microbiota is not well documented. According to the estimates, about 74000-113000 microparticles gain access into the human body every year. These numbers are dependent on the age and sex of the individual. Many studies conducted on animals have reported dysbiosis of the gut microbiota. But the available data from the human studies have revealed conflicting results. While there is a potential threat to the gut microbiota on exposure to microplastics, the ability of the gut bacteria to produce plastic-degrading enzymes was a significant finding showing their adaptive capability. While more studies are awaited, it is worth remembering the harmful effects of plastics and reduce their usage.
Lifestyle
Some of the lifestyle factors that contribute to gut dysbiosis are
Alcohol consumption
On a global note, the number of deaths as a result of alcoholism has risen significantly. An upward trend into the mortality rates and addiction has been noticed since the onset of covid-19 pandemic. According to the WHO estimates (2022), 3 million deaths occur worldwide as a result of alcohol abuse, accounting for 5.3% of all deaths. These figures are significantly higher in those aged 20-39 years.
It is a well-known fact that excessive alcohol consumption is associated with negative health effects. Alcoholic liver disease (ALD), which includes fatty liver, alcoholic hepatitis (inflammation of the liver), fibrosis (formation of scar tissue) and cirrhosis (extensive destruction of the liver tissue with scar formation), has risen to the status of a global health burden. Apart from affecting the liver, alcohol consumption makes an individual susceptible for cancer, cardiovascular diseases, pancreatitis, disturbances in the circadian rhythm (sleep wakefulness cycle) and altered immunity.
The relationship between alcohol consumption and gut dysbiosis has been an area of recent research. It is only in the last four decades studies have come up linking alcoholism to gut dysbiosis. The preliminary report regarding the effect of alcohol on the gut microbes was shown in the jejunal aspirates (fluids) of alcoholics. It was found that there was an increase in the population of gram-negative anaerobic bacteria compared to the normal individuals. In the years that succeeded, a number of studies were conducted regarding the effects of alcohol use disorder (AUD) and alcoholic liver disease (ALD) on gut microbes. In general, AUD refers to alcoholism, alcohol addiction, alcohol abuse and alcohol dependence.
Though most of the studies conducted in the initial stages showed imbalances in the Firmicutes and Bacteroidetes numbers, these findings were not convincing to ascertain the dysbiotic changes related to alcoholism. This is due to the fact that similar changes were noticed in obesity, intake of a high fat diet, aging and cardiovascular disorders. Also, in these studies the comparison in the gut microbial changes between alcoholics and non-alcoholics was at the phylum level (a higher ranking in classification of organisms).
On the other hand, a collection of studies which compared the gut microbial changes in those with AUD and ALD with those of non-alcoholics revealed more specific gut microbial changes as these studies analysed the microbial changes at the genus level (a ranking in the classification of organisms, lower than the phylum). A reduction in the number of gut health promoting bacteria like Faecalibacterium, Roseburia, Akkermansia and Bacteroides was noted. In addition to this, there was an increase in the number of harmful bacteria such as Streptococcus, Enterococcus and Proteobacteria (Salmonella, Vibrio, Escherichia).
The probable reason for these gut microbial changes is the increased production of unstable molecules called reactive oxygen species (ROS) secondary to excessive alcoholic metabolism in the gut. The accumulation of ROS molecules leads to cell damage.
A small number of studies have also explored the fungal microbial dysbiosis in individuals with AUD and ALD. Apart from bacteria, the gut microbial ecosystem also contains fungus, archaea and viruses, though bacteria dominate the picture. But most of the studies have focused on the fungal microbial changes at the genus level and hence fungal alterations specific to AUS and ALD have not been fully ascertained. However, these studies have noted higher numbers of the fungi Candida and Pichia in alcoholics, thus increasing the risk for fungal infections. Also, an increase in the population of a fungus called Debaryomyces in alcoholics could damage the intestinal lining and impedes healing of the intestines.
One of the possible reasons behind the fungal dysbiosis could be the presence of altered bacterial ecosystem, wherein the fungal colonies take an upper hand.
Alterations in the brain functions is a well-known consequence of AUD. In addition to the direct effects of alcohol on the brain, disruptions in the gut-brain axis contributes to the brain function alterations. The development of the leaky gut secondary to the intestinal mucosal damage leads to the escape of the microbial substances into the systemic circulation which in turn could affect the brain function. In addition to this, the increase in the number of harmful bacterial and fungal colonies and disturbances encountered in the production of short chain fatty acids and other metabolites impact the brain. Studies conducted on animal models have revealed that the increased presence of harmful bacteria such as Escherichia coli and Klebsiella in an alcoholic gut led to the development of anxiety.
