Gut Microbiota and SCFA Production: Impact on Health and Disease

The gut microbiota plays a crucial role in human health, and its composition and activity influence various physiological processes. One of its most critical functions is the production of short-chain fatty acids (SCFA), mainly acetic, propionic and butyric acids, through the fermentation of dietary fiber and resistant starch. These SCFA are not only by-products of bacterial metabolism, but also important signaling molecules and energy sources for intestinal cells and distant organs, and play an important role in regulating immune function.

SCFA production is highly dependent on the diversity and activity of the gut microbiota. Different species of bacteria in the gut ferment various types of carbohydrates, and their ability to produce SCFA is influenced by the substrates in the diet. For example, butyrate is mainly produced by the fermentation of resistant starch and dietary fiber, especially by bacteria such as Faecalibacterium prausnitzii and Roseburia intestinalis. These bacteria thrive in fiber-rich environments and can have an impact on intestinal health by maintaining intestinal barrier function and preventing inflammatory responses.

Diet has a significant impact on SCFA production by the gut microbiota. Diets rich in dietary fiber, polyphenols, and resistant starch promote the growth of beneficial SCFA-producing bacteria, thereby enhancing gut health and metabolism. In contrast, a high-fat, low-fiber Western diet reduces microbial diversity and impairs SCFA production, leading to metabolic disorders. Therefore, understanding the interactions between diet, gut microbiota, and SCFA production is essential for developing dietary strategies to improve metabolic health and prevent chronic disease.

Interaction of Intestinal Flora with SCFAs

Production of SCFAs and Key Bacteria

SCFAs are the main metabolites of anaerobic fermentation of non-digestible carbohydrates in the gut. Bacteria producing SCFAs mainly include anaerobic bacilli, bifidobacteria, fungi, streptococci, and lactobacilli. In addition, small amounts of isobutyric and isovaleric acids can be produced during the catabolism of branched-chain amino acids, and fermentation intermediates in microbiota such as lactic acid or ethanol can be metabolized to SCFAs.

Acetate formation

Acetate can be synthesized through two different pathways. Firstly, acetyl-CoA can be produced by decarboxylation of pyruvate, then, acetyl-CoA is hydrolyzed to acetate by an acetyl-CoA hydrolase.Most of the acetate is produced by enteric bacteria, including Prevotella spp., Ruminococcus spp., Bifidobacterium spp., Bacteroides spp., Clostridium spp., Streptococcus spp., A. muciniphila, and B. hydrogenotrophica, using this pathway. Secondly, the Wood-Ljungdahl pathway can be also used by acetogenic bacteria to form acetate from acetyl-CoA. Here, the reduction of carbon dioxide generates carbon monoxide, which reacts with a coenzyme A molecule and a methyl group to produce acetyl-CoA. At the same time, acetyl-CoA is the substrate to obtain acetate.

Propionate formation

Propionate can be synthesized through three different biochemical pathways, namely succinate, acrylate, and propanediol pathway. Bacteroidetes and several Firmicutes belonging to the Negativicutes class use namely succinate pathway for the propionate formation.

1,2-propanediol can be formed from deoxy sugars such as rhamnose and fucose in the propanediol pathway. 1,2-propanediol is sequentially converted into propionaldehyde and propionyl-CoA, which leads to the propionate formation. Salmonella enterica serovar Typhimurium, R. inulinivorans, Akkermansia municiphilla, Bacteroides and Escherichia coli can form 1,2-propanediol by fermentation of deoxy sugars, 1,2-propanediol which in turn forms propionate. Other bacteria, although not able to utilize deoxy sugars directly, are able to utilize 1,2-propanediol to produce propionic acid via cross-feeding, such as Limosilactobacillus reuteri.

A few bacteria in the Veillonellaceae and Trichosporonaceae produce propionic acid via the acrylate pathway

Butyrate formation

As with propionate, butyrate production is substrate specific. Ruminococcus bromii forms butyrate by fermenting resistant starch. As with propionate, butyrate production is substrate specific. Ruminococcus bromii forms butyrate by fermenting resistant starch. In the butyryl-CoA pathway, acetate CoA-transferase converts butyryl-CoA to butyric acid and acetyl-CoA using exogenous acetate. Coprococcus species. F. prausnitzii, E. rectale, E. hallii, and R. bromii then produces butyrate via the butyryl-CoA pathway.

