A healthy gut microbiome produces short-chain fatty acids (SCFAs) essential for immunity and health

A healthy gut microbiome helps produce short-chain fatty acids that are so important for our immune system and our overall health.

The gut microbiome (or more accurately, the gut microbiota) is the community of the trillions of microbes that co-exist with us in our digestive tract. Each person harbors hundreds of species of bacteria in the gut, primarily the large intestine (1). In fact, the total number of bacteria in the human body is larger than the number of our own cells (2)!

Short-chain fatty acids (SCFAs) are produced in the gut when beneficial gut microbes ferment the plant fibers that we eat. Our digestive tract inherently does not produce the enzymes necessary to completely break down dietary plant fibers. So when these fibers reach the large intestine, microbes living there helps us “digest” these fibers into simple sugars, which are then fermented by the beneficial bacteria (“good bacteria”) to yield short-chain fatty acids and other metabolites. Acetate, propionate, and butyrate are the three main short-chain fatty acids that play critical roles in maintaining gut health, regulating the immune system, and influencing our overall health (3, 4).

A promoter of gut health

Short-chain fatty acids are important for maintaining gut health because they are the main energy source for the cells that line our large intestine (the epithelial cells) and they help maintain an intact gut barrier, preventing “leaky gut” (1). At the same time, SCFAs also feed the beneficial bacteria in the gut, continuing the positive cycle. In fact, the gut microbes are an amazingly collaborative community: certain microbes serve as the primary fiber degraders at the top level of fiber breakdown, some of the breakdown products become available to secondary fiber degraders, and other cross-feeding microbes make use of some of the fermentation products generated by fiber degraders (4). This web of interactions between different gut microbes contribute to shaping the gut microbe ecosystem, which, in turn, can influence the sum of SCFAs produced in the gut.

Not surprisingly, the amount and type of fibers entering the large intestine are important in determining SCFA production, and a diverse range of polysaccharides (long-chain carbohydrates) liberated from fibers likely promotes a diverse gut microbiome, which is associated with health. What’s more, the SCFAs produced by the beneficial bacteria also help to prevent harmful bacteria from taking residence in the gut (4).

While most cells in the body use glucose (sugar) for energy, the cells that line our large intestine use a type of SCFA called butyrate as their main fuel source rather than glucose (1). In fact, because glucose cannot substitute for butyrate as an energy source for cells of the large intestine, the intestinal cells are dependent on the gut microbes to produce the SCFAs for their health and survival. So, when levels of SCFAs in the gut are reduced as a result of a disturbed or “unhealthy” gut microbiome (called dysbiosis), the health of the intestinal cells is compromised, leading to “leaky gut” and even cell death (3).

In contrast with healthy cells of the large intestine (colon), cancer cells do not use butyrate efficiently for energy. When butyrate accumulates inside colon cancer cells, it inhibits their growth and promotes the death of cancer cells (4). This fact illustrates an important point about the crucial role of SCFAs in the gut: they foster the proliferation of healthy cells in the colon, but they cause colon cancer cells to die. It is not surprising, then, to find that lower fecal SCFA levels correlate with a higher risk of developing colon cancer (4). This is one of the many reasons why an integrative medicine and functional medicine approach that addresses gut health is fundamental to our wellbeing at so many levels.

A basic function of the digestive tract is to mix the intestinal contents and propel them forward to aid digestion and absorption—we call this physiologic process “gut motility.” SCFAs have a role in promoting gut motility. In clinical research, fecal propionate and butyrate (which, as we mentioned above, are specific SCFAs) were found to be lower in people with the type of irritable bowel syndrome (IBS) where constipation predominates, while fecal butyrate was higher in people with the diarrhea-predominant type of IBS (4). Serotonin, a neurotransmitter thought to play a role in depression and anxiety, also plays a role in gut motility. About 90% of the body’s serotonin is actually produced in the gut, and SCFAs promote serotonin production (5), affecting gut motility through this and other mechanisms.

