Written by: Lauren Milligan Newmark, Ph.D. | Issue # 108 | 2022
- Beneficial gut microbes in the large intestine produce short-chain fatty acids when they ferment carbohydrates.
- Short-chain fatty acids have been identified in human milk and are hypothesized to provide protective effects against the development of allergies because of their numerous anti-inflammatory actions.
- Research is limited but suggests that early exposure to short-chain fatty acids, including through human milk, could reduce the risk of development of food allergies and other atopic diseases.
Short-chain fatty acids (SCFA) are small molecules with large impacts on human health. They are produced when gut bacteria in the large intestine break down indigestible dietary carbohydrates. But don’t be fooled by these humble beginnings. Once produced by beneficial gut microbes, SCFA can promote immunity by suppressing inflammatory responses in the gut, halting the growth of dangerous pathogens, and helping to maintain the integrity of the intestine’s epithelial barrier [1–6].
A growing body of research suggests early life exposure to SCFA could play a role in the developmental programming of immune disorders related to inflammation, including food allergies [1-6]. Human milk is one important early life source of SCFA. The concentration of SCFA in human milk may be low relative to other types of fatty acids, but new research [1, 2] suggests a little milk SCFAs could go a long way in providing protection against the development of allergies.
Good Things Come in Small Packages
SCFA are metabolites, small molecules that are the products of metabolic processes. In this case, the metabolic process is fermentation by gut bacteria of carbohydrates that could not be digested by enzymes in the small intestine. (And, if the diet happens to be human milk, these carbohydrates include human milk oligosaccharides or HMO). Not all bacteria are capable of fermenting dietary fiber or HMO, which means that the production of SCFA in the gut will be related to both the quantity of undigestible carbohydrates in the diet and the quantity of SCFA-producing microbes .
There are five SCFA (formate, acetate, proprionate, butyrate, and valerate), classified as short because they have fewer than six carbons in their molecular “chain.” Of these, acetate (two carbons), proprionate (three carbons), and butyrate (four carbons) make up the majority of SCFA species and have, as a result, received the most research attention.
Most SCFA stay in the gut where they exert numerous beneficial effects on gut health and immune function. One of the important functions of SCFA, particularly butyrate, is inhibiting the actions of an enzyme called histone deacetylase (HDAC) in gut and epithelial cells . HDAC’s job is to remove acetyl groups from the histone proteins that surround DNA molecules, an action that prevents DNA from expressing genes and making proteins. By inhibiting HDAC, butyrate effectively keeps the DNA turned “on” and upregulates the expression of numerous genes.
Butyrate’s inhibition of HDAC is associated with the increased expression of genes that make mucus and tight-junction proteins, leading to a thicker, less permeable intestinal mucus (or epithelial) layer . The integrity of the intestine’s mucus layer has been directly associated with preventing inflammation and infection, as well as maintaining gut homeostasis . For example, a thinner, more permeable gut is a risk factor for the development of allergies and other inflammatory conditions such as irritable bowel syndrome .
Butyrate inhibition of HDAC also influences the regulation and function of T regulatory (Treg) cells within the colon [1-4]. Treg cells are important suppressors of inflammatory immune responses, including allergies. By increasing Treg activity in the colon, butyrate inhibits the production of pro-inflammatory cytokines (chemical messengers between cells) [4, 7].
Lastly (but not least, as their actions are many), butyrate, acetate, and propionate can bind to protein receptors that sit on the outside of intestinal epithelial cells and Treg cells called G protein receptors (GPR). When SCFA binds to GPR on cells, it triggers these cells to produce anti-inflammatory cytokines . The importance of this triggering was demonstrated when researchers “knocked out” specific SCFA-sensitive GPR in mice . The knock-out mice without GPR on their cells developed more chronic inflammatory conditions such as colitis, asthma, and obesity relative to control mice with functional GPR .
A Gut Reaction
There are no knock-out experiments with human infants (for obvious reasons), but similar questions about SCFA function can still be answered because of natural variation in gut SCFA concentration., SCFA production varies across infants because of differences in dietary carbohydrates and quantity of SCFA-producing gut microbes. But unlike in adults, total SCFA present in the infant’s gut will also vary depending on human milk SCFA concentration, which itself is highly variable because of maternal factors such as diet and maternal gut microbial concentration [1-6]. For example, a recent study  demonstrated that mothers with an atopic condition (asthma, eczema, or a pet, food, or environmental allergy) had significantly lower levels of milk acetate and butyrate compared with non-atopic mothers.
“Atopic diseases are associated with gut dysbiosis,” explains Dr. Jennifer T. Smilowitz, Associate Director of Human Studies Research for the Foods for Health Institute and Lactation Education Counselor at UC Davis. “Mothers with atopic diseases [likely] produce milk with lower levels of SCFA because they have lower levels of the beneficial gut microbes that produce SCFA.”