A reduction encountered in the number of beneficial bacteria in an alcoholic gut means less protection to the brain. Evidence from the animal studies have shown that beneficial bacteria like Lactobacillus and Bifidobacterium are responsible for maintaining a balanced mental state, thus protecting from depression and anxiety.
The outcome from a recent study that was conducted less than a decade back on the effects of dysbiotic bacteria in encouraging alcohol intake revealed that individuals having a higher leaky gut had more neuropsychiatric problems and craving compared to those having a less leaky gut.
The gut dysbiosis also plays a role in the progression of alcoholic liver disease. In addition to the alterations in the bacterial and fungal diversity and the production of the health promoting metabolites by the gut microbes, individuals with alcoholic liver disease exhibit increased viral counts. Also, the presence of a leaky gut and disruptions in the bile acid metabolism has been shown to contribute to the severity of alcoholic liver disease.
Smoking
Cigarette smoking is one of the major causes of premature disease and death worldwide. According to the recent WHO statistics, there are 1.3 billion smokers worldwide. It is estimated that this global public health problem is responsible for more than 8 million deaths worldwide. Also, included in the above statistics is mortality due to passive smoking accounting for 1.2 million deaths.
In spite of strong scientific evidence and widespread awareness behind the health hazards of tobacco smoking over the last seven decades, it continues to be a major problem. Active smoking increases the risk of chronic obstructive pulmonary disease (COPD, wherein there is inflammation and obstruction of the airways), cardiovascular disease and cancer. On the other hand, passive smoking makes an individual more vulnerable for lung infections and worsening of asthma. In addition, smoking also contributes to the development of inflammatory bowel diseases (IBD- inflammation of the digestive tract involving small and large intestines).
The link between cigarette smoking and the gut microbial dysbiosis has been an area of recent research. Cigarette smoke contains innumerable chemicals such as nicotine, polycyclic aromatic hydrocarbons (PAH), nitrosamines, heavy metals and many others. In addition to being inhaled into the lungs, these chemicals enter the digestive tract by swallowing and negatively impact the gut microbial ecosystem.
Nicotine is one of the principal components of tobacco. On inhalation, it is fast absorbed in the lungs, skin and digestive system. Various lines of evidence from the human and animal studies have put forth the link between smoking and gut dysbiosis. Emerging reports have pointed to a reduction in the numbers of Bacteroidetes and Firmicutes and increase in Proteobacteria. Also, reductions in the short chain fatty acids and the Bifidobacterium numbers were noted. Smoking also increases the intestinal PH thus making it favorable for the survival of harmful bacteria.
Some of the polycyclic aromatic hydrocarbons include benzopyrene, coronene, anthanthrene and many others. They pose innumerable health hazards due to their toxic and carcinogenic effects. Though the evidence behind the effects of these compounds on gut microbes is sparse, some animal studies have revealed their negative impact on the diversity of the gut microbes. These studies have also shown that these compounds cause gut inflammation.
The exposure to volatile organic compounds like benzene in cigarette smoke has been linked to respiratory and cardiovascular diseases. Only very few studies have explored the possibility of gut microbial dysbiosis with benzene. These studies have revealed total disruption of gut microbial ecosystem and immune system imbalance with benzene exposure.
Cigarette smoke is also a source of aldehyde compounds and these enter the digestive system as tiny particles. The evidence behind the aldehydes and intestinal dysbiosis is scanty. However, acetaldehyde exposure has been said to cause gut inflammation and mucosal damage.
The toxic gases released from the tobacco smoke like carbon dioxide, carbon monoxide, hydrogen sulfide, ammonia etc, that are inhaled enter the blood stream through exchange of gases. They negatively impact the blood PH, oxygen transport, cause inflammation and many diseases. Though the effects of the toxic gases on gut microbes depends on factors such as tobacco manufacture and processing, there are reports linking carbon monoxide and hydrogen sulfide to gut dysbiosis and inflammation.
