"Cell": The baby is being "trained" with intestinal bacteria before being born!

Intestinal microbes affect a person's life
.

Many studies have shown that intestinal microbes are closely related to the early immune and physiological development of human life [1,2]
.

How gut microbes participate in the early development of the human body is still unclear
.

Does the fetus before birth possess gut microbes? Scientists have different opinions on this
.

Until May of this year, there are still studies pointing out that during normal pregnancy, the newborn is sterile in the mother's womb [3]
.

Recently, a team led by Florent Ginhoux from the Singapore Immunology Network/Shanghai Institute of Immunology published important research results in the Cell Journal [4]
.

Researchers found that in the second trimester (12-24 weeks, from healthy fetuses who had aborted pregnancy due to psychosocial reasons), there were a small amount of bacteria, such as staphylococcus and lactic acid bacteria, in the fetus intestines, skin, placenta and lungs
.

Furthermore, the researchers found that culturable bacteria isolated from fetuses can induce and activate memory T cells in fetal mesenteric lymph nodes in vitro
.

The above results indicate that not only microorganisms exist in fetal tissues, but microorganisms also play an important role in the establishment and activation of immunity during fetal development
.

Does the research model map people born with bacteria? Regarding this scientific question, we can say that we are on the first level, and Daniel is at least on the third level
.

Let's take everyone to appreciate the different scenery
.

As we all know, the fetal immune system develops during pregnancy
.

The researchers first studied T cells in multiple organs and tissues (lung, skin, intestine, thymus, liver, mesenteric lymph nodes and blood) of the fetus in the second trimester of pregnancy using mass spectrometry flow cytometry
.

Further research found that there is antigen stimulation in the fetus, which activates a variety of T cells including effector memory T cells
.

It's very interesting, what exactly stimulates the fetal immune system? There are many different types of T cells in the later stages of fetal development.
Researchers have used 16S rRNA gene sequencing to analyze the bacterial signals of multiple fetal tissues
.

In order to strictly avoid the contamination of the tissue samples during the experiment, the researchers also set up a series of controls (experimenter control, PBS negative control, experimental reagent control, environmental control)
.

PCoA, qPCR, and α and β diversity analysis of the sequencing results show that compared with the control, there is indeed a low biomass microbial signal in the fetal tissue
.

The researchers further clustered and enriched the sequencing data and showed that the microbial signal of the fetal tissue was significantly different from the control
.

Microorganisms enriched in fetal tissues include Flavobacterium, Lactobacillus, Staphylococcus, Affibo, Pseudomonas, Brachyrhizobium, and Brevundomonas
.

The microbial signal of the fetal tissue is significantly different from that of the control.
Through scanning electron microscopy, the researchers directly observed that there is indeed a discrete flora structure in the fetal intestine
.

Through RNA in situ hybridization, the researchers further obtained the localization of bacterial RNA in the fetal intestinal lumen, and the bacteria are tightly arranged in the intestinal epithelium
.

These observations indicate that there are indeed bacteria in the fetus in the second trimester of pregnancy
.

Under the electron microscope, the bacteria-like structure in the fetal intestinal cavity can be directly observed.
The above data shows that there are specific microorganisms in the fetal organs in the second trimester, especially the intestine
.

So do they have physiological significance and are they closely related to the diverse T cells of fetal tissues? In order to verify whether fetal T cells are activated through the presentation of bacterial antigens by dendritic cells (DCs), the researchers simulated the fetal intestinal environment and constructed an in vitro experimental system for monitoring
.

The researchers first incubated dendritic cells from the fetus with heat-inactivated fetal intestinal bacteria-lactic acid bacteria and staphylococci for 8 hours, and then co-cultured with T cells from the fetus, and detected T cell activation Situation
.

The results of the study show that both lactic acid bacteria and staphylococci can significantly activate memory T cells, and at the same time the total number of T cells significantly increases
.

It is worth noting that compared with lactic acid bacteria, staphylococcus-induced dendritic cells always have a higher T cell expansion, which indicates that the fetal T cell response has bacterial specificity
.

Cultureable bacteria isolated from the fetus can induce and activate memory T cells in fetal mesenteric lymph nodes in vitro.
Next, the researchers treated dendritic cells with paraformaldehyde (PFA) to observe the activation of T cells
.

The researchers found that the activation and expansion of T cells induced by living dendritic cells were significantly higher than those of dendritic cells after PFA fixation
.

This indicates that after bacterial exposure, the effect on fetal T cells is a combination of antigen presentation and cytokine-mediated signaling pathways
.

Of course, bacterial antigen presentation alone is sufficient to drive the activation of a large number of T cells
.

After PFA is fixed, dendritic cells can also significantly activate T cells.
This research really created a lot of precedents! For example, for the first time, the researcher used a fetus sample during pregnancy as the research object, and used a variety of technical means to prove the presence of low but persistent bacteria in the fetus
.

Furthermore, the researchers confirmed that the bacteria in the fetus play an important role in the early immune development of the fetus
.

This research really opened a door, and there are many questions left for scientists to do further research, for example, the source of fetal bacteria? The mechanism of vertical transmission of microorganisms from mother to child? The developmental mechanism of the fetal immune system and so on
.

References: [1] Ferretti P, Pasolli E, Tett A, et al.
Mother-to-Infant Microbial Transmission from Different Body Sites Shapes the Developing Infant Gut Microbiome.
Cell Host Microbe.
2018;24(1):133-145 .
e5.
doi:10.
1016/j.
chom.
2018.
06.
005[2] Roswall J, Olsson LM, Kovatcheva-Datchary P, et al.
Developmental trajectory of the healthy human gut microbiota during the first 5 years of life.
Cell Host Microbe .
2021;29(5):765-776.
e3.
doi:10.
1016/j.
chom.
2021.
02.
021[3] Kennedy KM, Gerlach MJ, Adam T, et al.
Fetal meconium does not have a detectable microbiota before birth [published online ahead of print, 2021 May 10].
Nat Microbiol.
2021;10.
1038/s41564-021-00904-0.
doi:10.
1038/s41564-021-00904-0[4] Mishra A, Lai GC, Yao LJ, et al.
Microbial exposure during early human development primes fetal immune cells [published online ahead of print, 2021 May 25].
Cell.
2021;S0092-8674(21)00574-2.
doi:10.
1016/j.
cell.
2021.
04.
039 The author of this article | Jiang Yongmao Editor | Dai Siyu