Protection against leaky gut

“Leaky gut” is a colloquial term for what researchers describe as increased intestinal permeability or compromised intestinal barrier integrity. The normal intestinal barrier contains a layer of cells that line the intestines (the epithelial cells) and are tightly connected to each other by what’s called tight junctions. A protective mucus gel layer lies on top of this layer of cells. A healthy gut barrier allows nutrients to be absorbed from the intestines into the bloodstream while preventing undesirable contents to be transferred or “leaked” from the intestines into the body’s blood circulation, such as microbes, bacterial endotoxins, and incompletely digested food fragments that can serve as antigens to trigger an inappropriate immune response (6). “Leaky gut” occurs when the integrity of this gut barrier is compromised, allowing potentially harmful materials to gain access to the bloodstream.

Research has linked “leaky gut” with many diseases, including inflammatory bowel disease, celiac disease, irritable bowel syndrome, cardiovascular disease, and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, lupus, and type 1 diabetes.

SCFAs maintain gut barrier integrity and help prevent “leaky gut.” They do so in many ways, such as 1) increasing the production of the proteins that form the tight junctions between the cells lining the intestines, mentioned above, 2) regulating the turnover of the cells lining the intestines, and 3) promoting the production of antimicrobial factors (3).

Immune system effects

SCFAs have anti-inflammatory properties (3). Research has shown that they impact the body’s production of inflammatory proteins called cytokines to dampen inflammation. For example, in active inflammatory bowel disease (such as Crohn’s disease and ulcerative colitis), there is a reduced level of fecal SCFAs because there is a decreased abundance of the “good bacteria” in the gut that produce them. Interestingly, oral preparations of butyrate in clinical research studies have shown some benefits in patients with ulcerative colitis and Crohn’s disease, but further studies are needed (4). (We talk about the pitfalls of “medicinalizing” such a natural substance as SCFA below.)

The colon is the richest source of SCFAs in the body. Some of these SCFAs are sent to the liver, and a small amount is released into the bloodstream. Importantly, SCFAs that are produced in the gut affect immunity elsewhere in the body, including the lungs, liver, reproductive tract, and brain. Reduced levels of SCFAs are associated with autoimmune diseases, food allergies, asthma, Alzheimer disease, Parkinson disease, chronic kidney disease, and many other conditions (3).

For example, in multiple sclerosis, an autoimmune disease, fecal levels of the SCFA butyrate are low, and fecal levels of the bacteria that produce butyrate are low as well. In autoimmune type 1 diabetes, levels of butyrate-producing bacteria are reduced in people with this disease, and giving mice the SCFAs butyrate and acetate protected them against diabetes (3).

Food allergy, asthma, and eczema in children are associated with decreased levels of butyrate-producing bacteria that are part of the gut microbiome. High fecal levels of SCFAs in children are linked to a decreased risk of food allergy. On the other hand, low fecal butyrate levels in early life are associated with food allergy later in life. Researchers think that the presence of butyrate in human milk influences the infant’s immune system in such a way that protects them against the development of food allergy (3).

Effects on metabolism and cardiovascular health

Beyond their beneficial effects on gut health and the immune system, SCFAs also affect our body’s metabolism and contributes to cardiovascular health.

A research study published in the prestigious journal Nature showed that people with type 2 diabetes have a moderate degree of disruption in the gut microbiome and a reduced abundance of some gut bacteria that produce the SCFA butyrate (7).

Higher fasting blood levels of SCFAs are associated with higher levels of GLP-1 (8). (GLP-1, which stands for glucagon-like peptide-1, is a hormone that helps control blood sugar, slows stomach emptying, and reduces food intake. GLP-1-based medications for diabetes and weight loss work through this mechanism.) SCFAs bind to specialized cells in the gut that secrete GLP-1, and higher production of SCFAs by beneficial bacteria in the colon is associated with increased GLP-1 secretion (9). Therefore, a healthy gut microbiome that optimally produces SCFAs is naturally doing the kind of work that GLP-1 weight-loss drugs attempt to mimic!