The effect of heavy metals on the gut microbiota has been investigated recently. Cigarette smoke contains heavy metals like cadmium, arsenic, lead, chromium, mercury, nickel and iron. Apart from being inhaled into the lungs, they also enter the digestive tract through swallowing. Reports from the preliminary studies have revealed gut microbial dysbiosis with heavy metal exposure. A reduction in the number of Firmicutes/Bacteroidetes, and increase in Proteobacteria, clostridia, Barnesiella have been noted. However, the gut microbial dysbiosis is dependent on factors such as type and duration of exposure.
Though evidence accumulated in the recent years have put forth the link between smoking and gut dysbiosis, more studies are warranted to expand the knowledge base regarding the mechanism behind this.
Stress
Stress is a state of physical, emotional and psychological strain that an individual feels in difficult situations. A well-coordinated reaction to stress involves the nervous, endocrine and the immune systems involving sympathetic-adreno-medullar axis (SAM), hypothalamus-pituitary-adrenal axis (HPA) and the immune system components. The SAM and the HPA axis are the important stress response systems that produce hormones namely adrenaline, noradrenaline (SAM axis) and glucocorticoids (HPA axis) thus enabling the body to adapt to a stressful situation. There is also activation of the immune system to fight against the harmful stressors (an agent causing stress).
The adaption of the body to a particular stressful situation is generally balanced in case of short exposure to the stressors. However, if the severity of the stressor is high and the exposure is recurrent (acute stress) or prolonged (chronic stress), there is an imbalance in the body’s adaptive mechanisms leading to negative health effects.
Both acute and chronic stress have been found to alter the gut microbial composition, in addition to causing inflammation and a leaky gut. It is said that the impact of stress on the gut microbes is as much as it is seen with a high fat diet. While the evidence behind the stress induced gut microbial changes is conflicting, the studies conducted have revealed a reduction in the Lactobacillus and Bifidobacterium and increase in the pathogenic bacteria such as Clostridium and Proteobacteria.
There are a few hypotheses that have been put forward to explain the reason behind the alterations brought about in the gut microbial composition due to stress. One possible reason is the stress induced dietary changes, wherein cravings and comfort eating shift the dietary pattern. Also, the elevated levels of the stress hormones encourage the growth of harmful bacteria. In addition to these, the changes in the gut motility (movement) and reductions in mucus production shifts the normal gut physiology making room for the growth of the unwanted bacterial colonies.
Recent lines of evidence from the animal studies point to the importance of gut bacteria in influencing the stress response in an individual. A balanced HPA axis response was noted in mice that were exposed to Bifidobacterium compared to the germ-free mice (sterile mice). Also, behavioral changes in the germ-free mice were noted when they were exposed to the microbes from patients with depression. These studies have provided insights to the role of gut bacteria in regulating the mood.
Sleep disturbances
Sleep can be defined as a natural process wherein the body and mind go into a state of rest for a time duration followed by awakening. A good quality sleep is essential for physical and mental well-being and is as important as food and water. Sleep is essential for the vital functions like development, conservation of energy, flushing out the brain toxins, balancing the immune system, cognition, performance and vigilance. Sleep difficulties lead to concentration and memory issues, low energy levels, lethargy, fatigue and emotional disturbances.
The sleep wakefulness cycle is regulated by the circadian rhythm, which is a 24-hour internal biological clock in the brain. Evidence accumulated from studies have revealed the role of gut microbes in regulating sleep. The gut microbes have been shown to exhibit circadian rhythm in line with the internal clock system. Studies have demonstrated that the gut microbes such as Lactobacillus, Firmicutes and Bacteroidetes show variations in numbers relating to the time of the day.
Researchers have identified the existence of the so called ‘sleep genes’ in humans showing that there is a genetic component related to sleep. The above-mentioned variations in the numbers of the gut microbes pertaining to the day and night cycle have been shown to schedule these genes in maintaining the normal circadian rhythm.
It is a well-known fact that the gut bacteria contribute to over 90% of the neurotransmitter serotonin produced by the body which plays a role in regulating the mood and sleep. It is also an important source of the hormone melatonin which has a key role in regulating the sleep wakefulness cycle. Recent studies have shown a direct relationship between the melatonin levels and the gut bacterial composition. Also, evidence from the upcoming studies have revealed that Firmicutes, Bacteroidetes and Actinobacteria produce gamma-amino butyric acid, a neurotransmitter which has a calming effect and enhances sleep quality.
