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Breastfeeding-Bifidobacterium-Infant and young children's immune system development, the molecular mechanism between these three has finally made new progress
.
A recent study led by Professor Henrik M.
Roager of the Technical University of Denmark, through sequencing analysis of the microbiota and metabolites in fecal samples of infants and young children, as well as a series of in vitro culture experiments, revealed that the bifidobacteria in the infant intestines pass through Aromatic lactate dehydrogenase (ALDH) converts carbohydrates and aromatic amino acids in breast milk into aromatic lactate, a mechanism that regulates immune cell function
.
The article was published in the journal Nature Microbiology [1]
.
Figure 1.
Source of the article Breast milk is the preferred food source for many newborn babies.
It not only provides nutrition, but also helps babies prevent certain pathogenic microbial infections and affects the composition of intestinal flora
.
Breastfed babies typically have a higher proportion of bifidobacteria in their guts because bifidobacteria are good at metabolizing carbohydrates in breast milk, such as human milk oligosaccharides (HMOs), giving them a competitive advantage in the infant gut
.
Not only that, some studies have even isolated live Bifidobacterium strains from breast milk [2], indicating that breast milk not only affects the composition of gut microbiota through nutrients, but can also directly deliver probiotics to infants
.
Bifidobacteria can not only help metabolize nutrients, but also affect the early immune system development of newborns and suppress excessive immune responses.
Infants and young children lacking bifidobacteria have a higher chance of developing allergies and asthma during growth [3]
.
However, the molecular mechanisms by which bifidobacteria metabolites regulate immune cell function remain unclear
.
To answer this question, researchers in the laboratory of Prof.
Henrik M.
Roager recruited 59 healthy non-preterm Danish infants and young children, with an average age of 9.
1 months, 24 who were still breastfeeding, weaned or not breastfeeding 35 people were fed
.
First, the feces of these infants and young children were collected for 16S rRNA gene sequencing and ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) to detect the bacterial composition and metabolite levels
.
Sure enough, the relative content of bifidobacteria in the intestines of the breastfed babies was higher, and the types of bifidobacteria in the feces of the two groups of babies were different.
The intestinal tracts of the breastfed babies were enriched with Bifidobacterium infantis, mainly including B.
longum , B.
bifidum and B.
breve, another group that is more non-breast-milking/acquired B.
adolescentis, including B.
adolescentis, B.
animalis/pseudolongum and B.
catenulatum, appears to be a food source in infancy It also determines the type of bifidobacteria in the baby's body
.
In terms of metabolites, the content of three kinds of aromatic lactic acid, indole lactic acid (ILA), 4-hydroxyphenyl lactic acid (4-OH-PLA), and phenyl lactic acid (PLA) in the feces of breastfed babies was higher than that of non-breast-fed babies.
One group, and the content of these three kinds of aromatic lactic acid was only significantly positively correlated with the abundance of the three strains of "Bifidobacterium infantis" B.
longum, B.
bifidum and B.
breve, in addition, aromatic propionic acid was also found The contents of , aromatic amino acids, and aromatic acetic acid were negatively correlated with the abundance of these strains of bifidobacteria
.
A similar gut microbiota structure was also observed in stool from another group of younger infants (0-6 months), as well as a positive correlation between Bifidobacterium infantis and aromatic lactic acid
.
Figure 2.
Similarity of gut microbiota composition and bifidobacteria content of babies in ab breastfeeding group (red) and weaning group (blue) So are these three strains of bifidobacteria that convert aromatic propionic acid and aromatic amino acids? What about aromatic lactic acid? To test this hypothesis, researchers cultured 12 Bifidobacterium strains in vitro in an anaerobic environment, adding glucose or human milk oligosaccharides as the sole source of carbohydrates, and adding three Aromatic amino acids
.
