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).

In this first blog of a three-blog series, we will discuss how SCFAs affect our gut health, immunity, cardiovascular health, and cancer prevention and therapy. In future blogs, we will discuss the role of SCFAs in the gut-brain connection, how environmental factors can influence the gut microbiome and SCFA production, how acupuncture affects the gut microbiome, and what it means to heal our body holistically through an integrative and functional medicine approach.

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).

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 in our next blog, 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.

In our next blog, we will discuss how SCFAs may affect the gut-brain connection, and explore how environmental factors can influence the gut microbiome and SCFA production.

References

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2.    Sender R, Fuchs S, Milo R. Are We Really Vastly Outnumbered? Revisiting the Ratio of Bacterial to Host Cells in Humans. Cell. 2016;164(3):337-40.

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

4.    Mukhopadhya I, Louis P. Gut microbiota-derived short-chain fatty acids and their role in human health and disease. Nat Rev Microbiol. 2025;23(10):635-51.

5.    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.

6.    Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol. 2009;9(11):799-809.

7.    Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature. 2012;490(7418):55-60.

8.    Muller M, Hernandez MAG, Goossens GH, Reijnders D, Holst JJ, Jocken JWE, et al. Circulating but not faecal short-chain fatty acids are related to insulin sensitivity, lipolysis and GLP-1 concentrations in humans. Sci Rep. 2019;9(1):12515.

9.    Kaji I, Karaki S, Kuwahara A. Short-chain fatty acid receptor and its contribution to glucagon-like peptide-1 release. Digestion. 2014;89(1):31-6.

10.  Bartolomaeus H, Balogh A, Yakoub M, Homann S, Marko L, Hoges S, et al. Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage. Circulation. 2019;139(11):1407-21.

11.  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.