The association between gut microbial dysbiosis and sleep problems is reciprocal. Disruptions in the circadian clock and sleep deprivation adversely affects the gut microbial composition. On the other hand, microbial dysbiosis causes sleep disorders. The postulated mechanisms behind these occurrences are that, disruptions relating to the circadian clock and sleep deprivation, impacts the gut bacteria and their metabolites. The gut is deprived off healthy bacteria such as Lactobacillus at the same time increasing the population of Enterococci, Lachnospiraceae and Ruminococcaceae.
On the other hand, the breakdown of the intestinal mucosal lining due to dysbiosis, causes the entry of harmful bacterial products into the circulation initiating an altered immune and inflammatory response. This impacts the functioning of the brain leading to sleep disorders.
Exercise
It is a well-known fact that regular exercise has a multitude of health benefits contributing to the overall physical and mental well-being. Evidence from the recent studies have supported the positive influence of exercise on the gut microbiota. Low and moderate intensity exercise on a regular basis has been shown to improve the diversity of the gut microbiota as well as the production of short chain fatty acids especially butyrate. This promotes the overall health of the colon as butyrate is an important source of nourishment for the cells of the large intestine.
On the other hand, intense physical exercise especially when not accompanied by cooling down breaks as well as psychological and physical stress as seen in competing athletes, adversely affects the intestinal health. In addition to promoting dysbiosis, the intestine becomes vulnerable to inflammation and injuries. Factors like increased levels of stress hormones (cortisol), muscle microtrauma (caused by the overuse of muscles wherein the changes can be seen microscopically) and an altered energy status in heavy physical exercise encourages the development of gut dysbiosis.
Gastrointestinal symptoms like nausea, cramps, diarrhoea, constipation, bloating and bleeding are quite common in athletes who are training intensely. Hence achieving an eubiotic state (a state of microbial balance) is essential for efficient performance.
The adverse effects of a sedentary lifestyle on the health and well being of an individual is well established in studies. An increase in the risk of cardiovascular diseases, type 2 diabetes, metabolic syndrome, obesity and non-alcoholic fatty liver disease is seen with physical inactivity. A combination of these risk factors along with unhealthy dietary habits increases the risk of gut microbial dysbiosis.
Environmental stressors
Heat exposure
Heat stress is one of the environmental stressors that has a negative impact on the health. Animals and humans have what is called as a ‘thermal comfort zone’ for normal functioning of the body. When there is increase in temperature beyond a certain level, the effects of heat stress begin to set in thus encouraging the growth of harmful bacteria. A reduction in the Firmicutes and increase in the Proteobacteria population has been noted.
A growing number of studies have revealed the link between exposure to heat and alterations in the gut microbial composition. The gut microbes have been shown to be sensitive to both the internal and the surrounding temperature fluctuations. Despite most of the evidence coming from animal studies, these findings have gained considerable attention because of their potential to speculate the weather and climate changes on the microbial ecosystem in humans as well. On the other hand, environmental variations in temperature have been shown to influence the gut function in many ways including digestion and motility. These alterations in the gut function have been shown to impact the gut microbes.
The mechanisms by which the changes in the temperature brings about gut microbial alterations is not fully known though much focus is laid on the disruption of the intestinal mucosal lining also called as the intestinal barrier. Exposure to heat directs the blood flow to the skin in order to promote heat loss. The consequence of this is an altered blood flow to the intestines that could contribute to disturbances in the mucosal lining.
Studies conducted on individuals with heat stroke have observed elevated plasma endotoxin levels (derived from the outer wall of the bacteria) which indirectly indicates a leaky gut. The plasma endotoxin levels reached normal levels after one hour of cooling but remained on the higher side compared to individuals at normal temperatures.
It has been proposed that the thermal (heat) treatments that are used for cancer, inflammatory conditions and psychological disorders like depression have the potential to alter the gut microbiota. However more studies are needed to ascertain this.
Cold exposure
Recent studies conducted on the relationship between the gut microbial composition and cold exposure have reported increase in the number and diversity of the bacteria Lachnospiraceae group (examples are Roseburia, Ruminicoccus), enhanced production of short chain fatty acids and an improved metabolic health in response to reduced body temperatures. This implies the adaptive response of the gut microbes in response temperature reductions.
However, chronic cold exposure and cold stress has been found to bring about reductions in the alpha diversity with disappearance of some bacterial species. Alpha diversity is the indicator of gut microbial health. Significant reductions in the Bacteroides and Firmicutes along with elimination in the Verrucomicrobia (includes gut health promoting bacteria such as Akkermansia muciniplila) were noted.