The results showed that B.
bifidum, B.
breve, B.
longum ssp.
longum, B.
longum ssp.
infantis and B.
scardovii were able to synthesize the above three kinds of aromatic lactic acid in large quantities, and they were also used in human milk oligosaccharide.
Yields are higher when used as a carbohydrate source
.
In addition, the researchers also found the key enzyme involved in this metabolic process-aromatic lactate dehydrogenase
.
When the aromatic lactate dehydrogenase in B.
longum ssp.
Infantis was transferred to E.
coli, E.
coli could also synthesize three kinds of aromatic lactic acids, indole lactic acid, 4-hydroxyphenyl lactic acid, and phenyl lactic acid
.
The ability of Bifidobacterium mutants lacking aromatic lactate dehydrogenase to synthesize aromatic lactic acid in vitro and in germ-free mice was significantly reduced
.
And this enzyme has high homology in B.
longum ssp.
longum, B.
longum ssp.
Infantis, B.
bifidum, B.
breve and B.
scardovii, but no homology was found in non-bifidobacterium greater than 60% of the genetic sequence
.
Figure 3.
In vitro culture experiments verify that bifidobacteria metabolize aromatic lactate dehydrogenase to synthesize aromatic lactate.
The next key question is how the metabolite of Bifidobacterium infantis, aromatic lactate, regulates immune cell function
.
In fact, many metabolites of aromatic amino acids, such as indole and indole lactate, have been shown to affect immune cell function by binding to cell surface hydroxycarboxylic acid receptors 3 and aromatic hydrocarbon receptors [4-5]
.
In this study, researchers isolated immune cells from human peripheral blood and focused on the effects of aromatic lactate on the differentiation and development of T cells and macrophages through in vitro experiments
.
Experiments found that indole lactate can promote the expression of interleukin 22 (IL-22) during the differentiation of Th17 cells by acting on the aryl hydrocarbon receptors on the surface of T cells
.
IL-22 plays an important role in maintaining tight junctions of intestinal epithelial cells and resisting the invasion of pathogenic microorganisms in the intestinal mucosa
.
On the other hand, indole lactate inhibited the expression of macrophage pro-inflammatory cytokine (IL-12p70) and excessive inflammatory response by acting on aryl hydrocarbon receptors and hydroxycarboxylic acid receptor 3 on the surface of macrophages
.
It is worth noting that aromatic lactic acid can be absorbed by intestinal epithelial cells and transferred into the blood, and participate in the systemic regulation of immune cell function, which may be why the influence of intestinal flora on the development of the immune system in infancy is not limited to the intestinal tract.
one of the reasons
.
Figure 4.
The regulation of T cells and macrophages in human peripheral blood by aromatic lactic acid It seems that bifidobacteria really contribute to the growth and development of babies
.
Some manufacturers have begun to add metabolites such as bifidobacteria or indole to formula milk or probiotics for mothers.
Will aromatic lactic acid become a new dietary supplement for regulating the development of the newborn's immune system? Of course, don't forget that there is an intricate competition between gut microbes in the body.
How much impact aromatic lactic acid can have on the development of the immune system remains to be verified by in vivo experiments
.
Reference 1.
Laursen, MF, et al.
, Bifidobacterium species associated with breastfeeding produce aromatic lactic acids in the infant gut.
Nature microbiology, 6, 1367–1382, 20212.
Gueimonde M, et al.
, Breast milk: a source of bifidobacteria for infant gut development and maturation? Neonatology, 92, 64-6 (2007).
3.
Stokholm, J.
et al.
Maturation of the gut microbiome and risk of asthma in childhood.
Nat.
Commun.
9, 141 (2018) .
4.
Peters, A.
et al.
Metabolites of lactic acid bacteria present in fermented foods are highly potent agonists of human hydroxycarboxylic acid receptor3.
PLoS Genet.
15, e1008145 (2019).
5.
Zelante, T.
et al.
Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22.
Immunity 39, 372–385 (2013).
Editor-in-chargeYing Yuyan
.
