In utero human intestine harbors unique metabolome, including bacterial metabolites

Li, Yujia; Toothaker, Jessica; Ben-Simon, Shira; Ozeri, Lital; Schweitzer, Ron; McCourt, Blake; McCourt, Collin C.; Werner, Lael; Snapper, Scott B.; Shouval, Dror S.; Khatib, Soliman; Koren, Omry; Agnihorti, Sameer; Tseng, George C.; Konnikova, Liza

doi:10.1172/jci.insight.138751

Cited by 47 publications

(28 citation statements)

References 64 publications

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“…However, the debate on the sterility of the womb goes back more than a hundred years [11], and we think it is fair to pose the question how it re-emerged although the ultimate (in Popper's words, "risky") experiments to disprove its overall premise have continuously been done for 70 years. Tens of millions of dollars have been spent to investigate microbial populations that likely do not exist, money that could have been used to study more plausible aspects of the prenatal microbiome, such as the role of pathogens, microbial products, and metabolites from the maternal microbiome in fetal and intrauterine sites [20,24,30,31].…”

Section: Discussionmentioning

confidence: 99%

“…Over the years, it also became increasingly obvious that contamination [16,17], or the so called "kitome" [18], represented a major problem when next-generation sequencing and PCR-based approaches were applied to low-biomass samples [19]. Consequently, several subsequent sequencing studies that used strict controls for contamination did not support the presence of microbial DNA in utero [18,[20][21][22][23][24][25]. We, the authors of this commentary here, argued early that the concept of "in utero colonization" was insufficiently supported by the newly created amplification/sequencing data, in our eyes biologically implausible, and in disagreement with a comprehensive body of experimental evidence [11,26].…”

Section: Introductionmentioning

confidence: 99%

“…For clarification, we focus on research that made claims on the existence of microbiomes (specific microbial communities that are in their majority alive and physiologically active) or the colonization of symbiotic microbial species in fetal habitats (niches, sites) in a healthy state. We do not refer to infections with known pathogens or the fetal exposure to microbial constituents and metabolites, for which we think there is strong evidence [20,24,30,31]. We further emphasize that our aim is not to provide a comprehensive overview on biological and technical aspects of the debate, and refer the reader to reviews that have covered these basics [11,19,26] and the two accompanying articles published in Microbiome [28,29].…”

Section: Introductionmentioning

confidence: 99%

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A philosophical perspective on the prenatal in utero microbiome debate

Walter

Hornef

2021

Microbiome

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Within the last 6 years, a research field has emerged that focuses on the characterization of microbial communities in the prenatal intrauterine environment of humans and their putative role in human health. However, there is considerable controversy around the existence of such microbial populations. The often contentious debate is primarily focused on technical aspects of the research, such as difficulties to assure aseptic sampling and to differentiate legitimate signals in the data from contamination. Although such discussions are clearly important, we feel that the problems with the prenatal microbiome field go deeper. In this commentary, we apply a philosophical framework to evaluate the foundations, experimental approaches, and interpretations used by scientists on both sides of the debate. We argue that the evidence for a “sterile womb” is based on a scientific approach that aligns well with important principles of the philosophy of science as genuine tests of the hypothesis and multiple angles of explanatory considerations were applied. In contrast, research in support of the “in utero colonization hypothesis” is solely based on descriptive verifications that do not provide explanatory insight, which weakens the evidence for a prenatal intrauterine microbiome. We propose that a reflection on philosophical principles can inform not only the debate on the prenatal intrauterine microbiome but also other disciplines that attempt to study low-biomass microbial communities.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A philosophical perspective on the prenatal in utero microbiome debate

Walter

Hornef

2021

Microbiome

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“…Regarding possible mechanisms for infant prenatal colonization in mothers with GDM, speculation suggests that the intrauterine maternal microbiota is a source of first colonizers in the infant gut, but the existence of an in utero microbiota remains controversial. A recent study suggests that microbial products or metabolites are detected in the human fetal intestine and drive in utero immune development and education (72); however, the source of the bacteria is unknown. Gestation-only colonization of mice with E. coli was reported to modify the intestinal mucosal innate immune system and transcriptome of the offspring (73).…”