It is well known that the brown adipose tissue present in the body stabilizes the body temperature through heat generation during cold stress. Reports from the emerging studies have pointed to the role of gut microbes in aiding with heat generation through enhanced dietary energy production. Also, the fermentation of dietary fibre by the gut bacteria directly contributes to the heat production. Thus, in a dysbiotic microbial ecosystem there is tendency for a cooler body temperature and increased risk for hypothermia on exposure to cold.
High altitude
Oxygen is vital for survival and the efficient functioning of the organ systems in the body. Inadequate supply of oxygen in the blood (hypoxemia) and tissues (hypoxia) negatively affects the cells, tissues and organs resulting in permanent damage. Hypoxia can occur as a result of internal and external factors. For example, diseases affecting the heart and lungs constitute the internal factors and exposure to high altitude is one of the common external causes. Generally, altitude sickness occurs at heights above 2500m due to difficulties in adaptation.
The term altitude sickness refers to the condition caused as a result of walking or climbing the higher elevations due to changes in the air pressure and oxygen levels. Some of the symptoms of hypoxia include headache, dizziness, tinnitus (ringing sound in the ears), nausea and vomiting. Severe hypoxia leads to loss of consciousness, purple skin discolouration, blood pressure reduction, dilated pupils and coma.
Exposure to high altitude, thin air and low oxygen content negatively impacts the digestive system affecting the mucosal layer causing the shift of bacteria and dysbiosis. Studies have shown that intestines are one of the important organs involved in stress response. The alterations in the blood flow to the digestive system and slowing of the intestinal movements in altitude stress promotes colonic inflammation and brings about imbalances in the gut microbial ecosystem.
Studies conducted on individuals going on mountaineering in the Himalayas have revealed reductions in the beneficial Bifidobacterium species and increases in Proteobacteria especially E. coli at altitudes above 5000m. The reductions in the Bifidobacterium species have been said to contribute to the negative health effects in high altitudes.
On the other hand, differences in microbial composition have been noted in people living in high altitudes compared to those living in plains. However more studies are needed to ascertain the gut microbial composition in populations living in high altitudes.
Noise
Noise can be defined as a type unwanted, unpleasant and loud sound that adversely affects the health. The different types of noises are continuous (factory equipment, engine noise), intermittent (passing by trains and aircraft), impulsive (construction and demolition) and low frequency noise (common background noise encountered in everyday life such as those coming from the vehicles, air-conditioning units, wind turbines and so on).
Sounds exceeding 85 decibels are generally considered harmful. Prolonged exposure to noise leads to hearing impairment, hypertension, heart disease, sleep disturbance and irritability. Recent studies have investigated the effects of chronic noise exposure on the gut microbiota. The preliminary data that has emerged from the animal studies has reported alterations in the gut microbial composition.
Noise stress has been shown to cause disruptions in the gut-brain axis. Continuous exposure to noise brings about an inflammatory response in the nervous system and alterations in the neurotransmitter production adversely affecting the gut. On the other hand, the reductions in the population of butyrate producing bacteria and increase in the number of pathogenic bacteria such as Staphylococcus causes disruptions in the intestinal lining and inflammation. The reductions in the butyrate means, loss of protection to the intestinal cells increasing their vulnerability to oxidative stress (a condition caused by the accumulation of unstable molecules called free radicals). The combination of intestinal dysbiosis and oxidative stress further triggers gut-brain axis disturbances.
The above changes have been found to increase the risk of early onset Alzheimer’s disease in animal models. Hence these finding provide insights into the adverse effects of chronic noise exposure that can be applied to vulnerable individuals.
Hygiene
The term hygiene is defined as the practices that contribute to health and well-being as well as prevent the spread of diseases. Among the hygiene practices hand, household and food hygiene are the key hygienic strategies at the home and community level. Also, respiratory hygiene which includes turning away while coughing and sneezing, careful disposal of tissues, clean hands and self-isolation are the recommended measures for infected people.
Studies conducted on the effectiveness of house hold and food hygiene practices in developing countries have revealed their health boosting effects. However, encouraging to be ‘too clean’ or excessive hygiene might have some negative effects.
The concept of ‘hygiene hypothesis’ which was put forth more than three decades back states that an exposure to infections early in life through ‘unhygienic contacts’ prevents the development of allergies in old age. This concept was further expanded in the later years according to which reduced exposure to microbes early in life increased the risk of allergies and asthma. The reduced exposure conditions the immune system in such a way that it increases the risk of developing allergies. The alternative names that have been proposed to this hypothesis are ‘microbial exposure’ or ‘microbial deprivation’ hypotheses. Overall, the main aim is to not only acquire a strong immune system, but also a balanced microbial ecosystem.
