Mol. Cells 2021; 44(10): 706-709
Published online October 20, 2021
https://doi.org/10.14348/molcells.2021.0246
© The Korean Society for Molecular and Cellular Biology
Correspondence to : sunkyungl@hanyang.ac.kr
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
“Sam-chil-il,” the three-seven day in Korean tradition, means the 21st day after birth. When a baby is born, a house gate is decorated with “Gheum-Jool,” a rice straw string skewed with wooden charcoal sticks that boot off evil spirits, signals a new arrival, and bans visitors to avoid potentially harmful contacts. On every 7th day for the first three weeks, offering seaweed soup to “Samsin,” a goddess of child-bearing, is performed. After the final worship, “Gheum-Jool” is removed and visitors are allowed to meet and greet the newborn and her mother, welcoming the new arrival to the world. The next big event is “Baek-il,” the 100th-day celebration. Parents share rice cakes with 100 people, wishing their child a long life of 100 years. While modern-day extricating newborn care reduces infant mortality for the first three months, mounting scientific evidence indicates that what babies experience and develop for the first three months is crucial for their well-being immediately and in their entire life.
Human breast milk contains numerous human milk oligosaccharides (HMOs) that play a vital role in babies’ healthy growth (Andreas et al., 2015). Such complex, energetically expensive sugars are digested by babies even if they lack necessary glucosidases; however, their gut microbes are adapted to metabolizing HMOs, such as
To monitor immunological events, Henrick et al. (2021) collected blood samples from newborns in Sweden, profiled 64 blood immune cell populations, and quantified 355 unique plasma proteins. Within the first three weeks, the same duration as Sam-chil-il, there was an initial innate immune response, such as expanding monocytes and a transient surge in interferon γ (IFNγ) and other indicators of active immune systems. There was also a gradual increase in the frequency of memory regulatory T cells (Tregs). Additionally, right after Sam-chil-il, the number of γδT cells, most abundant in the gut mucosa, robustly increased. These responses indicate transient innate and adaptive immune activities and key regulatory mechanisms during the first several weeks of human life.
They also observed an expansion of a mucosal-specific subset of memory CD4+ T cells (Yi et al., 2019). In addition, analysis of enriched blood transcriptional modules revealed that the mucosal-specific T cells recognize antigens in babies’ intestine after birth, circulate and expand in the bloodstream, and interact with natural killer cells and monocytes in the newborn intestinal immune system, indicating active immune responses in babies’ intestine that early.
Metagenomics analysis of the newborns’ stool waters indicates that gut bacterial composition was highly variable at birth but gradually converged later. Especially, Bifidobacteriaceae is a major microbe family that increased in abundance, reaching the first peak near the 8th week after birth. Additionally, breastfed babies not treated with antibiotics held expanded Bifidobacteriaceae, composed of multiple species, including
There were dramatic differences in immune system states between babies holding abundant Bifidobacteriaceae and those who failed. Babies with abundant Bifidobacteriaceae frequently had more anti-inflammatory monocytes, a highly suppressive Treg subset, and elevated Treg-associated cytokines, including IL-27. In contrast, babies lacking Bifidobacteriaceae had many neutrophils, basophils, plasmablasts, memory CD8+ T cells (indicators of immune activation), and elevated levels of critical mediators of intestinal inflammation, such as tumor necrosis factor α (TNFα), IL-17A, and Th2 cytokines. Additionally, analysis of cell–cell interaction using Spearman correlation matrices confirmed the inverse correlation between memory Tregs and activated CD8+ T cells and proinflammatory monocytes. Therefore, the lack of Bifidobacteriaceae for the first weeks may result in systemic immune dysregulation, leading to systemic and intestinal inflammation.