Relationship between Intestinal Flora Diversity and SCFA levels

There is a strong positive correlation between intestinal flora diversity and SCFAs levels, and the core mechanism is that diverse flora can efficiently catabolize a variety of dietary fibers through functional redundancy and metabolic complementarity, thus enhancing the production and stability of SCFAs.

Under the environment of high bacterial diversity, different bacteria share similar metabolic pathways, and even if some strains are reduced, other bacteria can still compensate to maintain the production of SCFAs; at the same time, diversified bacteria are able to catabolize a wider range of substrates, releasing more precursors of SCFAs. For example, acetic acid produced by Bifidobacterium can be converted to butyric acid by Faecalibacterium, while Bacteroides produces propionic acid via the succinic acid pathway, and this mutualistic symbiosis relies on the diversity of the colony to achieve synergistic effects.

Reduced diversity of the bacterial flora reduces the ability to synthesize SCFAs. In less diverse environments, opportunistic pathogens (e.g., Proteobacteria) may overpopulate, and their metabolites (e.g., hydrogen sulfide) may directly inhibit SCFAs synthase activity, a phenomenon that is particularly prominent in patients with inflammatory bowel disease (IBD).

SCFA production pathways (Figure from Kallie E. Hays, 2024)

Practical Tips to Increase SCFA Production in Gut

The human gut microbiota is capable of fermenting dietary fiber to produce SCFAs, a process that involves a complex microbial metabolism in which microbial interactions and regulatory factors in the intestinal environment have a significant impact on the formation of SCFAs. Meanwhile, environmental factors such as pH value and redox potential of the intestinal tract, as well as the host's dietary structure and living habits, all have an effect on microbial fermentation, which in turn affects the production and types of SCFAs.

Factors Affecting SCFA Production in The Gut

The production of short-chain fatty acids (SCFAs) is dependent on the metabolic activity of the intestinal flora, whose composition and function are regulated by a variety of factors, including diet, lifestyle, and medications.

Diet

• Dietary fiber: Soluble fiber (e.g., oats, legumes) and resistant starch (e.g., cold potatoes, green bananas) significantly elevate acetate and butyrate concentrations by selectively feeding SCFAs-producing flora (e.g., Bifidobacterium and Faecalibacterium).
• High-fat or high-sugar: High-fat or high-sugar diets can inhibit beneficial bacterial activity, e.g., saturated fat reduced butyric acid producers such as Roseburia by 40%, and refined sugar led to a metabolic imbalance in the flora and reduced the bioavailability of SCFAs.

Lifestyle 

Lifestyle and environmental factors also had a significant impact on SCFAs:

• Stress: Chronic stress reduces the abundance of Bifidobacterium and Lactobacillus by 30% by activating the "gut-brain axis" and inhibits the activity of key enzymes for butyric acid synthesis.
• Sleep: Sleep deprivation directly reduces the production of SCFAs by 20%, while circadian disruption (e.g. shift work) impairs the fermentation efficiency of the flora.
• Exercise: 150 minutes of aerobic exercise per week, on the other hand, increased Faecalibacterium abundance by 25%, thereby boosting butyric acid levels.
• Environment: Over-sanitary conditions associated with urbanization may reduce flora diversity, while air pollutants and plasticizers directly impair the function of SCFAs-producing bacteria, exacerbating the risk of metabolic disorders.

Medications

Drug use has a "double-edged sword" effect on the regulation of SCFAs.

• Antibiotics: e.g. amoxicillin removes 90% of SCFAs-producing flora in a short period of time, with a recovery cycle of up to 6-12 months.
• NSAIDs: e.g. ibuprofen reduces the absorption of SCFAs by disrupting the intestinal barrier and increases the risk of inflammatory bowel disease 2-fold
• Proton pump inhibitors: long-term use of omeprazole decreases butyric acid production by 15-20% by altering the gastric acid environment.

The interaction of these factors suggests that optimizing SCFAs requires synergistic interventions in terms of dietary modification, lifestyle improvement, and medication management to achieve a long-term balance between gut and systemic health.

Dietary Strategies to Promote Enterogenic SCFAs

High fiber food 

SCFAs precursor substances are the basis for the production of SCFAs. SCFAs precursor substances in food are mainly dietary fiber and resistant starch, which are fermented by intestinal flora to produce enteric-borne SCFAs; therefore, modulation of the intake of SCFAs precursor substances in food can regulate the production of enteric-borne SCFAs at the source.

