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It is nearly thirty years since the discovery of the first microRNA. These non-protein encoding sections of RNA, typically in the region of 20 nucleotides long, are now understood to have important roles in gene regulation. And yet scientists are far from clear on how and when they work exactly, and novel assessments of which are involved in key biological tasks still breaking fresh ground. A recent sweep of the microRNAs found in breastmilk is one such study. In this case, an international team of researchers surveyed the most consistently occurring microRNAs appearing in breastmilk produced 3, 60 and 90 days after a full-term birth [1].

The team behind this study had plenty of reasons to anticipate that they might uncover something interesting. For one thing, other researchers had already shown that breastmilk, like many body fluids, is rich in microRNAs (or miRNAs, for short), but breastmilk is unusually so [1]. Moreover, studies that have treated sedentary mice with merely the vesicle-encased miRNAs of physically active mice have reported that the sedentary mice started to gain some of the benefits of exercise. Despite continuing to not move around much, the mice improved their glucose tolerance [2]. This finding may have little to do with the regulation or effects of mammalian milk, but it does demonstrate the regulatory power of miRNAs.

Most of the time, miRNAs operate by interfering with messenger RNA (mRNA) [3]. This is the kind of long, single-stranded RNA that carries information stored in DNA code out of the nucleus for protein synthesis, known as “translation.” In many instances, miRNAs have been reported to interact with a particular end (the 3’ end) of a target mRNA in such a way as to suppress its expression, and in the process of controlling the rate of translation, they have been found to shuttle between subcellular compartments [4]. Yet miRNAs have many more modes of action. For example, they are known to affect transcription (the production of mRNAs inside the nucleus) as well as translation, by interacting with gene promotor regions [3]. Such is the extent of miRNA activity that they are believed, collectively, to exert control over more than 80% of the protein-coding genome [1].

In the new study, the authors began by recruiting pregnant women who regularly visited a medical center in the city of Lyon, France, and who were happy to provide milk samples after they were to give birth. Providing milk for the study required following standardized procedures, such as pumping from the same breast at about 11 AM in the morning and each time emptying the other breast manually. Then, from the group of women who supplied milk, the researchers randomly selected 44 individuals. The milk samples from these women were then frozen and sent to a research center in Lausanne, Switzerland, where the miRNAs in the milk could be profiled using a special machine, and via further treatments, their relative levels could be assessed. The members of the research team in Switzerland also transfected cells in culture with some of the miRNAs that were prominently present in breastmilk to seek clues as to their functions.

In all, the study found over 2,000 miRNAs present in breastmilk. Of these, 685 were commonly identified at all three time points across the longitudinal sampling, and 35 of them were particularly common and expressed at similar levels over time. Eleven of the 685 miRNAs showed interesting variation in their levels over the three time points. Even though the types and levels of different miRNAs have been measured longitudinally in other mammals, including rats, marsupials and cows, this study is the first to assess miRNAs in human milk over different time points in lactation [1].

As their investigations continued, the team decided to focus extra effort on the activities of two miRNAs—miR-3126 and miR-3184—which both showed stage-specific upregulation. Having transfected the culture cells with these miRNAs, they then looked for changes in the cells’ gene expression. Among the 41 upregulated genes in the transfected cells, the team identified, among the common target genes, glyoxalase 1 (which among other things induces apoptosis, or “cell suicide”) and insulin-like growth factor 2 (a member of a signalling pathway that regulates cell growth and differentiation during embryonic and postnatal development). These insights led the researchers to hypothesize about the roles that these miRNAs might have, such as their possible involvement in breast gland malignancies and in the maturation of the infant gut.

To be sure, the evidence of these possible effects on both mom and infant is speculative. But it is intriguing to imagine that the investigation of miRNAs in breast milk could, over time, add more detail to our understanding of the mechanisms by which breastmilk confers so many benefits to infants who consume it. As is true with any area of research, more studies are needed. In this area, however, it is especially so.

References

1. Raymond F., Lefebvre G., Texari L., Pruvost S., Metairon S., Cottenet G., Zollinger A., Mateescu B., Billeaud C., Picaud J-C., Silva-Zolezzi I., Descombes P., Bosco N. Longitudinal Human Milk miRNA Composition over the First 3 mo of Lactation in a Cohort of Healthy Mothers Delivering Term Infants. The Journal of Nutrition 2022; 152:94-106. doi: 10.1093/jn/nxab282
2. Castano C., Mirasierra M., Vallejo M., Novials A., Parrizas M. Delivery of Muscle-derived Exosomal miRNAs Induced by HIIT Improves Insulin Sensitivity through Down-regulation of Hepatic FoxO1 in Mice. Proceedings of the National Academy of Sciences 2020;117:30335–43.
3. O’Brien J., Hayder H., Zayed Y., Peng C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Frontiers in Endocrinology 2018; 9:402. doi: 10.3389/fendo.2018.00402
4. Haschke F., Haiden N., Thakkar S.K. Nutritive and Bioactive Proteins in Breastmilk. Annals of Nutrition and Metabolism 2016; 69(Suppl 2):17–26.