Henrick et al. (2021) observed that some HMO-utilization genes (key ecological determinants of fitness for
A peculiar point in the Swedish cohort is that there is no bacteria isolate expressing all HMO-utilization genes, likely responsible for the low abundance of HMO-utilization genes. To assess the beneficial effects of HMO-utilization genes, they fed breastfed babies in California with
To understand the direct effects of bifidobacterial metabolites and enteric cytokines on T cells, Henrick et al. (2021) isolated naïve CD4+ T cells from human adults and treated them with stool water collected from EVC001-supplemented babies. Stool waters from EVC001-supplemented babies induced the Th1-like state, whereas those from control babies induced the Th2-like state. A tryptophan metabolite, indole-3-lactic acid (ILA), is the most over-represented in EVC001-fed babies out of 564 significantly different biochemicals in assessing fecal metabolites. Thus, Naïve CD4+ T cells were treated with ILA alone without any stool water, and their polarized cell types and transcripts were analyzed using a multi-omics approach (Jung et al., 2020). Galactin-1, a negative regulator of T cell activation, was highly upregulated in polarizing T cells. Galectin-1 induces IL-27, acting through IFNβ-dependent reprogramming of tissue macrophages, which is essential in resolving inflammation (Yaseen et al., 2020). Therefore, HMO-metabolizing bacteria may induce anti-inflammatory and tolerogenic responses by elevating IL-27, IFNβ, and ILA-mediated upregulation of galectin-1 that acts on CD4+ T cells, which expresses AhR, an ILA receptor (Uhlen et al., 2019).
The study by Henrick et al. (2021) provides solid evidence of molecular and cellular mechanisms that helps explain why babies colonized early in life with
Immediately after birth, the sterile baby gut becomes colonized by various microbes from the surroundings and mother. Many factors influence the intestinal microbiota composition and its establishment: vaginal birth or C-section; breastmilk or formula; antibiotics or herbal medicine, or just mom’s touch (Kostandy and Ludington-Hoe, 2019; Lee et al., 2019). Choices are made depending on clinical, traditional, personal reasons, and availability, and whatever outcomes continue to be managed. Nevertheless, there is good news that
This work is supported by a funding supported by the National Research Foundation of Korea (2018R1A2A3074987).
The author has no potential conflicts of interest to disclose.
Mol. Cells 2021; 44(10): 706-709
Published online October 31, 2021 https://doi.org/10.14348/molcells.2021.0246
Copyright © The Korean Society for Molecular and Cellular Biology.
Bifidobacteria carrying beneficial genes utilizing human milk oligosaccharides (HMOs) help develop a healthy immune system in breastfed babies.
Sun-Kyung Lee*
Department of Life Sciences, Research Institute for Natural Sciences, College of Natural Sciences, Hanyang University, Seoul 04763, Korea
Correspondence to:sunkyungl@hanyang.ac.kr
This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.
“Sam-chil-il,” the three-seven day in Korean tradition, means the 21st day after birth. When a baby is born, a house gate is decorated with “Gheum-Jool,” a rice straw string skewed with wooden charcoal sticks that boot off evil spirits, signals a new arrival, and bans visitors to avoid potentially harmful contacts. On every 7th day for the first three weeks, offering seaweed soup to “Samsin,” a goddess of child-bearing, is performed. After the final worship, “Gheum-Jool” is removed and visitors are allowed to meet and greet the newborn and her mother, welcoming the new arrival to the world. The next big event is “Baek-il,” the 100th-day celebration. Parents share rice cakes with 100 people, wishing their child a long life of 100 years. While modern-day extricating newborn care reduces infant mortality for the first three months, mounting scientific evidence indicates that what babies experience and develop for the first three months is crucial for their well-being immediately and in their entire life.
Human breast milk contains numerous human milk oligosaccharides (HMOs) that play a vital role in babies’ healthy growth (Andreas et al., 2015). Such complex, energetically expensive sugars are digested by babies even if they lack necessary glucosidases; however, their gut microbes are adapted to metabolizing HMOs, such as
To monitor immunological events, Henrick et al. (2021) collected blood samples from newborns in Sweden, profiled 64 blood immune cell populations, and quantified 355 unique plasma proteins. Within the first three weeks, the same duration as Sam-chil-il, there was an initial innate immune response, such as expanding monocytes and a transient surge in interferon γ (IFNγ) and other indicators of active immune systems. There was also a gradual increase in the frequency of memory regulatory T cells (Tregs). Additionally, right after Sam-chil-il, the number of γδT cells, most abundant in the gut mucosa, robustly increased. These responses indicate transient innate and adaptive immune activities and key regulatory mechanisms during the first several weeks of human life.
