We do not live alone in our body. More than 50% of our cells are not human (1). They are microorganisms or, simply, microbes that have inhabited our body. Together with their genome, this collection of microbes is collectively known as the microbiome (2). In humans, the microbiome reaches the highest concentration in the gut, especially in the colon, and is made up mostly of bacteria, both good and bad (3).
Scientists have long known about the gut microbiome, but they’ve only recently begun to understand its importance. Some even consider it a virtual organ of the body (4). Human gut houses trillions of microorganisms (estimates vary between 40 to 100) that have up to 20 million genes (5) and weigh up to 2 kilograms. In comparison, the human genome only has 20000-25000 genes (6).
But why is the gut microbiome so abundant? Is it more than just something we flash away or does it do something that our body can’t? It turns out, it does: gut microbes are key to many aspects of human health including digestion, metabolism, brain function, mood and behavior, immune response, and even gene expression (7).
Gut Microbiome and Metabolism
The microbiomes basic job is to digest (ferment) a certain type of fiber called dietary fiber. Fiber is a natural compound found only in plants. From a nutritional point of view, fiber is a complex carbohydrate. But unlike refined sugar, fiber cannot be digested by our body, simply because it lacks the proper enzymes to do that. This fiber passes unchanged through the gastrointestinal tract, until it reaches the colon. Here, the microbiome converts it into compounds that can be absorbed by our colon, such as short-chain fatty acids (SCFA), certain B vitamins, and vitamin K (8).
The type of fiber feeding the healthy bacteria and has a beneficial role for the host has received the name prebiotic (9). It is found in whole grains, legumes, fruits and vegetables. Fiber isn’t the only prebiotic. Resistant starch found in foods like oats, rice, legumes, and potato is not fiber but behaves in a similar way. Plant photochemicals named polyphenols found in apple, pomegranate, blueberries, wine or dark chocolate are also prebiotics.
The current view in the microbiome field is that the more fiber/prebiotic we eat and the more divers it is, the better we feed and support the growth and diversity of healthy bacteria, which in turn suppresses the growth of pathogenic bacteria. At the opposite end there is loss of diversity in the microbiome, with unhealthy bacteria growing at the expense of healthy ones. This state is known as dysbiosis and can be caused by many factors, including stress, medication, and a diet that is rich in refined sugars and unhealthy fats, while poor in fiber (10).
Research has shown that gut microbiome composition differs in overweight versus thin individuals. A study published in Nature in 2013 showed that obese participants examined over the course of nine years had a relatively low diversity in their microbiome, correlated with increased weight throughout the study period (11). Not only an altered gut microbiome connects with obesity (12), but also with insulin resistance and diabetes (13).
Perhaps one of the best direct correlations between gut microbiome and metabolism was published in 2013 in Science (14). Researchers selected four pairs of identical female twins (to rule out any potential genetic differences); of each pair, one twin was obese, while the other one was thin. From these twins, they performed fecal transplant to microbiome-free mice. As a result, the mice that received fecal transplant from the obese twin gained weight, while the other one remained thin. Furthermore, to rule out the possibility that diet might be a factor for the mice to gain weight, researchers fed all mice on a correct diet, low in fat and rich in fiber.
Studies show that weight loss achieved across a range of diets is typically regained. There are estimates that 60-80% of people who lose weight following a conventional low carb-low fat diet would regain in the next 5 years more weight than they lost (15). However, a diverse, fiber-rich diet that supports a healthy microbiome makes people lose weight and remain lean without having to count calories (16, 17).
There is evidence that gut microbes produce metabolites, which control the release of hormones that regulate appetite (18). Scientist have also come up with the hypothesis that the gut microbiome might even control cravings (19). For instance, when we crave for chocolate, that is code for gut microbes signaling to our brain for it. However, scientific evidence to support this idea is only circumstantial: people who desire chocolate have different microbial metabolites in their urine than “chocolate indifferent”, despite eating the same diets (20).
Gut Microbiome and the Brain: Cognition, Mood, Behaviour
The nervous system and the gastrointestinal tract are communicating through a two-way network of signaling pathways called the gut-brain axis, which consists of multiple connections, including the vagus nerve, the immune system, neurotransmitters, hormones and signaling molecules (21). The gut is actually considered the second brain (Michael Gerson, The Second Brain, 1998) and it contains even more nerves than the spinal column.
How do we know that gut microbes can influence the brain function? Rats and mice given fecal transplants from people with Parkinson’s, schizophrenia, autism, or depression often develop the rodent equivalents of those problems. Conversely, giving those animals fecal transplants from healthy people sometimes relieves their symptoms (22). The presence or absence of certain microbes in young mice affects how the mice respond to stress as adults (23), and other studies in mice have pointed to a role of the gut microbes in the development of the nervous system (24).
Certain gut cells produce neurotransmitters, those important biochemicals that the brain needs in order to regulate thought and emotion. For example, serotonin is a crucial neurotransmitter regulating learning, the feelings of happiness, anxiety, sleep and other neurological functions. Serotonin is involved in other physiological processes as well, including gastrointestinal secretion and motility, respiration, vasoconstriction. While serotonin is broadly used throughout the body, 90–95% of serotonin is produced in the gastrointestinal tract (25, 26).