A recent study led by Professor Henrik M.
Roager of the Technical University of Denmark, through sequencing analysis of the microbiota and metabolites in fecal samples of infants and young children, as well as a series of in vitro culture experiments, revealed that the bifidobacteria in the infant intestines pass through Aromatic lactate dehydrogenase (ALDH) converts carbohydrates and aromatic amino acids in breast milk into aromatic lactate, a mechanism that regulates immune cell function
.
The article was published in the journal Nature Microbiology [1]
.
Figure 1.
Source of the article Breast milk is the preferred food source for many newborn babies.
It not only provides nutrition, but also helps babies prevent certain pathogenic microbial infections and affects the composition of intestinal flora
.
Breastfed babies typically have a higher proportion of bifidobacteria in their guts because bifidobacteria are good at metabolizing carbohydrates in breast milk, such as human milk oligosaccharides (HMOs), giving them a competitive advantage in the infant gut
.
Not only that, some studies have even isolated live Bifidobacterium strains from breast milk [2], indicating that breast milk not only affects the composition of gut microbiota through nutrients, but can also directly deliver probiotics to infants
.
Bifidobacteria can not only help metabolize nutrients, but also affect the early immune system development of newborns and suppress excessive immune responses.
Infants and young children lacking bifidobacteria have a higher chance of developing allergies and asthma during growth [3]
.
However, the molecular mechanisms by which bifidobacteria metabolites regulate immune cell function remain unclear
.
To answer this question, researchers in the laboratory of Prof.
Henrik M.
Roager recruited 59 healthy non-preterm Danish infants and young children, with an average age of 9.
1 months, 24 who were still breastfeeding, weaned or not breastfeeding 35 people were fed
.
First, the feces of these infants and young children were collected for 16S rRNA gene sequencing and ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS) to detect the bacterial composition and metabolite levels
.
Sure enough, the relative content of bifidobacteria in the intestines of the breastfed babies was higher, and the types of bifidobacteria in the feces of the two groups of babies were different.
The intestinal tracts of the breastfed babies were enriched with Bifidobacterium infantis, mainly including B.
longum , B.
bifidum and B.
breve, another group that is more non-breast-milking/acquired B.
adolescentis, including B.
adolescentis, B.
animalis/pseudolongum and B.
catenulatum, appears to be a food source in infancy It also determines the type of bifidobacteria in the baby's body
.
In terms of metabolites, the content of three kinds of aromatic lactic acid, indole lactic acid (ILA), 4-hydroxyphenyl lactic acid (4-OH-PLA), and phenyl lactic acid (PLA) in the feces of breastfed babies was higher than that of non-breast-fed babies.
One group, and the content of these three kinds of aromatic lactic acid was only significantly positively correlated with the abundance of the three strains of "Bifidobacterium infantis" B.
longum, B.
bifidum and B.
breve, in addition, aromatic propionic acid was also found The contents of , aromatic amino acids, and aromatic acetic acid were negatively correlated with the abundance of these strains of bifidobacteria
.
A similar gut microbiota structure was also observed in stool from another group of younger infants (0-6 months), as well as a positive correlation between Bifidobacterium infantis and aromatic lactic acid
.
Figure 2.
Similarity of gut microbiota composition and bifidobacteria content of babies in ab breastfeeding group (red) and weaning group (blue) So are these three strains of bifidobacteria that convert aromatic propionic acid and aromatic amino acids? What about aromatic lactic acid? To test this hypothesis, researchers cultured 12 Bifidobacterium strains in vitro in an anaerobic environment, adding glucose or human milk oligosaccharides as the sole source of carbohydrates, and adding three Aromatic amino acids
.
The results showed that B.
bifidum, B.
breve, B.
longum ssp.
longum, B.
longum ssp.
infantis and B.
scardovii were able to synthesize the above three kinds of aromatic lactic acid in large quantities, and they were also used in human milk oligosaccharide.