Section: Discussionmentioning

confidence: 99%

Gestational Diabetes Is Uniquely Associated With Altered Early Seeding of the Infant Gut Microbiota

et al. 2020

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Gestational diabetes mellitus (GDM) is a worldwide public health problem affecting up to 27% of pregnancies with high predictive values for childhood obesity and inflammatory diseases. Compromised seeding of the infant gut microbiota is a risk factor for immunologic and metabolic diseases in the offspring; however, how GDM along with maternal obesity interact to alter colonization remains unknown. We hypothesized that GDM individually and in combination with maternal overweight/obesity would alter gut microbial composition, diversity, and short-chain fatty acid (SCFA) levels in neonates. We investigated 46 full-term neonates born to normal-weight or overweight/obese mothers with and without GDM, accounting for confounders including cesarean delivery, lack of breastfeeding, and exposure to antibiotics. Gut microbiota in 2-week-old neonates born to mothers with GDM exhibited differences in abundance of 26 microbial taxa; 14 of which showed persistent differential abundance after adjusting for pre-pregnancy BMI. Key pioneering gut taxa, including potentially important taxa for establishing neonatal immunity, were reduced. Lactobacillus, Flavonifractor, Erysipelotrichaceae, and unspecified families in Gammaproteobacteria were significantly reduced in neonates from mothers with GDM. GDM was associated with an increase in microbes involved in suppressing early immune cell function (Phascolarctobacterium). No differences in infant stool SCFA levels by maternal phenotype were noted; however, significant correlations were found between microbial abundances and SCFA levels in neonates. Our results suggest that GDM alone and together with maternal overweight/obesity uniquely influences seeding of specific infant microbiota in patterns that set the stage for future risk of inflammatory and metabolic disease.

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“…Maternal and fetal commensal bacterial colonization could be playing a role in modulating fetal immune education and protective immunity prior to delivery. New studies are opening exciting new frontiers by identifying microbial components and metabolites, which may be the messengers that are vertically transmitted to the fetus during pregnancy to prime the developing fetal immune system [ 48 , 49 ]. This would support Medawar’s concept that ‘actively acquired immunologic tolerance’ could occur as a result of in utero fetal exposure to microbial antigens transmitted vertically irrespective of the location of the microbial source [ 46 , 50 ].…”

Section: Group Therapy: Showing How Each Partner’s Position Makes Senmentioning

confidence: 99%

Group therapy on in utero colonization: seeking common truths and a way forward

Silverstein

Mysorekar

2021

Microbiome

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The human microbiome refers to the genetic composition of microorganisms in a particular location in the human body. Emerging evidence over the past many years suggests that the microbiome constitute drivers of human fate almost at par with our genome and epigenome. It is now well accepted after decades of disbelief that a broad understanding of human development, health, physiology, and disease requires understanding of the microbiome along with the genome and epigenome. We are learning daily of the interdependent relationships between microbiome/microbiota and immune responses, mood, cancer progression, response to therapies, aging, obesity, antibiotic usage, and overusage and much more. The next frontier in microbiome field is understanding when does this influence begin? Does the human microbiome initiate at the time of birth or are developing human fetuses already primed with microbes and their products in utero. In this commentary, we reflect on evidence gathered thus far on this question and identify the unknown common truths. We present a way forward to continue understanding our microbial colleagues and our interwoven fates.

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In utero human intestine harbors unique metabolome, including bacterial metabolites

Cited by 47 publications

References 64 publications

A philosophical perspective on the prenatal in utero microbiome debate

A philosophical perspective on the prenatal in utero microbiome debate

Gestational Diabetes Is Uniquely Associated With Altered Early Seeding of the Infant Gut Microbiota

Group therapy on in utero colonization: seeking common truths and a way forward

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