When the microbiome is disrupted, the gut is not functioning properly, hence it cannot synthesize enough of serotonin or other neurotransmitters. Microbiome-free mice have a significant reduction of serotonin level in the blood and colon. Serotonin levels can be restored if these mice are recolonized with a microbiome (27).
Disrupted serotonin levels are accompanied by feelings of sadness, hopelessness, insecurity, anxiety, agitation, insomnia, and digestive issues. Low serotonin levels can lead to depression (28). Research in humans has shown that people with depression lack the same two bacterial strains in their gut (29). Many depressed people also struggle with irritable bowel syndrome (30).
The precursor of serotonin is tryptophane, which some gut bacteria produce. Cells can also turn tryptophan into a substance called kynurenine, which reacts further to form products that can be toxic to neurons. Research has shown, for example, that people with depression convert tryptophan into kynurenine more readily than into serotonin (31).
Dopamine is another example of neurotransmitter that is affected by the gut microbiome diversity (32). Dopamine is described as a main regulator of cognitive functions such as memory, attention, decision making, motivation and reward, but it has also been involved in emotion or food intake. Dysregulation of the dopamine system has been linked to anxiety and depression, but also to gut microbes via the vagus nerve-mediated gut-brain axis (33). Fifty percent of dopamine is actually produced in the gut (34), which might explain why gut microbiome could alleviate anxiety and/or depression-like behavior in mouse models of depression induced by decreased dopamine levels (33).
Emerging data not only support the role of gut microbiome in influencing anxiety and depressive-like behaviors as described above, but also in eating disorders (35), autism (36), and brain aging (37). The later has been concluded from several studies, of which the most recent, published in Nature Aging in 2021, shows that microbiome transplant from young mice to old mice reversed many of the effects of aging on learning and memory (37).
Gut Microbiome and Immune System
Surprisingly, our gut is a crucial part of the immune system. Actually, 70-80% of the immune system is located in the gut itself. Separated from the gut internal milieu by a single layer of cells, the immune system has the enormous task to protect the body from bacteria, viruses or toxins that enter the gastrointestinal tract.
The gut microbiome is key to proper immune system development and maintenance and studies show that having the wrong mix of microbes can derail that process and promote inflammation (38). In a dysbiotic state, the colon wall is no longer protected against the “bad guys” and the result is increased intestinal permeability or “leaky gut” that allows contents such as bacterial molecules (endotoxins), as well as bacteria themselves to leak through the intestine into the systemic circulation. Bacterial escape from the gut is the root cause of inflammation.
Inflammation caused by increased intestinal permeability affects the function of intestinal lining, leading to diarrhea or constipation, bloating and abdominal pain, which are all hallmarks of irritable bowel syndrome (39). There is increasing evidence that inflammation is associated with weight gain, obesity, and insulin resistance (40). Mice that are obese as a result of a high-fat diet also have increased levels of endotoxemia, inflammation, and gut permeability, which are reduced by manipulating the gut microbiota with antibiotic treatment (41). Moreover, the inflammation triggers an overproduction of insulin (the hormone that regulates the blood sugar), causing the body to store fat instead of burning it (42), and impacts signaling to satiety hormones, maintaining a feeling of hunger (43).
Increased intestinal permeability disturbs the host immune system, which has been demonstrated in inflammatory bowel disease, diabetes, allergies, neurodegenerative disorders, cancer, and multiple autoimmune disorders (44, 45, 46, 47). Autoimmune disorders are characterized by the generation of antibodies that attack the body’s own tissues, resulting in damage. In other words, the immune system creates inflammation that attacks not only the gut, but also the brain and other parts of the body.
Research has shown that probiotics (a certain type of good bacteria) can reverse the leaky gut (48), supporting the role of gut microbiome in maintaining the integrity of the intestinal epithelial barrier and therefore regulating what molecules enter the circulation via the gut (49). Here is how it works…
On the bright side, the gut microbiome has the capacity to modify the chemical structures of numerous dietary molecules, thus preventing the immune system to see them as enemies. One study showed that the microbiome can actually break down gluten and therefore reduce its capacity to induce an immune reaction in humans (50).
Note that food sensitivity is not the same as food intolerance or food allergy (51). Food sensitivity causes symptoms such as abdominal pain, joint pain, fatigue, rashes and brain fog. It is not life-threatening and can be reversed through elimination-reintroduction diets. Food intolerance does not involve the immune system. It is caused by the inability to digest certain foods. The best known is lactose intolerance, which is due to the fact that, with age, our gut cannot make enough of the enzyme that processes lactose, a type of sugar found in milk and dairy products.