Humans and dogs may be distant relatives on the tree of life, but they share very similar evolutionary stories. In high-altitude Tibet, humans and dogs have the same gene mutation that reduces physiological stress from low oxygen levels [1]. In West Africa, both human and dog genomes show evidence of natural selection for a gene that provides protection against malaria infection [2]. And now a new study [3] reports European and Middle Eastern dog genomes, like those of their human companions from the same regions, are more likely to have a mutation that allows them to drink milk.

Adaptations to high-altitudes and malaria reflect shared environments, but an adaptation for lactose digestion reflects shared food. As humans adopted and adapted to new dietary practices, so did their four-legged companions that consumed their leftovers. Dog food companies might have you believe that your dog is essentially a carnivorous wolf with floppy ears and a wagging tail, but genetic studies [3-5] demonstrate that being human’s best friend resulted in more human-like digestive abilities.

Survival of the Friendliest

Dogs are the first animals domesticated by humans, but the when, where, and why of their domestication are still being worked out by researchers. “Dog evolution is highly debated,” explains Dr. Jessica Hekman, DVM, PhD, a veterinary researcher at Karlsson Laboratory in the Broad Institute of MIT and Harvard, “but the current consensus is that the domestication event happened close to 30,000 years ago.” Genetic data indicate that the closest living relative of dogs (Canis lupus familiaris) are gray wolves (Canis lupus), and that both are descendants of a now-extinct wolf species [6]. As for where dogs were domesticated, “we actually have no idea,” Hekman says. “But not in North America or Australia, probably in Eurasia.”

If these dates and location hold, dog domestication began during the Last Glacial Maximum of the Pleistocene when much of Europe and Asia were covered with ice sheets and human populations were practicing a hunting-gathering mode of subsistence. “The invention of agriculture did not spur canid domestication,” says Hekman. Then what did? A leading hypothesis suggests prehistoric table scraps may have led to wolves domesticating themselves [7]. Friendlier, less timid wolves could have benefited from staying close to human camps to scavenge on leftover meat. In turn, humans could have benefited from their presence if these friendlier wolves helped keep other predators away.

By the time humans started domesticating plants and dairy animals, dogs were an integral part of human culture [8]. And human cultural practices, in turn, had major impacts on dog evolution. As Hekman explains, “dogs literally change themselves to fit in to our niche, because we create so much food.”

Prehistoric Puppuccinos

In parts of the world where excess food included milk, yogurt, and cheese, it stands to reason dogs could have been under similar evolutionary pressures as humans to adapt to lactose digestion. All mammals are born with the ability to digest the milk sugar lactose, via the enzyme lactase, but then essentially “turn off” lactase production after weaning. Among humans, natural selection increased the frequency of lactase persistence—through genetic changes that keep the lactase enzyme turned on—in multiple populations that have a long history of dairy culture.

Dog and wolf genomes were compared to determine whether dog breeds that trace their ancestry to Europe and the Middle East were under similar evolutionary pressures for lactose digestion [3]. The researchers analyzed the genomes of 242 European and Middle Eastern dogs, 38 Southeast Asian indigenous dogs, and 41 gray wolves for evidence of positive selection. Mutations can increase in frequency in a population for many reasons, but if they do so because they offer a selective advantage (that is, they increase reproductive success or ability to survive), they will leave a telltale signature in the DNA.

Using statistical tools that identify these genetic signatures of positive selection, the team identified three genetic markers from European dogs with strong positive selection signals [3]. One of these three markers was in the lactase (LCT) gene and was found in 91.7% of European dogs, 61.8% of Southeast Asian dogs, and just 6.1% of wolves [3]. Based on research in mice and humans, the genetic change associated with this LCT marker is believed to increase the expression of the LCT gene; dogs who have this mutation would keep this gene turned on more and make more lactase than those that have the original, or ancestral, LCT gene [3].

These results suggest that in places where human populations relied heavily on dairy for nutrition (either by dairy farming or pastoralism), humans and their dogs evolved adaptations for improved lactose digestion. Dr. Pat Shipman, Professor Emeritus of Anthropology at Pennsylvania State University, is not surprised by these results. “Adapting to milk obviously meant a new, high-protein and high-fat source of food. Dogs obviously would reap similar advantages [to humans] if they could digest a milk-based diet.”

