Short-chain fatty acids are substances made by gut bacteria that may help strengthen the intestinal barrier, regulate immune responses and support the body’s natural defenses against infection. Here we explore their importance for immunity based on the latest research.
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Introduction: Why are scientists interested in SCFAs and immunity?
Short-chain fatty acids, or SCFAs for short, are microbial metabolites that act as molecular links between the thriving ecosystem in the colon called the gut microbiome and your immune system. They help to regulate immunity, protect the integrity of the gut barrier lining, and can influence both the innate and adaptive immune systems, making them an intriguing topic for scientists because they could offer valuable insights into how your gut may contribute to your body’s natural defenses against infection.
By using a 2026 review published in Clinical Microbiology Reviews, we look to explain the special relationship between your gut and immune system, which appears to be facilitated by SCFAs, and how this could benefit science in the future. We’ll also look at how you can harness your gut microbiome now to potentially bolster your own immune defenses.
What are short-chain fatty acids (SCFAs)?
Short-chain fatty acids are small fatty acid molecules that are produced in the gut when beneficial bacteria break down (ferment) certain carbohydrates. The most abundant SCFAs are acetate, propionate, and butyrate, accounting for 90% of the total SCFAs produced by your gut bacteria [1].
Although they share similar properties, they each interact with the body differently, influencing energy production, gut-barrier maintenance, and immune signaling.
Fermentation is the process by which microorganisms, like bacteria, break down substances for energy. It’s used commercially to produce foodstuffs such as yogurt, cheese, and alcohol, but it also occurs naturally inside the body. Foods like fiber cannot be broken down by the body, so they travel relatively untouched to the colon, where certain bacteria break it down and release SCFAs in the process.
What do acetate, propionate, and butyrate do?
Acetate, propionate, and butyrate are produced at a ratio of approximately 60:20:20 in the human body, although this can slightly vary between individuals [2]. They each have distinct roles, such as:
|
SCFA |
What is it? |
Key role |
|
Acetate |
Most abundant SCFA |
Known to reduce appetite and influence energy regulation [3] |
|
Propionate |
An SCFA that is mainly processed by the liver |
Regulates immune activity, metabolism, and mucosal homeostasis [4] |
|
The preferred fuel for colon cells |
Provides fuel for the epithelial lining in the colon to support the gut barrier and regulates inflammation [5] |
How SCFAs support immunity
There are several ways SCFAs can support immunity. Firstly, we must look at how SCFAs can support your immune system to resist bacterial, fungal, and viral infections. There are 2 important signal transduction pathways which facilitate this: receptor-mediated signal activation and epigenetic regulation.
Receptor-mediated signal activation
Receptor-mediated signal activation is the process whereby an extracellular molecule binds to a specific cell membrane receptor, changing its shape and resulting in internal biochemical changes [6].
SCFAs can communicate with immune and intestinal cells by attaching to specialized receptors and influencing how certain genes are used. Through these pathways, they may help balance inflammation, support antibody production and guide immune-cell activity. Their role is regulatory rather than simply “boosting” immunity, because an effective response must also avoid excessive inflammation.
One pathway involves receptors on the surfaces of cells. SCFAs can attach to receptors such as GPR41, GPR43 and GPR109A, triggering signals inside the cell. Propionate can also bind to the Olfr78 receptor and have anti-rectal cancer effects as a result.
Epigenetic regulation
SCFAs can also operate via epigenetic regulation, where they control gene expression, effectively switching genes on or off in response to certain signals [7].
Butyrate and propionate can regulate the expression of anti-infection-related genes by affecting enzymes called histone deacetylases (HDACs). SCFAs such as butyrate and propionate can add small chemical tags to proteins that help control how genes behave. These tags may support DNA repair and switch on genes that immune cells use to fight infections. Butyrate can also help these protective tags remain in place. Propionate may reduce Salmonella’s ability to switch on genes it needs to invade cells.
How SCFAs can aid infection resistance
Some of the mechanisms through which SCFAs resist infections include strengthening the intestinal epithelial gut barrier functions, regulating host immune responses, and acting on distant organs such as the liver and the lungs.
Figure 1. How SCFAs can support infection resistance. SCFAs support the intestinal barrier in several ways: (A) They strengthen tight junctions by increasing ZO-1 and Claudin-1 and reducing Occludin-2. (B) They encourage MUC2 production, creating a thicker mucus layer that separates gut microbes from intestinal cells while providing a suitable environment for beneficial bacteria. (C) They help control inflammation and stabilize HIF-1α, supporting normal cell function. (D) They encourage the release of antimicrobial peptides (AMPs).
SCFAs may also affect organs beyond the gut: (E) Along the gut–liver axis, they travel to the liver through the portal vein, where they may help regulate inflammation, limit oxidative damage and protect liver cells. (F) Along the gut–lung axis, they may reduce inflammation in the lungs through GPR and HDAC pathways and influence blood-cell production in the bone marrow, supporting lung immune defenses.