SCFAs precursors are found in many types of foods, including whole grains, which are rich in resistant starch and dietary fiber, vegetables and fruits, which are rich in pectin and non-starch polysaccharides, and legumes, which are rich in non-starch polysaccharides, hemicellulose, and pectin.

Increasing the intake of dietary fiber-rich foods facilitates the promotion of fermentation by intestinal flora using precursors of SCFAs, thus increasing SCFAs in the colon.

Probiotics

Supplementation with specific probiotics can be effective in increasing intestinal levels of short-chain fatty acids (SCFAs) through both direct metabolic acid production and indirect regulation of flora ecology.

• Direct acid-producing strains：Selecting probiotics with efficient SCFA synthesis ability, supplementing Clostridium butyricum directly generates butyric acid through the butyric acid kinase pathway; supplementing Bifidobacterium longum can convert dietary fiber into acetic acid, which can be further converted to butyric acid by indigenous bacteria such as Faecalibacterium prausnitzii to butyric acid, forming a synergistic metabolic network.
• Indirect regulation of flora: Some probiotics (e.g., Lactobacillus plantarum) do not directly produce high levels of SCFAs, but indirectly enhance butyric acid and propionic acid levels by secreting antimicrobial peptides to inhibit the proliferation of pathogenic bacteria and vacate ecological niches for acid-producing bacteria.
• Synergistic with prebiotics: The combination of probiotics with prebiotics (e.g., oligofructose) can significantly amplify the effect, e.g., Bifidobacterium lactis combined with oligogalactose increased the total amount of acetic acid and butyric acid by 50%.

Effects of SCFA on Host Health and Disease 

Gut microbiota-derived SCFAs play an important role in human health and disease. An in-depth understanding of their generation mechanisms, interactions with the host, and roles in disease is important for the development of new therapeutic strategies and the maintenance of human health.

Health Benefits of SCFA

On the immune system

SCFAs can regulate the activity and differentiation of immune cells and influence the onset and development of inflammatory responses. For example, some SCFAs can inhibit the production of pro-inflammatory cytokines and reduce inflammatory responses, which is essential for maintaining the immune balance of the body. This regulatory effect is not only limited to the local immune system in the intestine, but also affects the whole body's immune function through blood circulation. 

Gut health aspects

SCFAs can regulate the acid-base balance in the intestinal tract, maintain the stability of the intestinal environment, and create suitable conditions for the survival and reproduction of intestinal microorganisms. At the same time, SCFAs can also influence the function of intestinal epithelial cells, promote the integrity of the intestinal barrier, and enhance the intestinal resistance to harmful substances.

Antimicrobial aspect

SCFAs can inhibit the proliferation and virulence of pathogenic bacteria by lowering intestinal pH and destroying the integrity of pathogen cell membranes. In addition, SCFAs synergistically enhance the intestinal immune barrier by promoting the secretion of host antimicrobial peptides (e.g., β-defensins), forming a "chemical-immune dual defense" against pathogenic bacteria.

Relationship between SCFA and Disease

SCFA are important mediators between the microbiota and host physiology. Decreased SCFA production has been associated with metabolic diseases. SCFA have been identified as important metabolic biomarkers of disease-related changes, and they have been strongly implicated in a wide range of disorders, including gastrointestinal disorders, obesity, diabetes mellitus, inflammation, nephropathy, cancer, and neurological disorders.

Inflammations

In macrophages, neutrophils and dendritic cells, short-chain fatty acids (SCFAs) can activate MAPK pathway through G protein coupled receptor, inhibit β-arrestin2/NF-κB pathway, inhibit the synthesis of cyclic adenosine monophosphate (cAMP), and promote calcium ion (Ca2þ) into nucleus, thus regulating the gene expression related to inflammation and immunity.

In addition, SCFAs can enter cells through passive diffusion to inhibit mitochondrial/AMPK/mTOR pathway, inhibit histone deacetylation, and inhibit MAPK pathway via promoting MKP expression. However, in macrophages, neutrophils and dendritic cells, whether SCFAs can also pass through the cell membrane through transporters still needs further study.

Diseases of the brain

Free SCFAs in the gut can cross the blood-brain barrier via monocarboxylic acid transporter proteins, which allows SCFAs to act as signaling molecules to transmit gut states to the brain. In neurological disorders such as Parkinson's disease and Alzheimer's disease, SCFAs may also play a role in the disease process by modulating neuroinflammation and influencing the synthesis and release of neurotransmitters.

