Gut-brain connection and environmental influences on the gut microbiome

In our previous blog, we discussed how a healthy gut microbiome helps produce for us short-chain fatty acids (SCFAs) that are important for our gut health, immunity, cardiovascular health, and cancer prevention. SCFAs are produced in the gut when beneficial gut microbes ferment the plant fibers that we eat.

In this blog, the second of a three-blog series, we will explore how SCFAs may affect the gut-brain connection and how environmental factors can influence the gut microbiome and SCFA production. In the next blog, we will discuss how acupuncture affects the gut microbiome.

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. The gut microbiome (or, more accurately, the gut microbiota) is a major player in this gut-brain connection, which influences our mood, memory, and gut health. SCFAs produced by the gut microbes may influence the gut-brain connection directly or indirectly through these communication pathways (1). 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 (1).

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 (2).

As mentioned in the first blog of this three-blog series, the gut produces about 90% of the body’s serotonin, a neurotransmitter that plays a role in depression, anxiety, memory, appetite, gut motility, and other functions. SCFAs promote serotonin production (3), and the serotonin produced in the gut influences the brain through different mechanisms. One way it does so is by binding to and activating serotonin receptors on the vagus nerve, which connects the gut to the brain—this is the signaling pathway that is responsible for the nausea and vomiting associated with chemotherapy (4).

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 (5).

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 (6). In other words, a higher abundance of gut bacteria that produce SCFAs naturally diminished these young adults’ desires for such unhealthy foods.

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 (7).

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) (8, 9), 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 (9). This observation is not surprising, given the immune system effects of SCFAs as we discussed in first blog of this three-blog series.

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 (9). 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 (8).

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 (8). 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) (10). 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 (11).

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 (8).

Social stress also disrupts the gut microbiome (8), and a laboratory study using mice showed that stress exposure reduced levels of beneficial SCFA levels in the colon (12).

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 have described in this blog series 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.

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 pharmaceutical agent. 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. If and when there might be a disease-specific condition that clinical researchers understand to be potentially benefitted by the administration of isolated butyrate, for example, we should still not lose sight of the fact that our own healthy gut microbiome is capable of producing this amazingly beneficial substance for us and more.

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 (13). 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.

In our next blog, we will discuss how acupuncture affects the gut microbiome and SCFA production in the gut.

References

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2.    Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Burmann J, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls. Parkinsonism Relat Disord. 2016;32:66-72.

3.    Reigstad CS, Salmonson CE, Rainey JF, 3rd, Szurszewski JH, Linden DR, Sonnenburg JL, et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2015;29(4):1395-403.

4.    Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med. 2008;358(23):2482-94.

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6.    Medawar E, Beyer F, Thieleking R, Haange SB, Rolle-Kampczyk U, Reinicke M, et al. Prebiotic diet changes neural correlates of food decision-making in overweight adults: a randomised controlled within-subject cross-over trial. Gut. 2024;73(2):298-310.

7.    Bharmal N. Social Determinants and Health Equity in Functional Medicine. Phys Med Rehabil Clin N Am. 2022;33(3):665-78.

8.    Mann ER, Lam YK, Uhlig HH. Short-chain fatty acids: linking diet, the microbiome and immunity. Nat Rev Immunol. 2024;24(8):577-95.

9.    Madan JC, Hoen AG, Lundgren SN, Farzan SF, Cottingham KL, Morrison HG, et al. Association of Cesarean Delivery and Formula Supplementation With the Intestinal Microbiome of 6-Week-Old Infants. JAMA Pediatr. 2016;170(3):212-9.

10.  Estevinho MM, Midya V, Cohen-Mekelburg S, Allin KH, Fumery M, Pinho SS, et al. Emerging role of environmental pollutants in inflammatory bowel disease risk, outcomes and underlying mechanisms. Gut. 2025;74(3):477-86.

11.  Lin R, Zhang Y, Chen L, Qi Y, He J, Hu M, et al. The effects of cigarettes and alcohol on intestinal microbiota in healthy men. J Microbiol. 2020;58(11):926-37.

12.  Maltz RM, Keirsey J, Kim SC, Mackos AR, Gharaibeh RZ, Moore CC, et al. Social Stress Affects Colonic Inflammation, the Gut Microbiome, and Short-chain Fatty Acid Levels and Receptors. J Pediatr Gastroenterol Nutr. 2019;68(4):533-40.

13.  Wastyk HC, Fragiadakis GK, Perelman D, Dahan D, Merrill BD, Yu FB, et al. Gut-microbiota-targeted diets modulate human immune status. Cell. 2021;184(16):4137-53 e14.