"Cell": Bifidobacterium, you are awesome!

The leader of the probiotics world, Bifidobacteria, a marker of healthy flora, has ushered in a new moment of highlight
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Recently, a research team led by Professor Petter Brodin of the Women and Children's Health Center of Karolinska University Hospital and Research Institute in Sweden published an important research result in the journal Cell[1]
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They found that the human milk oligosaccharides (HMOs) metabolism gene expressed by bifidobacteria activated the tryptophan metabolism pathway and increased the metabolite of indole-3-lactic acid, thereby promoting the anti-inflammatory cytokine interleukin 27 (IL -27), the expression of interferon beta (IFN-β), and induce T cells to secrete the regulatory factor galectin-1, thereby maintaining the homeostasis of the intestinal and peripheral immune system, and inhibiting the occurrence of excessive immune responses
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More importantly, if newborns are given oral bifidobacteria from day 7 to day 29 after birth, their blood levels of Th2 cells and pro-inflammatory cells Th17 related to allergies are lower
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Screenshot of the paper’s homepage The first three months after birth is a critical period for the establishment of intestinal flora.
If an imbalanced intestinal flora is formed during this period, such as too many proteobacteria strains, the child will grow up.
During the process, the risk of suffering from colic, atopic wheeze, allergies, and even type I diabetes and Crohn’s disease is higher [2, 3]
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Research and statistics on neonatal flora and diseases in Finland, Ecuador and other places show that newborns with Bifidobacterium in the early intestines have a lower risk of intestinal inflammation and autoimmune diseases [4, 5], but The reason and mechanism behind this statistical association are not yet clear
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In addition, Bifidobacterium is a microorganism that can decompose human milk oligosaccharides in breast milk, and the human body lacks enzymes to metabolize this oligosaccharide, so Bifidobacteria can also help breast milk digestion and absorption [6]
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In more modern areas, the proportion of Bifidobacteria colonized in early infancy is lower, and the chance of obtaining an imbalanced flora is also higher [7]
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Therefore, understanding the effect of early colonization of bifidobacteria on the development of the intestinal immune system and its mechanism of action, and making reasonable use of it, may become the key to helping newborns to establish a healthy flora
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To answer this question, the researchers recruited 208 babies and collected blood samples (858 cases in total) and stool samples (357 cases in total) at different time points from 0-1452 days after birth
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For blood samples, the researchers designed an antibody cocktail that can recognize 44 types of cell markers.
Flow cytometry can detect the number and functions of 64 types of immune cells
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In addition, Olink assays was used to measure the content of 355 plasma cell proteins in the blood
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For stool samples, the researchers used metagenomics sequencing technology to determine the composition of the intestinal flora
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The samples collected in the experiment and the schematic diagram of the main detection methods.
The blood test results show that the infant’s natural immune cells (monocytes) and immune factors (interferon) began to be up-regulated from 0-7 days after birth, and the expression of interleukin 17 ( IL-17) adaptive immune cells γδT cells, and a transient increase of IL-17 in plasma was detected in about 2 months
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What’s more interesting is that the tissue-specific T cells (CD38+ CD62L-) in the intestinal mucosa have migrated to the blood and circulate at the time of birth, and the proportion of blood memory T cells continues to increase until birth.
In the next 29 days, it reached a relatively high percentage of 65%
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The proportion of intestinal mucosal tissue-specific T cells in the blood to overall memory T cells.
Researchers sorting and mRNA sequencing of these intestinal mucosal tissue-specific T cells found that these cells express higher levels of interference compared with other memory cells Interleukin (IFN), interleukin 15 (IL-15) and macrophage colony stimulating factor (M-CSF) have a regulatory effect on the functions of natural killer cells and monocytes in the blood
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Therefore, memory T cells induced by food or bacterial antigens in the intestines have already surpassed geographical restrictions in the first month of our lives, and systematically affect the development of the peripheral immune system through the blood
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So what is the difference in the composition of blood immune cells in newborns with and without bifidobacteria? From an overall point of view, the content of bifidobacteria in baby stool samples gradually increased with growth, and stabilized at around 9 weeks, accounting for about 35% of all bacteria
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However, there are still some newborns who have not detected bifidobacteria in the stool during the first month after birth or the entire sample collection period (0-24 weeks)
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The structure of neonatal intestinal flora changes with time after birth.