Food allergies involve a very strong and fast reaction of the immune system to foods such as peanuts or seafoods and can be life threatening. Symptoms of food allergies include rashes, swelling of the face and throat, and breathing difficulties that can lead to anaphylactic shock. Celiac disease is an immune reaction to gluten, a protein found in wheat, barley and rye. In people with celiac disease, eating gluten triggers an immune response in the small intestine that, over time, damages the intestine and prevents it from absorbing nutrients (52). It is also a genetic disease, meaning that one must carry the gene in order to develop the disease. However, one can be gluten sensitive without having celiac disease.
Gut Microbiome Meets Estrogen
The gut microbiome has been shown to be influenced by estrogen, but also to significantly affect estrogen levels. When inactive estrogen makes its way down to the intestine for elimination, a special microbiome population called estrobolome breaks down estrogen into its active form, which is reabsorbed into the circulation. In a dysbiotic state, this process is impaired, resulting in a reduction of circulating estrogens. The alteration of circulating estrogens may contribute to the development of obesity, metabolic syndrome, endometriosis, polycystic ovary syndrome, infertility, cancer, endometrial hyperplasia, cardiovascular disease or cognitive function (53).
Short Chain Fatty Acids (SCFA)
SCFAs: acetate, propionate, and butyrate are the main metabolites produced in the colon by bacterial fermentation of dietary fiber and resistant starch, and are thought to play essential roles in health and the development of disease (54).
SCFA are absorbed by the colon, of which they represent the dominant source of energy. They also make the colon more acidic, preventing the growth of inflammatory, pathogenic bacteria (55). SCFAs prevent or repair leaky gut and protect from intestinal inflammation (56). Butyrate has been shown to reduce abdominal pain associated with irritable bowel syndrome (57), by increasing intestinal motility (58). Butyrate is also known to inhibit tumor formation and might play a role in reducing the risk of colorectal cancer (59). SCFA that are not metabolized in the colon are transported to the liver and used as an energy source. In addition, acetate is used in the synthesis of cholesterol and fatty acids (55).
Numerous studies have demonstrated that increased intake of dietary fiber reduces the risk for developing irritable bowel syndrome, inflammatory bowel disease, cardiovascular disease, diabetes, and colon cancer, possibly by changing gut microbiome composition and diversity with increased production of SCFAs (60, 61 and references within). Animal studies suggest that SCFAs have an important role in the prevention and treatment of obesity associated with insulin resistance (62). They have also been involved in the control of appetite and fat burning (63).
Recent findings support the hypothesis that butyrate might contribute to the development of immunological tolerance to food, especially in the first 3 years of life, and in the prevention and treatment of food allergies (64).
In addition to their local role in the colon and in metabolism, SCFA are one way the gut communicates with the brain (65). SCFA play an important role in maintaining the integrity of the blood-brain barrier that controls the passage of molecules and nutrients from the circulation to the brain (66). Through interactions with the gut-brain axis, SCFA can directly or indirectly affect emotion, cognition, sleep, and pathophysiology of brain disorders, including but not limited to autism, depression, Alzheimer’s disease, and Parkinson’s disease (67). Immune responses and inflammation might also be involved in the pathogenesis of psychiatric disorders. SCFA are thought to reduce inflammation either indirectly, by improving intestinal barrier as we have seen, or through a direct interaction with immune cells (68).
Take Home Message
The composition of the microbiome can change as rapidly within 24hrs, reaching an imbalance called dysbiosis in response to stress, medication or major illness. Conversely, it can rebalance in just a few weeks through a healthy diet. That is, a diet high in prebiotics, as well as probiotics or good bacteria found in fermented food such as yoghurt, kefir or sauerkraut, to name a few.
At the opposite end of prebiotics is the Western diet, rich in refined sugar, processed food, meat and dairy products. When consumed regularly, the later not only causes a loss of diversity within the gut microbial community, but also the rise in pathogenic, inflammatory bacteria.
However, consumption of industrialized food is only one of the factors that account for the worrying increase in allergies, autism and autoimmune disorders in the Western world over the last few decades. Additional factors may include Cesarean delivery, antibiotics, pesticide exposure, and infant formula feeding (69, 70).
Understanding the human microbiome is rapidly transforming our understanding of diseases ranging anywhere from inflammatory bowel disease to obesity, diabetes, autoimmune disorders, allergies, asthma, depression, anxiety, autism, Alzheimer’s disease, Parkinson’s disease or even cancer, and the list does not stop here.
In other words, intestinal health is absolutely crucial to our metabolism, appetite, weight, but also mood, appearance, energy level, and ability to withstand stress, infection, and malignancy.
Basically, our overall health depends on the health of the gut microbiome.
Featured image by Kindel Media on Pexels.
Article first published HERE and reproduced with permission by the author.
Author:
Dr. Viorica Ivan
Dr. Viorica Ivan is a holistic nutrition & stress coach, scientist, and science writer. She has a PhD in cell biology from Utrecht University, the Netherlands. Viorica is the founder of Smart Science Holistic Health, a health & nutrition coaching service provider. Her mission is to educate and help women manage stress, break free from stress-associated digestive upsets, and nourish their body and mind with real food, exercise, meditation, new patterns of thought and emotion. Viorica is passionate about nutrition science, sports, cooking, and gardening. Connect with Viorica on her website or Facebook page.
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