SCFAs also help regulate immunity: (G) They influence dendritic cells, neutrophils and other immune cells, helping strengthen innate defenses while limiting excessive inflammation. (H) They affect B-cell development, IgA and IgG antibody production, and the formation of regulatory B cells. (I) They also promote regulatory T-cell development and help balance Th1 and Th17 immune responses.
Can SCFAs help the body defend itself against infections?
SCFAs may contribute to infection defenses by strengthening the gut barrier, changing local acidity, influencing immune cells and altering the growth or behavior of certain pathogens. However, their effects are not universally protective. Results differ between microorganisms, and some SCFAs can produce opposing effects under different conditions. They are not proven stand-alone infection treatments.
The review examined relationships between SCFAs and several pathogens, including:
-
Salmonella species
-
Campylobacter jejuni
-
Vibrio cholerae
-
Influenza virus
-
Respiratory syncytial virus
-
Rotavirus
-
SARS-CoV-2
Researchers have proposed several ways that SCFAs might influence infections. They may restrict the growth of certain pathogens, interfere with microbial communication, affect biofilm formation or alter the genes microbes use during colonization.
SCFAs may also work indirectly by supporting immune responses and maintaining the gut lining. Some of their signals can potentially travel beyond the digestive tract, forming part of communication networks such as the gut–lung and gut–liver axes.
Do SCFAs affect every pathogen in the same way?
No. The effects of SCFAs depend on the microorganism, the individual SCFA, its concentration and the surrounding environment. The review reports inhibitory effects against several pathogens but also describes exceptions. Some SCFAs may support Campylobacter jejuni colonization, while butyrate may restrict C. difficile growth yet increase toxin expression under laboratory conditions.
Could SCFAs become treatments for infections?
Potentially. To date, most studies have been based on animal experimental models, which differ from human models. So, large-scale clinical trials in humans or human models are needed to assess the safety and effectiveness of SCFAs in treating infections.
Some of the interventions that have already been studied include:
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High-fiber diets and SCFA precursors: Fiber, resistant starch, inulin and certain omega-3-rich or fermented foods may encourage SCFA-producing bacteria, potentially supporting the gut’s defenses against infection.
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Probiotics and fecal microbiota transplantation: Probiotics and FMT may restore a healthier microbial balance and increase the number of bacteria that naturally produce SCFAs.
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Direct administration of SCFAs: Oral or rectal SCFA preparations may increase SCFA levels. Early animal and small human studies suggest possible benefits for gut-barrier damage and inflammation, but stronger clinical evidence is needed.
-
Combined therapy with SCFAs: Researchers are investigating SCFAs alongside other treatments to determine whether their combined effects are more useful than either approach alone.
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Combination with prebiotics: Prebiotics such as inulin, fructooligosaccharides and 2′-fucosyllactose may feed SCFA-producing bacteria and complement direct SCFA supplementation.
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Combination with antibiotics: Adding SCFAs to antibiotic treatment may help offset losses of SCFA-producing bacteria and could improve the activity of some antibiotics against resistant bacteria. Most supporting evidence is currently preclinical.
How can you support your gut’s natural SCFA production?
Supporting the natural microbial fermentation processes that are already taking place in your colon is easy with a few simple interventions. Increasing your SCFA production doesn’t need to be complicated or expensive. Some of the practical ways you can support your gut microbiome to increase your SCFA production include:
🍎 Eat a varied range of fruit, vegetables, wholegrains, legumes, nuts, and seeds to nourish your gut microbes and increase their SCFA production
🥔 Include resistant-starch sources such as beans, lentils, cooked and cooled potatoes, rice, and pasta, which are also a great way to feed your gut bacteria
⚖️Increase your fiber intake gradually; stepping up your intake too quickly can leave you with uncomfortable digestive symptoms
🥤As you increase your fiber intake, make sure you also increase how much water you drink to help fiber move smoothly through your digestive tract
💊 Consider incorporating prebiotic supplements, such as human milk oligosaccharides, into your daily diet to help nourish your gut microbiome and enhance its SCFA output
Summary
SCFAs are microbial metabolites that help connect diet, gut bacteria, the intestinal barrier, and the immune system. The latest review highlights several ways they could influence infection defenses, but it also shows that these relationships are complex. Supporting a diverse gut microbiome is sensible, while using SCFAs or prebiotics to treat infections remains an area of research.
A varied, fiber-rich diet can provide gut bacteria with fermentable substrates. Prebiotic compounds such as 2′-FL may offer another source of microbial fuel, but their effects depend partly on the bacteria already present in an individual’s gut.
Interested in learning more about how HMOs such as 2′-FL interact with your gut microbiome? Explore Layer Origin Nutrition’s HMO products or visit the Knowledge Center for accessible, science-led guides to HMOs, Bifidobacterium, microbial cross-feeding, and gut health.
Author details
Written by: Leanne Edermaniger, M.Sc. Leanne is a professional science writer who specializes in human health and enjoys writing about all things related to the gut microbiome. She has written extensively on inflammatory bowel disease, prebiotics, and microbiome research.
Her work focuses on translating complex medical science into evidence-based, practical health guidance.