Obese

SCFA has important effects on improving body weight, lipid distribution, and insulin sensitivity. Dietary butyrate inhibits and reverses lipid synthesis by decreasing peroxisome proliferator-activated receptor (PLAR) expression and activity to facilitate the transition from lipid synthesis to utilization.

SCFA-independent pathways also have important effects on obesity. SCFA produced by intestinal microorganisms has a significant effect on obesity by inhibiting histone deacetylase receptor activity, and it can also inhibit HDAC to induce the gene expression of fibroblast growth factor 21 in the liver, which promotes the β-oxidation of long-chain fatty acids and ketone body production.

Diabetes

SCFA are closely associated with diabetes and have a major impact on insulin sensitivity and glucose homeostasis by regulating the gut-brain-metabolism axis. type 2 diabetic patients have a reduced number of SCFA-producing bacteria (e.g., Faecalibacterium) in the gut, and butyric acid levels are reduced by 30-40%, resulting in insulin resistance and impaired β-cell function.

SCFAs promote GLP-1 secretion, inhibit hepatic gluconeogenesis, and reduce adipose tissue inflammation by up to 50% through activation of G protein-coupled receptors.

SCFAs can also reduce chronic inflammation caused by endotoxins entering the bloodstream by maintaining the integrity of the intestinal barrier, a mechanism that is particularly important in obesity-related diabetes. High-fiber diets or targeted modulation of SCFAs-producing flora have emerged as new strategies for diabetes intervention.

Irritable bowel syndrome

Patients with Irritable Bowel Syndrome (IBS) often exhibit dysbiosis and abnormal levels of SCFAs, e.g., patients with diarrhea (IBS-D) have fecal butyric acid concentrations that are 20-30% lower than those of healthy individuals, whereas patients with constipation (IBS-C) may have diminished intestinal peristalsis due to reduced acetic acid.

SCFAs affect symptoms by modulating intestinal motility (butyric acid inhibits smooth muscle hypercontractions), decreasing visceral hypersensitivity (propionate activates FFAR3 receptors to alleviate abdominal pain), and repairing the intestinal barrier (reduces "leaky gut"-mediated immune activation).

Supplementation with soluble fiber (e.g., oligofructose) reduces bloating symptoms by 40% in patients with irritable bowel syndrome, but excess soluble fiber may exacerbate discomfort due to fermentation and gas production, suggesting the need for individualized interventions.

In addition, the abundance of butyric acid-producing bacteria (e.g., Enterococcus faecalis) was negatively correlated with the severity of irritable bowel syndrome symptoms, suggesting that targeted modulation of the flora-SCFA axis may be a potential therapeutic strategy.

Effects of short-chain fatty acids on G protein-coupled receptor-mediated signalling and histone deacetylases (Figure from Elizabeth R. Mann, 2024)

References

1. WANG K, et al. HDAC inhibitors alleviate uric acid-induced vascular endothelial cell injury by way of the HDAC6/FGF21/PI3K/AKT pathway. Journal of Cardiovascular Pharmacology. 2023，81(2):150-164.
2. Yao Y, et al. The role of short-chain fatty acids in immunity, inflammation and metabolism. Crit Rev Food Sci Nutr. 2022;62(1):1-12. https://doi.org/10.1080/10408398.2020.1854675
3. Ríos-Covián D, et al. Intestinal Short Chain Fatty Acids and their Link with Diet and Human Health. Front Microbiol. 2016 Feb 17;7:185. https://doi.org/10.3389/fmicb.2016.00185
4. Nogal, A., et al. (2021). The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health. Gut Microbes, 13(1). https://doi.org/10.1080/19490976.2021.1897212
5. Mann, E.R., et al. Short-chain fatty acids: linking diet, the microbiome and immunity. Nat Rev Immunol 24, 577–595 (2024). https://doi.org/10.1038/s41577-024-01014-8
6. Mukhopadhya, I., et al. Gut microbiota-derived short-chain fatty acids and their role in human health and disease. Nat Rev Microbiol (2025). https://doi.org/10.1038/s41579-025-01183-w
7. Hays KE, et al. The interplay between gut microbiota, short-chain fatty acids, and implications for host health and disease. Gut Microbes. 2024 Jan-Dec;16(1):2393270. https://doi.org/10.1080/19490976.2024.2393270
8. Li X, et al. Short-chain fatty acids in nonalcoholic fatty liver disease: New prospects for short-chain fatty acids as therapeutic targets. Heliyon. 2024 Feb 27;10(5):e26991. https://doi.org/10.1016/j.heliyon.2024.e26991