They also observed an expansion of a mucosal-specific subset of memory CD4+ T cells (Yi et al., 2019). In addition, analysis of enriched blood transcriptional modules revealed that the mucosal-specific T cells recognize antigens in babies’ intestine after birth, circulate and expand in the bloodstream, and interact with natural killer cells and monocytes in the newborn intestinal immune system, indicating active immune responses in babies’ intestine that early.
Metagenomics analysis of the newborns’ stool waters indicates that gut bacterial composition was highly variable at birth but gradually converged later. Especially, Bifidobacteriaceae is a major microbe family that increased in abundance, reaching the first peak near the 8th week after birth. Additionally, breastfed babies not treated with antibiotics held expanded Bifidobacteriaceae, composed of multiple species, including
There were dramatic differences in immune system states between babies holding abundant Bifidobacteriaceae and those who failed. Babies with abundant Bifidobacteriaceae frequently had more anti-inflammatory monocytes, a highly suppressive Treg subset, and elevated Treg-associated cytokines, including IL-27. In contrast, babies lacking Bifidobacteriaceae had many neutrophils, basophils, plasmablasts, memory CD8+ T cells (indicators of immune activation), and elevated levels of critical mediators of intestinal inflammation, such as tumor necrosis factor α (TNFα), IL-17A, and Th2 cytokines. Additionally, analysis of cell–cell interaction using Spearman correlation matrices confirmed the inverse correlation between memory Tregs and activated CD8+ T cells and proinflammatory monocytes. Therefore, the lack of Bifidobacteriaceae for the first weeks may result in systemic immune dysregulation, leading to systemic and intestinal inflammation.
Henrick et al. (2021) observed that some HMO-utilization genes (key ecological determinants of fitness for
A peculiar point in the Swedish cohort is that there is no bacteria isolate expressing all HMO-utilization genes, likely responsible for the low abundance of HMO-utilization genes. To assess the beneficial effects of HMO-utilization genes, they fed breastfed babies in California with
To understand the direct effects of bifidobacterial metabolites and enteric cytokines on T cells, Henrick et al. (2021) isolated naïve CD4+ T cells from human adults and treated them with stool water collected from EVC001-supplemented babies. Stool waters from EVC001-supplemented babies induced the Th1-like state, whereas those from control babies induced the Th2-like state. A tryptophan metabolite, indole-3-lactic acid (ILA), is the most over-represented in EVC001-fed babies out of 564 significantly different biochemicals in assessing fecal metabolites. Thus, Naïve CD4+ T cells were treated with ILA alone without any stool water, and their polarized cell types and transcripts were analyzed using a multi-omics approach (Jung et al., 2020). Galactin-1, a negative regulator of T cell activation, was highly upregulated in polarizing T cells. Galectin-1 induces IL-27, acting through IFNβ-dependent reprogramming of tissue macrophages, which is essential in resolving inflammation (Yaseen et al., 2020). Therefore, HMO-metabolizing bacteria may induce anti-inflammatory and tolerogenic responses by elevating IL-27, IFNβ, and ILA-mediated upregulation of galectin-1 that acts on CD4+ T cells, which expresses AhR, an ILA receptor (Uhlen et al., 2019).
The study by Henrick et al. (2021) provides solid evidence of molecular and cellular mechanisms that helps explain why babies colonized early in life with
Immediately after birth, the sterile baby gut becomes colonized by various microbes from the surroundings and mother. Many factors influence the intestinal microbiota composition and its establishment: vaginal birth or C-section; breastmilk or formula; antibiotics or herbal medicine, or just mom’s touch (Kostandy and Ludington-Hoe, 2019; Lee et al., 2019). Choices are made depending on clinical, traditional, personal reasons, and availability, and whatever outcomes continue to be managed. Nevertheless, there is good news that
This work is supported by a funding supported by the National Research Foundation of Korea (2018R1A2A3074987).
The author has no potential conflicts of interest to disclose.