Yields are higher when used as a carbohydrate source
.
In addition, the researchers also found the key enzyme involved in this metabolic process-aromatic lactate dehydrogenase
.
When the aromatic lactate dehydrogenase in B.
longum ssp.
Infantis was transferred to E.
coli, E.
coli could also synthesize three kinds of aromatic lactic acids, indole lactic acid, 4-hydroxyphenyl lactic acid, and phenyl lactic acid
.
The ability of Bifidobacterium mutants lacking aromatic lactate dehydrogenase to synthesize aromatic lactic acid in vitro and in germ-free mice was significantly reduced
.
And this enzyme has high homology in B.
longum ssp.
longum, B.
longum ssp.
Infantis, B.
bifidum, B.
breve and B.
scardovii, but no homology was found in non-bifidobacterium greater than 60% of the genetic sequence
.
Figure 3.
In vitro culture experiments verify that bifidobacteria metabolize aromatic lactate dehydrogenase to synthesize aromatic lactate.
The next key question is how the metabolite of Bifidobacterium infantis, aromatic lactate, regulates immune cell function
.
In fact, many metabolites of aromatic amino acids, such as indole and indole lactate, have been shown to affect immune cell function by binding to cell surface hydroxycarboxylic acid receptors 3 and aromatic hydrocarbon receptors [4-5]
.
In this study, researchers isolated immune cells from human peripheral blood and focused on the effects of aromatic lactate on the differentiation and development of T cells and macrophages through in vitro experiments
.
Experiments found that indole lactate can promote the expression of interleukin 22 (IL-22) during the differentiation of Th17 cells by acting on the aryl hydrocarbon receptors on the surface of T cells
.
IL-22 plays an important role in maintaining tight junctions of intestinal epithelial cells and resisting the invasion of pathogenic microorganisms in the intestinal mucosa
.
On the other hand, indole lactate inhibited the expression of macrophage pro-inflammatory cytokine (IL-12p70) and excessive inflammatory response by acting on aryl hydrocarbon receptors and hydroxycarboxylic acid receptor 3 on the surface of macrophages
.
It is worth noting that aromatic lactic acid can be absorbed by intestinal epithelial cells and transferred into the blood, and participate in the systemic regulation of immune cell function, which may be why the influence of intestinal flora on the development of the immune system in infancy is not limited to the intestinal tract.
one of the reasons
.
Figure 4.
The regulation of T cells and macrophages in human peripheral blood by aromatic lactic acid It seems that bifidobacteria really contribute to the growth and development of babies
.
Some manufacturers have begun to add metabolites such as bifidobacteria or indole to formula milk or probiotics for mothers.
Will aromatic lactic acid become a new dietary supplement for regulating the development of the newborn's immune system? Of course, don't forget that there is an intricate competition between gut microbes in the body.
How much impact aromatic lactic acid can have on the development of the immune system remains to be verified by in vivo experiments
.
Reference 1.
Laursen, MF, et al.
, Bifidobacterium species associated with breastfeeding produce aromatic lactic acids in the infant gut.
Nature microbiology, 6, 1367–1382, 20212.
Gueimonde M, et al.
, Breast milk: a source of bifidobacteria for infant gut development and maturation? Neonatology, 92, 64-6 (2007).
3.
Stokholm, J.
et al.
Maturation of the gut microbiome and risk of asthma in childhood.
Nat.
Commun.
9, 141 (2018) .
4.
Peters, A.
et al.
Metabolites of lactic acid bacteria present in fermented foods are highly potent agonists of human hydroxycarboxylic acid receptor3.
PLoS Genet.
15, e1008145 (2019).
5.
Zelante, T.
et al.
Tryptophan catabolites from microbiota engage aryl hydrocarbon receptor and balance mucosal reactivity via interleukin-22.
Immunity 39, 372–385 (2013).
Editor-in-chargeYing Yuyan