SCFAs lower blood pressure and have other beneficial cardiovascular effects. In laboratory experiments, giving mice the SCFA propionate reduced hypertension and susceptibility to dangerous abnormal heart rhythms, and decreased the size of plaques in arteries (10).

Gut-brain connection

The gut-brain connection is a two-way communication network between the gut and the brain. The communication happens through various pathways, including nerves, hormones, immune system, and metabolic signals. SCFAs may influence the gut-brain connection directly or indirectly through these pathways (11). However, most research in this area has been done using animal models, so more research is needed to better understand the role of SCFAs in human brain function.

According to animal-based research, SCFAs can affect the gut-brain connection and influence nerve functioning, learning, memory, and mood. The vagus nerve is a long nerve that connects almost all of the digestive tract with the brain, and SCFAs may directly activate the vagus nerve to suppress appetite (11).

SCFAs may have protective roles in the human brain. For example, individuals with Parkinson disease have decreased fecal levels of SCFAs and an altered gut microbiome compared with healthy controls (12).

An interesting human study randomly assigned 20 healthy men to receive either an intervention that increased the large intestinal production of the SCFA propionate (experimental intervention), or a control intervention. The men then underwent functional MRI imaging of their brain while they looked at images of pleasurable, high-calorie foods. Afterward, they were given a buffet meal. The study results showed that in the men who received the experimental intervention, the parts of their brain associated with reward responses (which drive the pleasure-seeking behavior to eat calorie-dense foods) did not light up as much on the MRI when they were looking at the high-calorie food images, compared with the controls. In other words, the MRI brain images showed that higher SCFA production in the gut reduced the enticing effects of calorie-dense foods on the brain. Subjectively, these men also rated the high-calorie foods as less appealing, and at the buffet meal, their calorie intake was significantly lower (13).

Another similar study showed that a prebiotic intervention given to overweight young adults changed the gut microbiome toward an increased abundance of bacteria that produce SCFAs. Brain functional MRI in these study participants showed that the areas of the brain involved in reward processing and pleasure-seeking of high-calorie foods did not light up as much as the controls (14). In other words, a higher abundance of gut bacteria that produce SCFAs naturally diminished these young adults’ desires for such unhealthy foods.

Effects on cancer

Beyond its protective effect against colon cancer as we discussed above, the SCFA butyrate has beneficial effects in cancers of the breast, liver, lung, cervix, and bladder. In addition, butyrate can alleviate the side effects of chemotherapy (4). Higher levels of SCFAs are associated with better responses to various cancer therapies, including chemotherapy and immunotherapy. Given these observations, researchers suggest that “manipulating” SCFA levels in combination with cancer therapies may be a useful therapeutic strategy (3). However, as we will discuss below, an optimal path to health avoids the pitfall of taking a constricted, reductionistic route in disease treatment—such as the use of a single agent, be it a drug or even a substance such as SCFA—and values a holistic, integrative medicine approach that restores the gut microbiome and the body’s full potential to produce SCFAs and optimizes the immune system in many other ways not even considered in this blog.

Environmental factors that influence the gut microbiome and SCFA levels

Many environmental factors affect the makeup of the gut microbiome and, in turn, the production of healthful SFCAs in the gut. Some of these factors include the delivery mode at birth, type of feeding (breastfeeding or formula), diet, antibiotic use, environmental pollutants, infections, and social stress—which, in the functional medicine framework, can be classified as antecedents, triggers, and/or mediators of physical dysfunction or disease (15).

