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Previous studies have shown that gut microbiota in infancy could affect neurodevelopment, and infants delivered by cesarean are not exposed to potentially helpful microbes acquired by infants during vaginal delivery, wrote Lepeng Zhou, MD, of Southern Medical University, Guangdong, China, and colleagues.
“Infants delivered by C-section start life with very different bacteria than those born vaginally,” corresponding author Jose Clemente, PhD, of Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Because this is the first time the newborn is exposed to microbes, we and others have hypothesized for some time that this ‘first encounter’ might be significant to shape the development of the baby,” he said.
“A few years ago, we demonstrated that it is possible to change the microbiome of C-section–delivered infants using an intervention that makes their microbiome more similar to that of a vaginally-delivered infant,” Dr. Clemente told this news organization. “In this study just published, we show that this procedure not only changes the microbiome of C-section infants, but it also modifies a health outcome (in this case, neurodevelopment). This is highly significant because it opens the way to reduce the risk that C-section infants have for certain conditions through a very simple microbial intervention,” he said.
‘Significantly higher’ ASQ-3 scores
In the current study, published in Cell Host & Microbe, the researchers examined the impact of vaginal microbiota transfer (VMT) on the neurodevelopment of cesarean-delivered infants. They randomized 35 women scheduled for cesarean delivery with a single infant to VMT and 41 to a control intervention of saline gauze for their infants immediately after delivery.
The primary outcome of infant neurodevelopment was assessed using the Ages and Stages Questionnaire (ASQ-3) score at 6 months. The researchers also collected fecal samples and assessed safety outcomes for the infants at 3, 7, 30, and 42 days after birth. The final analysis comprised 32 infants in the VMT group and 36 in the control group. The mean age of the mothers was 32 years; the mean gestational age of the infants was 39 weeks, but the difference was significant and slightly less in the VMT group compared with the controls (38.38 weeks vs. 39.13 weeks, P = .007). A group of 33 vaginally-delivered infants (VD) underwent ASQ-3 testing to serve as a reference group.
At 6 months, ASQ-3 scores were significantly higher (10.09%, P = .014) with VMT compared with controls, and the difference remained significant after adjustment for multiple factors including gestational age.
ASQ-3 total scores at 6 months were not significantly different between the VMT group and the VD reference group (mean difference of 8.84 VMT to VD, P = .346); scores between these groups also were similar at 3 months (mean difference of –1.48 VMT to VD, P = .900) and no significant differences appeared in ASQ-3 subdomains between these groups at either time period.
An examination of gut metabolites in stool showed significant differences in fecal metabolites and metabolic function, signs of gut microbiota maturation, the researchers noted.
“Interestingly, all the genera and metabolites that exhibited positive correlations with neurodevelopmental scores were upregulated in the VMT group, whereas the only negative correlation of Klebsiella was downregulated, indicating that VMT may impact neurodevelopment through the modulation of specific gut microbial genera and metabolites,” the researchers wrote.
No serious adverse events occurred in either group during the study period. Nine adverse events were reported; 4 in the VMT group and 5 in the control group. The most common AEs were mild skin disorders, including papules, pustules, and erythema.
The findings were limited by several factors including the potential for transfer not only of vaginal microbiota, but also vaginal metabolites, mycobiome, and virome, which blurs the potential mechanism of VMT, the researchers noted. Other limitations were the relatively short study period, small sample size, and cervical HPV screening within the past 5 years, not during pregnancy, they wrote.
However, the results suggest that VMT is safe, and may help improve the fecal microbiome in cesarean-delivered infants, and the long-term effects merit further studies in larger populations, they concluded.
Limitations and outlook
Dr. Clemente said in an interview that the researchers were “hopeful that the study would demonstrate a health benefit, as it does with some limitations.” The current study findings confirm some previous results showing that modification of the microbiomes of C-section infants is possible through a transfer of maternal vaginal microbes, he said.
“There is also an important aspect that was confirmed here: The lack of serious adverse events associated with the procedure, and the fact that transferring vaginal microbes did not increase the risk of adverse events compared to the control group or to vaginally-delivered infants. This is fundamental to establish that using rigorous exclusion criteria we can perform this procedure safely for infants and mothers,” he added.