The impact of agriculture on dog evolution is not limited to lactase persistence. Compared with wolf DNA, dog DNA was found to have more copies of the gene for amylase, an enzyme that helps digest starchy foods [4]. Human populations that eat diets high in starch have more copies of the amylase gene than do those with less starchy diets [9], suggesting selection favored increased copy numbers in both humans and dogs in response to dietary changes. Lactase persistence adds one more example of convergent evolution between dogs and humans that resulted from dietary changes during the development of agriculture.

Kibble with Cheese?

            For those wondering what these results mean for their own dog’s ability to digest lactose, take note. The mutation that increases the expression of the LCT gene is nearly fixed (that is, close to 100%) in dog breeds of European and Middle Eastern ancestry but is also present in more than half of the dogs from Southeast Asia. The lower frequency in Southeast Asian dogs may be because of reduced selective pressure for lactase persistence in this region or it could be an artifact of their smaller sample size in the data set. “I wouldn’t draw the conclusion that since my dog’s breed is historically from a particular part of the world, my dog will be lactose intolerant,” says Hekman. To get a better idea of how the lactase persistence mutation is distributed across current dog breeds, future studies on lactase persistence should increase the number of non-European dogs. Perhaps one day soon, dog DNA analyses can tell you your dog’s breed and whether they can eat a bowl of ice cream without digestive issues.

References

1. 1. 1. Gou X, Wang Z, Li N, Qiu F, Xu Z, Yan D, Yang S, Jia J, Kong X, Wei Z, Lu S. 2014. Whole-genome sequencing of six dog breeds from continuous altitudes reveals adaptation to high-altitude hypoxia. Genome Research 24(8):1308-15.
      2. Liu YH, Wang L, Xu T, Guo X, Li Y, Yin TT, Yang HC, Hu Y, Adeola AC, Sanke OJ, Otecko NO. 2018. Whole-genome sequencing of African dogs provides insights into adaptations against tropical parasites. Molecular Biology and Evolution 35(2):287-98.
      3. Liu YH, Wang L, Zhang Z, Otecko NO, Khederzadeh S, Dai Y, Liang B, Wang GD, Zhang YP. 2021. Whole-genome sequencing reveals lactase persistence adaptation in European dogs. Molecular Biology and Evolution 2021 Nov;38(11):4884-90.
      4. Axelsson E, Ratnakumar A, Arendt ML, Maqbool K, Webster MT, Perloski M, Liberg O, Arnemo JM, Hedhammar Å, Lindblad-Toh K. 2013. The genomic signature of dog domestication reveals adaptation to a starch-rich diet. Nature 495(7441):360-4.
      5. Wang GD, Zhai W, Yang H-C, Fan R-X, Cao X, Zhong L, Wang L, Liu F, Wu H, Cheng L-G. 2013. The genomics of selection in dogs and the parallel evolution between dogs and humans. Nature Communications 4:1-9.
      6. Perri AR, Feuerborn TR, Frantz LA, Larson G, Malhi RS, Meltzer DJ, Witt KE. 2021. Dog domestication and the dual dispersal of people and dogs into the Americas. Proceedings of the National Academy of Sciences 118(6): https://doi.org/10.1073/pnas.2010083118
      7. Ollivier M, Tresset A, Frantz LA, Bréhard S, Bălăşescu A, Mashkour M, Boroneanţ A, Pionnier-Capitan M, Lebrasseur O, Arbogast RM, Bartosiewicz L. 2018. Dogs accompanied humans during the Neolithic expansion into Europe. Biology Letters 14(10): 20180286.
      8. Perry G, Dominy N, Claw K. et al. 2007. Diet and the evolution of human amylase gene copy number variation. Nature Genetics 39: 1256–1260.

It’s no secret that type 2 diabetes is a widespread public health concern, with around 463 million people around the world suffering from the disease [1]. Researchers have known for some time that yogurt consumption has a protective effect against the ails of type 2 diabetes, but the physiological and molecular mechanism behind this effect has been largely unknown [2,3]. In a new multi-tiered study, researchers discovered that gut microbiota, as well as metabolites produced by the lactic acid bacteria in yogurt, help with type 2 diabetes in mice [4].

Type 2 diabetes is often associated with obesity and an excess of glucose in the bloodstream. The disease is characterized by the body losing sensitivity to insulin, the hormone that causes cells to take up blood sugar, and symptoms of type 2 diabetes can include increased thirst, fatigue, frequent urination, blurred vision, and tingling in the extremities [5].

Previous studies have found that yogurt consumption was associated with lower body weight and lower incidence of type 2 diabetes [6–8], and the new paper, published in Nature Communications, sought to figure out the mechanism behind that correlation by experimenting and testing with a dietary mouse model of obesity-linked type 2 diabetes [4].