For example, the gut microbiome of a newborn baby is affected by the delivery mode. When a baby is delivered vaginally, the mother’s vaginal and gut microbiomes contribute beneficial bacteria to the baby’s developing gut microbiome (including Lactobacillus, Bifidobacteria, and Bacteroides). On the other hand, when a baby is delivered by cesarean section, the mother’s skin microbiome contributes to the baby’s gut microbiome (primarily Staphylococcus bacteria, which are not significant SCFA producers) (3, 16), and the baby’s gut microbes, therefore, will have a reduced ability to produce SCFAs. Cesarean delivery is associated with the baby’s increased risks of immune system-related diseases, including allergy, asthma, celiac disease, and type 1 diabetes (16). This observation is not surprising, given the immune system effects of SCFAs as we just discussed above.

Breastfeeding also affects the infant’s gut microbiome. Interestingly, the gut microbiomes of infants who were fed a combination of formula and breast milk were very similar to those of infants who were fed formula exclusively, rather than being similar to infants who were breastfed exclusively. In other words, exclusive breastfeeding shapes the gut microbiome uniquely. Research has linked breastfeeding with lower risks of asthma, infection, metabolic syndrome, diabetes, and obesity, compared with formula feeding (16). The disruption of the gut microbiome (dysbiosis)—resulting in the depletion of beneficial bacteria that produce SCFAs—plays a significant role in these diseases.

Because dietary fibers are broken down and fermented by beneficial gut bacteria to produce SCFAs, it comes as no surprise, then, that diets high in fruits, vegetables, whole grains, and legumes are associated with an increase in intestinal SCFA levels. On the other hand, a typical Western diet—with a high intake of processed foods, red meat, saturated fats, and refined carbohydrates and low intake of whole plant foods—delivers only limited fermentable nutrients to the gut microbes for SCFA production. Such a diet is associated with low levels of SCFAs in the stool and blood (3).

While antibiotics are important in treating bacterial infections and can be lifesaving, its use causes dysbiosis in the gut. In research on mice, antibiotics reduced the levels of SCFAs in the gut. In epidemiological studies, antibiotic use in early life is associated with inflammatory diseases such as asthma and inflammatory bowel disease later in life (3). A well-known potential adverse effect of antibiotics is an infection in the colon called C. difficile colitis that results from a disruption of the normal gut microbiome and can be potentially serious for some people. For these and other reasons, during and after a patient’s antibiotic treatment course, integrative and functional medicine interventions that aim to restore the gut microbiome are crucial to short-term and long-term health.

Environmental toxicants such as air pollution, heavy metals, pesticides, and “forever chemicals” are associated with dysbiosis (as we discussed in a previous blog) (17). In a study that enrolled more than 100 healthy men, cigarette smoking and alcohol consumption was linked to altered gut microbiome and decreased SCFA levels (18).

COVID-19 is another environmental factor that affects the gut microbiome and SCFA production. It causes a depletion of bacteria that produce SCFAs, while promoting the growth of harmful bacteria in the gut. People with severe COVID-19 were found to have much lower fecal SCFA levels, which remained reduced for more than 30 days after the disease had resolved (3).

Social stress also disrupts the gut microbiome (3), and a laboratory study using mice showed that stress exposure reduced levels of beneficial SCFA levels in the colon (19).

Acupuncture effects on the gut microbiome and SCFA production

Acupuncture treatment is an important part of an integrative and functional medicine approach to health and has been extensively studied across a wide spectrum of diseases and conditions. Research has shown that acupuncture changes the gut microbiome composition in many diseases. Most remarkably, acupuncture appears to change the gut microbiome in the direction that restores the disruption back to a healthy state, rather than indiscriminately changing parameters in only one direction, as conventional pharmaceutical treatments tend to do.

For example, two major groups of bacteria in a normal gut microbiome are called Firmicutes and Bacteroidetes, and in healthy people, they coexist in a balanced proportion, which some researchers characterize as the Firmicutes to Bacteroidetes ratio, or F/B ratio for short. Inflammatory bowel disease (such as ulcerative colitis) is often, but not always, associated with a decreased F/B ratio (that is, there is a lower abundance of Firmicutes bacteria relative to Bacteroidetes) (20). On the other hand, obesity is often, but not always, associated with an increased F/B ratio (higher abundance of Firmicutes relative to Bacteroidetes), and the ratio falls with weight loss (21). (Lactobacillus, often found in probiotic supplements, belongs to the Firmicutes group.)