The importance of hand hygiene dates back to several centuries wherein it was an integral part of religious and cultural ceremonies. However, the relationship between poor hand hygiene and the spread of diseases was put forth only a couple of centuries back. The discovery of microbes and the diseases spread by them provided further insights into the importance of maintaining hand hygiene. However, the evolution of the concept of microbiota and their indispensable role in human health has increased the awareness about beneficial microbes and the ways to promote them.
While it is a well-established fact that poor hand hygiene leads to the entry of harmful microbes and causes imbalances in the gut microbial ecosystem, over exaggeration of the hand hygiene practices has its own drawbacks. The excessive use of the cleaning products could lead to skin irritation, dryness and damage the skin. This makes the skin vulnerable for the growth of unwanted microbes. Most importantly it leads to the disruption of the skin microbial colonies which in turn affects the gut microbes.
But it is important to encourage and follow the recommendations of hand hygienic practices. However, care should be taken to avoid overuse of the cleaning products and minimising skin damage, keeping in mind about maintaining the skin microbial ecosystem.
It is well known that the oral cavity harbours the second largest microbial ecosystem next to the gut. Any imbalances in the oral microbiota as a consequence of periodontal disease, dental caries or oral cancers has been shown to negatively impact the gut microbes. The pathogenic oral bacteria Porphyromonas gingivalis and Fusobacterium nucleatum have been associated with not only oral but also gut dysbiosis.
In particular, the displacement of the bacteria P. gingivalis happens in the presence of chronic periodontitis wherein they are swallowed along with the saliva. In addition to this, they also gain access into the blood stream which triggers an inflammatory reaction affecting the organ systems.
Despite the existence of gut protective barriers such as the presence of acid in the stomach, health promoting gut bacteria and the gut immune system, oral bacteria can gain access into the gut and cause gut microbial dysbiosis leading to an array of negative health effects. The bacteria P. gingivalis has been shown to be tolerant to the acidity of the stomach. They are capable of rapidly multiplying in the digestive system replacing the healthy gut bacteria.
Gut Inflammation
The presence of gut inflammation as in the case of inflammatory bowel disease (IBD), infections, colonic cancer and food allergies triggers gut microbial dysbiosis. Evidence from the recent studies have revealed that the presence of inflammation encourages the ‘bloom’ of harmful bacteria. Bacterial bloom refers to the rapid increase in the unwanted bacterial colonies. In relation to the gut inflammation, enterobacterial blooms have been observed.
The Enterobacteriaceae group includes bacteria like E. coli, Klebsiella species and proteus species which constitute a minority of the gut bacteria. As a matter of fact, a sudden increase in their numbers or over growth is encountered in gut inflammation. The presence of gut inflammation is said to provide an ideal environment for their rapid growth as they are programmed to absorb nutrients from an inflamed gut. The bacteria E. coli that belongs to this group is known for its ability to flourish in an inflamed gut.
Aging
In the elderly people, the factor that possibly influences the health status and life span is the gut microbial composition. Even though the gut microbial composition changes in the elderly, the presence of a diverse beneficial bacterial population supports healthy aging. Factors such as diet, physical exercise, body mass index and the overall health status determines the diversity of the beneficial bacteria. Studies conducted on elderly people over the age of 65 have found that individuals who are lean and physically active had higher numbers of beneficial microbes compared to the individuals who were less fit and healthy.
On the other hand, studies also have shown aging as a risk factor for gut dysbiosis. Several factors such as lifestyle changes, level of nutrition, reduced mobility, age related changes in the organ systems, frailty and altered dental health affecting the fibre and protein intake lead to gut dysbiosis.
The gut microbial studies in the elderly can be divided into two types i.e., changes related to aging and changes related to age associated diseases. On a general note, in the elderly, there is a shift of the gut microbiome towards a more pathogenic side, which means that the gut in the elderly is dominated by bacteria which are responsible for inflammatory changes in the gut. The consequence of these changes is the reduction in the number of beneficial microbes like Akkermansia muciniplila and the short chain fatty acids producing bacteria, gut leakiness leading to systemic inflammation and premature death.
Genetics
awesome. Very well written