A reconceptualized framework for human microbiome transmission in early life

Abstract

Human development and physiology are fundamentally linked with the microbiome. This is particularly true during early life, a critical period for microbiome assembly and its impact on the host. Understanding microbial acquisition in early life is thus central to both our basic understanding of the human microbiome and strategies for disease prevention and treatment. Here, we review the historical approaches to categorize microbial transmission originating from the fields of infectious disease epidemiology and evolutionary biology and discuss how this lexicon has influenced our approach to studying the early-life microbiome, often leading to confusion and misinterpretation. We then present a conceptual framework to capture the multifaceted nature of human microbiome acquisition based on four key components: what, where, who, and when. We present ways these parameters may be assigned, with a particular focus on the 'transmitted strain' through metagenomics to capture these elements. We end with a discussion of approaches for implementing this framework toward defining each component of microbiome acquisition.

Fig. 1. Prenatal transmission of microbes, microbial DNA and metabolites, highlighting “what” can be transferred and the other parameters of the 4 W framework.

Different microbes colonize the mother at multiple body sites, although the focus is on gut bacteria here. Microbially derived metabolites (what) can translocate from the mother gut (from who) during pregnancy (when) into the intestinal lamina propria and blood circulatory system. Metabolites can also cross via the placenta and affect the developing brain of the fetus (where to). Microbially derived DNA from the parent gut can translocate into circulation, cross via the placenta, and may enter different sites in the fetus, including the gut. Sequencing-based techniques may detect the presence of microbial DNA, even when live microbes are not occurring in the system. Live organisms are not expected to translocate outside the gut or cross the placental barrier into the fetus. Pathogenic microorganisms like L. monocytogenes can translocate from the gut and infect the placenta and fetal brain tissue.

Fig. 2. Species-specific operational definition of a transmitted strain.

Strain boundaries should be identified on a species-by-species basis and based on a comparison of (phylo-) genetic distance distributions of strains detected in longitudinal samples from the same individual (same strain; green distribution) to those between unrelated individuals who have never been in contact (different strain; orange distribution). While some strain replacement events might occur within an individual’s microbiome even without any intervention (e.g., antibiotic treatment, diet changes), these are a limited minority in samples taken less than six months apart. Once such thresholds are established, the origin of a strain in the infant can be inferred (maternal: pink distribution; from an unknown source: gray distribution). Sampling of more environments, individuals, and body sites thus adds to the “from where/who” and “to where/who” dimensions, while the collection of samples from multiple time points allows to establish “when” the transmission event took place.

Fig. 3. Microbial acquisition during birth, highlighting “from where” microbes can be transferred as well as other parameters of the 4 W framework.

A During vaginal birth (when), microbes (what) are transferred from the mother’s (who) vaginal and fecal communities (where from) to the child’s oral, gastrointestinal, and skin communities (to where). B During Cesarean section, skin microbes are transferred from the skin of the mother and health personnel to the infant.

Fig. 4. Microbial acquisition after birth, highlighting the parameters of the 4 W framework.

AThe mother (who) transfers microbes and metabolites (what) to the child via breastfeeding (when) from breast milk (from where) to the mouth, gut, or skin of the infant (to where). B Transfer of microbes from the dog’s skin and mouth to the baby’s skin and mouth.