In a study of studies that reviewed the results from 20 animal studies and 3 human studies on the effect of acupuncture on the gut microbiome, researchers concluded that acupuncture significantly influences the gut microbiome and is able to change the relative abundance of bacteria such as Firmicutes and Bacteroidetes to restore balance in the gut microbiome (22). In animal studies on colitis that investigated the effects of acupuncture, the microbiome F/B ratios changed inconsistently with the disease across studies, but regardless of the direction of the change, acupuncture treatments reversed the changes in the F/B ratio, while improving colitis severity and levels of inflammatory markers. In animal experiments on obesity, acupuncture treatments decreased the relative abundance of Firmicutes in obese subjects (in other words, moved it in the right direction toward normal) (22).

Given the beneficial effect of acupuncture on the gut microbiome, research also shows unsurprisingly that acupuncture improves SCFA production. In a study that enrolled 80 people with functional constipation, acupuncture treatment was associated with an increased abundance of beneficial bacteria such as Lactobacillus and increased levels of the SCFA butyrate in the gut, which correlated with an improved frequency of bowel movements (23). In a mouse model of Alzheimer disease, diseased mice had decreased cognitive ability, decreased SCFAs in feces and blood, and leaky gut, but acupuncture treatments reversed all of these changes, including reversal of the decreased SCFA levels (24).

A holistic approach to health

An integrative medicine and functional medicine approach to health includes considerations for the role of the gut microbiome and SCFAs in immune system regulation, disease prevention and management, and overall health.

“Food as Medicine” is an important part of a holistic medicine approach to health. The example of the science behind the many health benefits of SCFAs as we just described illustrates how the food we eat every day can influence the body’s health at so many different levels, amazingly more so than any single medication can do—and without the medication side effects.

Dietary interventions can reliably modulate SCFA levels and affect health in a fundamental way. As an example, in a small randomized trial, a diet high in fermented foods promoted the diversity of the gut microbiome and reduced markers of inflammation, while a high intake of plant fibers increased the production of SCFAs (25). The use of integrative and functional medicine principles to restore gut health, including the clinical use of “food as medicine” interventions, can promote a sustainable optimization of the gut microbiome and, in turn, healthful levels of SCFAs.

Now a caveat: While SCFAs have many health effects, which ongoing research continues to bring to light, it may be tempting to consider the use of SCFAs as a dietary supplement or even a drug. However, an attempt at “medicinalizing” such a natural substance as SCFA is a reductionistic approach rather than a holistic approach. Without addressing the root cause of the imbalance or dysfunction that led to the disrupted microbiome and compromised production of SCFAs in the first place, such an attempt is simply using a stopgap measure, at best, and ignoring the problem at the fundamental level.

Something with such a remarkably wide range of health benefits as SCFAs is not what we can find in a drug, and yet our body produces them for us—or more precisely, our gut microbes produce most of them for us. That’s why a holistic approach to health, using principles of integrative medicine and functional medicine, helps us heal our body wholly rather than in a fragmented and side-effect-laden way. To simply isolate a healthful substance such as butyrate or another SCFA and use it as a pharmaceutical would be completely missing the point of a holistic approach to health. Even if there might be a disease-specific condition benefitted by butyrate, for example, we should not lose sight of the fact that our own healthy gut microbiome is capable of producing this amazingly beneficial substance for us and more.

The symbiotic relationship between human beings and the gut bacteria is a testament to the great value that nature places on harmonious collaboration and co-existence. Realizing this, how could we let any unnatural divisions cause us to lose sight of the timeless harmony that nature has always intended for all living beings on this planet?

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