“We are at very early stages yet to talk about clinical implications,” said Dr. Clemente. “This is one of the first studies to demonstrate a benefit to the transfer of microbes from mothers to infants, and as such it opens the way for future trials that confirm these findings. The clinical application is still in the future, but this is an important first step towards that goal.”
Interest in restoring gut microbiota to potentially benefit infants persists, but a recent study published in Frontiers and Cellular and Infection Microbiology contradicted the potential association between maternal vaginal microbiome and an infant’s gut microbiome based on an analysis of infant stool.
“There are many reasons why different studies might reach different conclusions: The experimental procedures, the analytical methods, the cohort under study,” Dr. Clemente said when asked to comment on the Frontiers study. “Further studies are needed to establish whether this procedure is equally effective under all conditions and whether health benefits are generalizable or specific to particular populations.”
Several research gaps remain, Dr. Clemente said. “First, neurodevelopment was measured through a questionnaire that captures various aspects such as communication, motor skills, or problem solving. While this is a standard way to establish that an infant is in the correct neurodevelopmental pathway, it is not a ‘hard’ measure of cellular or biochemical processes being impacted by the intervention. Some of our results suggest that there is a change in the metabolome of this infants, particularly an enrichment in GABA, a neurotransmitter, but the exact mechanisms by which the intervention is resulting in a health benefit still remains to be explored,” he said.
“We have an ongoing study here at Mount Sinai to test whether this microbial intervention can be effective in lowering the risk of developing food allergies in newborns who are at high risk, so that is another important future question: What other conditions could benefit from this approach,” said Dr. Clemente.
A third research goal, he added, is “determining what microbes precisely are responsible for the health benefits; this study uses a full microbial community to colonize infants. We show that this is effective and, importantly, that there were no significant adverse events in the treated infants,” he noted. “However, identifying what specific microbes are beneficial would further lower the risk of any potential side effects, while facilitating the development of drugs based on defined microbial consortia,” he said.
Safety and efficacy support further studies
“It is widely accepted that the gut microbiome of neonates varies based on mode of delivery,” Anna K. Knight, PhD, assistant professor of gynecology and obstetrics at Emory University, Atlanta, said in an interview.
“C-sections have been associated with increased risk of asthma and metabolic disease, and have been associated with differences in the development of the immune system,” said Dr. Knight, who was not involved in the study. “There have been small pilot studies examining the use of vaginal microbiome transplants to shift the gut microbiome of neonates born by C-section to be more like the gut microbiome of neonates born via vaginal delivery, but the safety and efficacy of this treatment has not been well established. This study examines both, while also evaluating potential changes in the metabolome and neurodevelopmental trajectories.”
The current study confirmed the impact of the neonatal gut microbe on neurodevelopmental outcomes during a sensitive period, said Dr. Knight. “The fact that these differences persisted at 6 months suggests that even if the microbiome composition between vaginally-delivered and preterm infants converged at 1-2 years old, there may be lasting impacts of mode of delivery,” she said.
“The results of this study suggest that vaginal microbiome transplant may be a safe and effective way to mitigate the negative impacts of C-section delivery on the neonatal gut microbiome, and may be protective for neurodevelopment,” she added.
Regarding the Frontiers in Medicine study, Dr. Knight noted that it examined a very different population, with Zhou and colleagues focusing on Chinese infants, while Dos Santos and colleagues focused on Canadian infants.
“There was also a substantial difference in sample size between the two studies, with Dos Santos and colleagues examining > 500 more infants,” she said. “Additionally, the two studies differed in the sequencing technology used, sample collection methods, and antibiotic exposure, which can all impact microbiome study results.”
Since the current study showed efficacy and safety of VMT in a small clinical trial, larger trials with more diverse participants are needed to further examine the impact of VMT, said Dr. Knight. “The risks of vaginal microbiome transplant in mothers with infections should also be considered, and the mechanisms by which the neonatal gut microbiome impacts neurodevelopment need further investigation,” she said.
The study was funded by the National Key R&D Program of China, the Canadian Institute of Health Research, the National Natural Science Foundation of China, the Clinical Research Startup Program of Southern Medical University, China, and the Top Talent Program of Foshan Women and Children Hospital, China. The researchers and Dr. Knight had no financial conflicts to disclose.