In addition, combining the test results of blood samples with the abundance of bifidobacteria, the scientists found that newborns without bifidobacteria have more macrophages in their blood.
Phage cells, basophils, plasmablasts, memory CD8+ T cells and higher levels of pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin 17 (IL-17); In newborns with bifidobacteria, there are more anti-inflammatory monocytes, regulatory T cells with immunosuppressive function, and anti-inflammatory cytokines in the blood
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Based on the test results of the above samples, Professor Petter Brodin and researchers at the University of California designed a more intuitive and bold experiment
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Oral bifidobacteria to newborns
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All the sixty infants participating in the experiment received breastfeeding only.
From the 7th to the 29th day after birth, 29 newborns were given a daily oral intake of 1.
8*1010 Bifidobacterium (B.
longum subsp.
Infantis EVC001), and the other 31 The infant served as a blank control
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The flow chart of the neonatal experiment is similar to the test results of the Swedish neonatal samples.
The infants who took oral bifidobacteria in the early stage had lower levels of IL-13, IL-17, IL-21 and IL-33 in the blood on the 60th day after birth.
There are fewer Th2 cells and pro-inflammatory cells Th17 associated with allergic reactions
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The difference is that these newborns have higher levels of IFN-β in the blood, but the effect of this cytokine on the development of early immune cells is still unclear
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So how do bifidobacteria induce the development of anti-inflammatory immune cells? Because the metabolites of bifidobacteria can bind to immune cell receptors, they can regulate the function of immune cells [8]
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So scientists focused their attention on the metabolites of human milk oligosaccharides (HMOs) that are specifically decomposed by bifidobacteria
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They found from samples from Swedish babies that the expression of human milk oligosaccharide metabolism genes derived from bifidobacteria in feces is related to the pro-inflammatory factors IL-6, TNF-α, IL-17A and allergic reaction-related cytokines in plasma.
IL-13 is negatively correlated
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Researchers at the University of California also used the fecal supernatant of two groups of newborns (without live bacteria) to co-culture with undifferentiated naive T cells in vitro.
They observed that oral bifidobacteria promoted neonatal fecal supernatants.
In order to improve the differentiation and development of Th1 cells, the fecal supernatant of neonates in the control group induced the differentiation of Th2 cells
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The fecal supernatants of the two groups induced Th17 differentiation, but the Th17 cells in the control group expressed higher Ki67 genes, indicating that their replication and division were more active
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This in vitro experiment shows that the metabolites of bifidobacteria or other factors can directly regulate the differentiation of naive T cells
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There is still a key question that has not been solved until now.
What product of human milk oligosaccharides metabolized by bifidobacteria plays a role in regulating the development of T cells? The scientists compared the feces of newborn infants with oral bifidobacteria and those of control infants and found that among the 564 metabolites detected, Bifidobacterium infantis significantly activated the tryptophan metabolic pathway and increased indole-3-lactic acid.
(ILA) This metabolite
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In vitro experiments have shown that co-culture of ILA with naive T cells can inhibit the differentiation of naive T cells into pathogenic Th2 and Th17, and induce T cells to secrete the regulatory factor galectin-1
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In general, the colonization of bifidobacteria within one month of birth can inhibit the differentiation of Th2 and Th17 cells through its metabolite indole-3-lactic acid (ILA), and promote the anti-inflammatory cytokine interleukin 27 (ILA).
-27), the expression of β-interferon (IFN-β), and induce T cells to secrete the regulatory factor galectin-1
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These cytokines maintain the homeostasis of the intestinal and peripheral immune system and inhibit the occurrence of excessive immune responses
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The article brings us a lot of thinking, such as whether other intestinal symbiotic bacteria that metabolize human milk oligosaccharides play the same role in the early development of the immune system? Can bifidobacteria in non-breastfeeding newborns have the same effect? Is it safer and more effective to directly supplement the metabolite of indole-3-lactic acid to infants? It is worth noting that there are uncontrollable variables in the experiment of supplementing infants with bifidobacteria, such as the intake of environmental microorganisms, which may affect the results of the experiment
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The short sample collection and testing time and the single sample (peripheral blood only) are also some small shortcomings of this study.
I hope that more comprehensive data and more accurate conclusions can be obtained in subsequent studies
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Published 2020 Nov 23.
doi:10.
1186/s12866-020-02023-y Chief EditorBioTalker