What does this variation in available SCFA mean for human infants? Using fecal concentration of SCFA as a proxy for available gut SCFA suggests a protective effect of SCFA in the development of allergies. Children with cow’s milk allergy had significantly lower levels of fecal butyrate compared with non-allergic children, and one-year old children with the highest fecal concentration of butyrate were less likely to have asthma between three and six years of age than those with lower fecal butyrate levels . Some of this protection may come from milk derived SCFA. Infants with atopic dermatitis (eczema) received significantly lower levels of SCFA, specifically acetate, in human milk compared with healthy controls .
Values of SCFA in milk are low relative to the concentration of milk medium- and long-chain fatty acids—at what concentration are milk levels protective and able to exert tolerogenic mechanisms in the infant gut? A recent study  had a clever methodology to tackle this very question. They measured butyrate concentration in milk samples from 109 healthy mothers and used the median concentration (0.75 mM) to conduct a series of in vitro (human) and in vivo (mouse) experiments. This “Goldilocks” value of milk butyrate—not the highest, but not the lowest—was associated with multiple modulatory effects that would provide protection against the development of food allergies . In the mouse model they observed upregulation of tight-junction protein expression and an increase in mucus layer thickness. In lymphocytes (T cells and B cells) from human children with food allergies they were able to shift the cells from a pro-inflammatory to an anti-inflammatory state. Specifically, stimulating in vitro cells with a dose of 0.50 mM butyrate elicited the release of interleukin-10 (IL-10) (an anti-inflammatory cytokine) with maximum effect of IL-10 production at the 0.75 mM concentration .
If this median level of SCFA is sufficient when it comes to providing protection from allergy development, how can we ensure that all infants—both human milk- and formula-fed—get appropriate exposure? For human milk, SCFA presumably come from the mother’s gut and so the focus would be on increasing maternal production of SCFA. “This requires increasing two variables: the beneficial gut microbes that produce SCFA and those microbes’ diet, which is in the form of indigestible carbohydrates from the [mother’s] diet,” says Smilowitz.
But increasing milk SCFA may not be the only way to increase SCFA exposure for human milk-fed infants, or the most effective as it leaves out infants that drink formula. “I would recommend using human milk as a guide for understanding just how much SCFA are needed in infant formulas,” says Smilowitz. Luckily, formula supplementation is not the only potential avenue for increasing SCFA intake. “The main source of SCFA is from microbial fermentation,” explains Smilowitz. “So rather than add more SCFA to infant formulas, I recommend focusing on supporting a beneficial gut microbiome that will produce SCFA.”
- Wang LC, Huang YM, Lu C, Chiang BL, Shen YR, Huang HY, Lee CC, Su NW, Lin BF. 2022. Lower caprylate and acetate levels in the breast milk is associated with atopic dermatitis in infancy. Pediatric Allergy and Immunology 33(2): e13744.
- Paparo L, Nocerino R, Ciaglia E, Di Scala C, De Caro C, Russo R, Trinchese G, Aitoro R, Amoroso A, Bruno C, Di Costanzo M. 2021. Butyrate as a bioactive human milk protective component against food allergy. Allergy 76(5): 1398-415.
- Stinson LF, Gay MC, Koleva PT, Eggesbø M, Johnson CC, Wegienka G, Du Toit E, Shimojo N, Munblit D, Campbell DE, Prescott SL. 2020. Human milk from atopic mothers has lower levels of short chain fatty acids. Frontiers in Immunology 11: 1427.
- Di Costanzo M, De Paulis N, Biasucci G. 2021. Butyrate: a link between early life nutrition and gut microbiome in the development of food allergy. Life 11(5): 384.
- Ojo-Okunola A, Cacciatore S, Nicol MP, du Toit E. 2020. The determinants of the human milk metabolome and its role in infant health. Metabolites 10(2): 77.
- Gay MC, Koleva PT, Slupsky CM, Toit ED, Eggesbo M, Johnson CC, Wegienka G, Shimojo N, Campbell DE, Prescott SL, Munblit D. 2018. Worldwide variation in human milk metabolome: indicators of breast physiology and maternal lifestyle?. Nutrients 10(9): 1151.
- Li M, van Esch BC, Wagenaar GT, Garssen J, Folkerts G, Henricks PA. 2018. Pro-and anti-inflammatory effects of short chain fatty acids on immune and endothelial cells. European Journal of Pharmacolog 831: 52-9.
- Parada Venegas D, De la Fuente MK, Landskron G, González MJ, Quera R, Dijkstra G, Harmsen HJ, Faber KN, Hermoso MA. 2019. Short chain fatty acids (SCFAs)-mediated gut epithelial and immune regulation and its relevance for inflammatory bowel diseases. Frontiers in Immunology 10: 277.
- Ang Z, Ding JL. 2016. GPR41 and GPR43 in obesity and inflammation–protective or causative? Frontiers in Immunology 7: 28.