Previous studies have shown that gut microbiota in infancy could affect neurodevelopment, and infants delivered by cesarean are not exposed to potentially helpful microbes acquired by infants during vaginal delivery, wrote Lepeng Zhou, MD, of Southern Medical University, Guangdong, China, and colleagues.
“Infants delivered by C-section start life with very different bacteria than those born vaginally,” corresponding author Jose Clemente, PhD, of Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Because this is the first time the newborn is exposed to microbes, we and others have hypothesized for some time that this ‘first encounter’ might be significant to shape the development of the baby,” he said.
“A few years ago, we demonstrated that it is possible to change the microbiome of C-section–delivered infants using an intervention that makes their microbiome more similar to that of a vaginally-delivered infant,” Dr. Clemente told this news organization. “In this study just published, we show that this procedure not only changes the microbiome of C-section infants, but it also modifies a health outcome (in this case, neurodevelopment). This is highly significant because it opens the way to reduce the risk that C-section infants have for certain conditions through a very simple microbial intervention,” he said.
‘Significantly higher’ ASQ-3 scores
In the current study, published in Cell Host & Microbe, the researchers examined the impact of vaginal microbiota transfer (VMT) on the neurodevelopment of cesarean-delivered infants. They randomized 35 women scheduled for cesarean delivery with a single infant to VMT and 41 to a control intervention of saline gauze for their infants immediately after delivery.
The primary outcome of infant neurodevelopment was assessed using the Ages and Stages Questionnaire (ASQ-3) score at 6 months. The researchers also collected fecal samples and assessed safety outcomes for the infants at 3, 7, 30, and 42 days after birth. The final analysis comprised 32 infants in the VMT group and 36 in the control group. The mean age of the mothers was 32 years; the mean gestational age of the infants was 39 weeks, but the difference was significant and slightly less in the VMT group compared with the controls (38.38 weeks vs. 39.13 weeks, P = .007). A group of 33 vaginally-delivered infants (VD) underwent ASQ-3 testing to serve as a reference group.
At 6 months, ASQ-3 scores were significantly higher (10.09%, P = .014) with VMT compared with controls, and the difference remained significant after adjustment for multiple factors including gestational age.
ASQ-3 total scores at 6 months were not significantly different between the VMT group and the VD reference group (mean difference of 8.84 VMT to VD, P = .346); scores between these groups also were similar at 3 months (mean difference of –1.48 VMT to VD, P = .900) and no significant differences appeared in ASQ-3 subdomains between these groups at either time period.
An examination of gut metabolites in stool showed significant differences in fecal metabolites and metabolic function, signs of gut microbiota maturation, the researchers noted.
“Interestingly, all the genera and metabolites that exhibited positive correlations with neurodevelopmental scores were upregulated in the VMT group, whereas the only negative correlation of Klebsiella was downregulated, indicating that VMT may impact neurodevelopment through the modulation of specific gut microbial genera and metabolites,” the researchers wrote.
No serious adverse events occurred in either group during the study period. Nine adverse events were reported; 4 in the VMT group and 5 in the control group. The most common AEs were mild skin disorders, including papules, pustules, and erythema.
The findings were limited by several factors including the potential for transfer not only of vaginal microbiota, but also vaginal metabolites, mycobiome, and virome, which blurs the potential mechanism of VMT, the researchers noted. Other limitations were the relatively short study period, small sample size, and cervical HPV screening within the past 5 years, not during pregnancy, they wrote.
However, the results suggest that VMT is safe, and may help improve the fecal microbiome in cesarean-delivered infants, and the long-term effects merit further studies in larger populations, they concluded.
Limitations and outlook
Dr. Clemente said in an interview that the researchers were “hopeful that the study would demonstrate a health benefit, as it does with some limitations.” The current study findings confirm some previous results showing that modification of the microbiomes of C-section infants is possible through a transfer of maternal vaginal microbes, he said.
“There is also an important aspect that was confirmed here: The lack of serious adverse events associated with the procedure, and the fact that transferring vaginal microbes did not increase the risk of adverse events compared to the control group or to vaginally-delivered infants. This is fundamental to establish that using rigorous exclusion criteria we can perform this procedure safely for infants and mothers,” he added.