An international research team from Canada and France fed one group of mice a high-sugar and high-fat diet to induce diabetes, and fed a similar diet that also included the equivalent of two servings of yogurt to another group of mice. After 12 weeks, they examined a variety of physical metrics including body weight, liver function, insulin resistance, blood sugar, and the metabolites present in the mice’s livers and muscle tissue [4].

They found that metabolites called branched-chain hydroxy acids (BCHAs) produced during lactic acid fermentation of yogurt had a protective effect against insulin insensitivity. “BCHAs are found in fermented dairy products and are particularly abundant in yogurt. Our body produces BCHA naturally, but weight gain seems to affect the process,” says Dr. Hana Koutnikova, a lead author of the paper from Danone Nutricia Research, in a press release.

“In the group that was not given yogurt, the amount of these metabolites in the bloodstream and in the liver decreased with weight gain. In the yogurt group, the amount of BCHA was partially maintained,” explains Andre Marette, another lead author from Laval University in Quebec, Canada.

Remarkably, the researchers also found that BCHA modulated glucose metabolism in both liver and muscle cells, proving that blood sugar can be controlled at an individual, cellular level by these metabolites [4].

In a second part of the study, the scientists also examined how the gut microbiota was affected by yogurt. Feces from the mice that were fed either a yogurt-supplemented or non-yogurt diet were transplanted into other mice. That changed the bacterial assemblage in the gut, which in turn, improved blood sugar control and insulin sensitivity in the mice that were fed the yogurt-fed fecal transplant [4].

While this study was conducted on mice to determine the cause of the metabolic effects of dietary yogurt in a mouse model of obesity-linked type 2 diabetes, similar principles should also apply in humans. We look forward to yogurt intervention trials in humans to find out—perhaps skipping those fecal transplants.

References

1. 1. International Diabetes Federation. IDF Diabetes Atlas, 9th edn. Brussels, Belgium: International Diabetes Federation, (2019). https://www.idf.org/e-library/epidemiology-research/diabetes-atlas/159-idf-diabetes-atlas-ninth-edition-2019.html
   2. Drouin-Chartier J.P., Li Y., Korat A.V., Ding M, Lamarche B, Manson J.E., Rimm E.B., Willett W.C., Hu F.B. Changes in dairy product consumption and risk of type 2 diabetes: results from 3 large prospective cohorts of US men and women. Am J Clin Nutr. 110, 1201–1212 (2019).
   3. Fernandez M.A., Panahi S., Daniel N., Tremblay A., Marette A. Yogurt and cardiometabolic diseases: a critical review of potential mechanisms. Adv Nutr. 8, 812-29 (2017).
   4. Daniel, N., Nachbar, R.T., Tran, T.T.T., Ouellette, A., Varin, T.V., Cotillard, A., Quinquis, L., Gagné, A., St-Pierre, P., Trottier, J., Marcotte, B. Gut microbiota and fermentation-derived branched chain hydroxy acids mediate health benefits of yogurt consumption in obese mice. Nat Commun. 13, 1-8 (2022). https://doi.org/10.1038/s41467-022-29005-0
   5. Mayo Clinic. Internet: https://www.mayoclinic.org/diseases-conditions/type-2-diabetes/symptoms-causes/syc-20351193
   6. Mozaffarian, D., Hao, T., Rimm, E.B., Willett, W.C., Hu, F.B. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med. 364, 2392-404 (2011).
   7. Sayon-Orea C., Martínez-González M.A., Ruiz-Canela M., Bes-Rastrollo M. Associations between yogurt consumption and weight gain and risk of obesity and metabolic syndrome: a systematic review. Adv Nutr. 8:1 (2017).
   8. Soedamah-Muthu S.S., De Goede J. Dairy consumption and cardiometabolic diseases: systematic review and updated meta-analyses of prospective cohort studies. Curr Nutr Rep. 7, 171-82 (2018).

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 [4].

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 [4]. 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 [4]. The integrity of the intestine’s mucus layer has been directly associated with preventing inflammation and infection, as well as maintaining gut homeostasis [7]. 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 [8].

Butyrate inhibition of HDAC also influences the regulation and function of T regulatory (T_reg) cells within the colon [1-4]. T_reg cells are important suppressors of inflammatory immune responses, including allergies. By increasing T_reg 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 T_reg cells called G protein receptors (GPR). When SCFA binds to GPR on cells, it triggers these cells to produce anti-inflammatory cytokines [4]. The importance of this triggering was demonstrated when researchers “knocked out” specific SCFA-sensitive GPR in mice [9]. 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 [9].

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 [3] 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 [4]. 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 [1].

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 [2] 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 [2]. 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 [2].

Gut Check

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.”

References

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. Ang Z, Ding JL. 2016. GPR41 and GPR43 in obesity and inflammation–protective or causative? Frontiers in Immunology 7: 28.