“We are at very early stages yet to talk about clinical implications,” said Dr. Clemente. “This is one of the first studies to demonstrate a benefit to the transfer of microbes from mothers to infants, and as such it opens the way for future trials that confirm these findings. The clinical application is still in the future, but this is an important first step towards that goal.”
Interest in restoring gut microbiota to potentially benefit infants persists, but a recent study published in Frontiers and Cellular and Infection Microbiology contradicted the potential association between maternal vaginal microbiome and an infant’s gut microbiome based on an analysis of infant stool.
“There are many reasons why different studies might reach different conclusions: The experimental procedures, the analytical methods, the cohort under study,” Dr. Clemente said when asked to comment on the Frontiers study. “Further studies are needed to establish whether this procedure is equally effective under all conditions and whether health benefits are generalizable or specific to particular populations.”
Several research gaps remain, Dr. Clemente said. “First, neurodevelopment was measured through a questionnaire that captures various aspects such as communication, motor skills, or problem solving. While this is a standard way to establish that an infant is in the correct neurodevelopmental pathway, it is not a ‘hard’ measure of cellular or biochemical processes being impacted by the intervention. Some of our results suggest that there is a change in the metabolome of this infants, particularly an enrichment in GABA, a neurotransmitter, but the exact mechanisms by which the intervention is resulting in a health benefit still remains to be explored,” he said.
“We have an ongoing study here at Mount Sinai to test whether this microbial intervention can be effective in lowering the risk of developing food allergies in newborns who are at high risk, so that is another important future question: What other conditions could benefit from this approach,” said Dr. Clemente.
A third research goal, he added, is “determining what microbes precisely are responsible for the health benefits; this study uses a full microbial community to colonize infants. We show that this is effective and, importantly, that there were no significant adverse events in the treated infants,” he noted. “However, identifying what specific microbes are beneficial would further lower the risk of any potential side effects, while facilitating the development of drugs based on defined microbial consortia,” he said.
Safety and efficacy support further studies
“It is widely accepted that the gut microbiome of neonates varies based on mode of delivery,” Anna K. Knight, PhD, assistant professor of gynecology and obstetrics at Emory University, Atlanta, said in an interview.
“C-sections have been associated with increased risk of asthma and metabolic disease, and have been associated with differences in the development of the immune system,” said Dr. Knight, who was not involved in the study. “There have been small pilot studies examining the use of vaginal microbiome transplants to shift the gut microbiome of neonates born by C-section to be more like the gut microbiome of neonates born via vaginal delivery, but the safety and efficacy of this treatment has not been well established. This study examines both, while also evaluating potential changes in the metabolome and neurodevelopmental trajectories.”
The current study confirmed the impact of the neonatal gut microbe on neurodevelopmental outcomes during a sensitive period, said Dr. Knight. “The fact that these differences persisted at 6 months suggests that even if the microbiome composition between vaginally-delivered and preterm infants converged at 1-2 years old, there may be lasting impacts of mode of delivery,” she said.
“The results of this study suggest that vaginal microbiome transplant may be a safe and effective way to mitigate the negative impacts of C-section delivery on the neonatal gut microbiome, and may be protective for neurodevelopment,” she added.
Regarding the Frontiers in Medicine study, Dr. Knight noted that it examined a very different population, with Zhou and colleagues focusing on Chinese infants, while Dos Santos and colleagues focused on Canadian infants.
“There was also a substantial difference in sample size between the two studies, with Dos Santos and colleagues examining > 500 more infants,” she said. “Additionally, the two studies differed in the sequencing technology used, sample collection methods, and antibiotic exposure, which can all impact microbiome study results.”
Since the current study showed efficacy and safety of VMT in a small clinical trial, larger trials with more diverse participants are needed to further examine the impact of VMT, said Dr. Knight. “The risks of vaginal microbiome transplant in mothers with infections should also be considered, and the mechanisms by which the neonatal gut microbiome impacts neurodevelopment need further investigation,” she said.
The study was funded by the National Key R&D Program of China, the Canadian Institute of Health Research, the National Natural Science Foundation of China, the Clinical Research Startup Program of Southern Medical University, China, and the Top Talent Program of Foshan Women and Children Hospital, China. The researchers and Dr. Knight had no financial conflicts to disclose.
Previous studies have shown that gut microbiota in infancy could affect neurodevelopment, and infants delivered by cesarean are not exposed to potentially helpful microbes acquired by infants during vaginal delivery, wrote Lepeng Zhou, MD, of Southern Medical University, Guangdong, China, and colleagues.
“Infants delivered by C-section start life with very different bacteria than those born vaginally,” corresponding author Jose Clemente, PhD, of Icahn School of Medicine at Mount Sinai, New York, said in an interview. “Because this is the first time the newborn is exposed to microbes, we and others have hypothesized for some time that this ‘first encounter’ might be significant to shape the development of the baby,” he said.
“A few years ago, we demonstrated that it is possible to change the microbiome of C-section–delivered infants using an intervention that makes their microbiome more similar to that of a vaginally-delivered infant,” Dr. Clemente told this news organization. “In this study just published, we show that this procedure not only changes the microbiome of C-section infants, but it also modifies a health outcome (in this case, neurodevelopment). This is highly significant because it opens the way to reduce the risk that C-section infants have for certain conditions through a very simple microbial intervention,” he said.
‘Significantly higher’ ASQ-3 scores
In the current study, published in Cell Host & Microbe, the researchers examined the impact of vaginal microbiota transfer (VMT) on the neurodevelopment of cesarean-delivered infants. They randomized 35 women scheduled for cesarean delivery with a single infant to VMT and 41 to a control intervention of saline gauze for their infants immediately after delivery.
The primary outcome of infant neurodevelopment was assessed using the Ages and Stages Questionnaire (ASQ-3) score at 6 months. The researchers also collected fecal samples and assessed safety outcomes for the infants at 3, 7, 30, and 42 days after birth. The final analysis comprised 32 infants in the VMT group and 36 in the control group. The mean age of the mothers was 32 years; the mean gestational age of the infants was 39 weeks, but the difference was significant and slightly less in the VMT group compared with the controls (38.38 weeks vs. 39.13 weeks, P = .007). A group of 33 vaginally-delivered infants (VD) underwent ASQ-3 testing to serve as a reference group.
At 6 months, ASQ-3 scores were significantly higher (10.09%, P = .014) with VMT compared with controls, and the difference remained significant after adjustment for multiple factors including gestational age.
ASQ-3 total scores at 6 months were not significantly different between the VMT group and the VD reference group (mean difference of 8.84 VMT to VD, P = .346); scores between these groups also were similar at 3 months (mean difference of –1.48 VMT to VD, P = .900) and no significant differences appeared in ASQ-3 subdomains between these groups at either time period.
An examination of gut metabolites in stool showed significant differences in fecal metabolites and metabolic function, signs of gut microbiota maturation, the researchers noted.
“Interestingly, all the genera and metabolites that exhibited positive correlations with neurodevelopmental scores were upregulated in the VMT group, whereas the only negative correlation of Klebsiella was downregulated, indicating that VMT may impact neurodevelopment through the modulation of specific gut microbial genera and metabolites,” the researchers wrote.
No serious adverse events occurred in either group during the study period. Nine adverse events were reported; 4 in the VMT group and 5 in the control group. The most common AEs were mild skin disorders, including papules, pustules, and erythema.
The findings were limited by several factors including the potential for transfer not only of vaginal microbiota, but also vaginal metabolites, mycobiome, and virome, which blurs the potential mechanism of VMT, the researchers noted. Other limitations were the relatively short study period, small sample size, and cervical HPV screening within the past 5 years, not during pregnancy, they wrote.
However, the results suggest that VMT is safe, and may help improve the fecal microbiome in cesarean-delivered infants, and the long-term effects merit further studies in larger populations, they concluded.
Limitations and outlook
Dr. Clemente said in an interview that the researchers were “hopeful that the study would demonstrate a health benefit, as it does with some limitations.” The current study findings confirm some previous results showing that modification of the microbiomes of C-section infants is possible through a transfer of maternal vaginal microbes, he said.
“There is also an important aspect that was confirmed here: The lack of serious adverse events associated with the procedure, and the fact that transferring vaginal microbes did not increase the risk of adverse events compared to the control group or to vaginally-delivered infants. This is fundamental to establish that using rigorous exclusion criteria we can perform this procedure safely for infants and mothers,” he added.
“We are at very early stages yet to talk about clinical implications,” said Dr. Clemente. “This is one of the first studies to demonstrate a benefit to the transfer of microbes from mothers to infants, and as such it opens the way for future trials that confirm these findings. The clinical application is still in the future, but this is an important first step towards that goal.”
Interest in restoring gut microbiota to potentially benefit infants persists, but a recent study published in Frontiers and Cellular and Infection Microbiology contradicted the potential association between maternal vaginal microbiome and an infant’s gut microbiome based on an analysis of infant stool.
“There are many reasons why different studies might reach different conclusions: The experimental procedures, the analytical methods, the cohort under study,” Dr. Clemente said when asked to comment on the Frontiers study. “Further studies are needed to establish whether this procedure is equally effective under all conditions and whether health benefits are generalizable or specific to particular populations.”
Several research gaps remain, Dr. Clemente said. “First, neurodevelopment was measured through a questionnaire that captures various aspects such as communication, motor skills, or problem solving. While this is a standard way to establish that an infant is in the correct neurodevelopmental pathway, it is not a ‘hard’ measure of cellular or biochemical processes being impacted by the intervention. Some of our results suggest that there is a change in the metabolome of this infants, particularly an enrichment in GABA, a neurotransmitter, but the exact mechanisms by which the intervention is resulting in a health benefit still remains to be explored,” he said.
“We have an ongoing study here at Mount Sinai to test whether this microbial intervention can be effective in lowering the risk of developing food allergies in newborns who are at high risk, so that is another important future question: What other conditions could benefit from this approach,” said Dr. Clemente.
A third research goal, he added, is “determining what microbes precisely are responsible for the health benefits; this study uses a full microbial community to colonize infants. We show that this is effective and, importantly, that there were no significant adverse events in the treated infants,” he noted. “However, identifying what specific microbes are beneficial would further lower the risk of any potential side effects, while facilitating the development of drugs based on defined microbial consortia,” he said.
Safety and efficacy support further studies
“It is widely accepted that the gut microbiome of neonates varies based on mode of delivery,” Anna K. Knight, PhD, assistant professor of gynecology and obstetrics at Emory University, Atlanta, said in an interview.
“C-sections have been associated with increased risk of asthma and metabolic disease, and have been associated with differences in the development of the immune system,” said Dr. Knight, who was not involved in the study. “There have been small pilot studies examining the use of vaginal microbiome transplants to shift the gut microbiome of neonates born by C-section to be more like the gut microbiome of neonates born via vaginal delivery, but the safety and efficacy of this treatment has not been well established. This study examines both, while also evaluating potential changes in the metabolome and neurodevelopmental trajectories.”
The current study confirmed the impact of the neonatal gut microbe on neurodevelopmental outcomes during a sensitive period, said Dr. Knight. “The fact that these differences persisted at 6 months suggests that even if the microbiome composition between vaginally-delivered and preterm infants converged at 1-2 years old, there may be lasting impacts of mode of delivery,” she said.
“The results of this study suggest that vaginal microbiome transplant may be a safe and effective way to mitigate the negative impacts of C-section delivery on the neonatal gut microbiome, and may be protective for neurodevelopment,” she added.
Regarding the Frontiers in Medicine study, Dr. Knight noted that it examined a very different population, with Zhou and colleagues focusing on Chinese infants, while Dos Santos and colleagues focused on Canadian infants.
“There was also a substantial difference in sample size between the two studies, with Dos Santos and colleagues examining > 500 more infants,” she said. “Additionally, the two studies differed in the sequencing technology used, sample collection methods, and antibiotic exposure, which can all impact microbiome study results.”
Since the current study showed efficacy and safety of VMT in a small clinical trial, larger trials with more diverse participants are needed to further examine the impact of VMT, said Dr. Knight. “The risks of vaginal microbiome transplant in mothers with infections should also be considered, and the mechanisms by which the neonatal gut microbiome impacts neurodevelopment need further investigation,” she said.
The study was funded by the National Key R&D Program of China, the Canadian Institute of Health Research, the National Natural Science Foundation of China, the Clinical Research Startup Program of Southern Medical University, China, and the Top Talent Program of Foshan Women and Children Hospital, China. The researchers and Dr. Knight had no financial conflicts to disclose.
FROM CELL HOST & MICROBE