Maternal microbiomes in preterm birth: Recent progress and analytical pipelines
Introduction
The World Health Organization estimates that each year, 15 million infants are born preterm, putting them at increased risk of morbidity and mortality.1 Simplistically, preterm birth (PTB) occurs when normal term labor events—uterine contractions and cervical remodeling—occur early.2 However, PTB is challenging to explain, predict, and prevent because up to 40–45% of cases are idiopathic (spontaneous), and numerous risk factors are known, including maternal history, demographics, nutritional status, stress, and infection.2
Approximately 30% of PTB cases are caused by infection and inflammation.2 Traditionally, infection-related PTB was thought to ensue from foreign microbes reaching the uterus via ascending infection or hematogenous transfer. During ascending infections, microbes from the vagina travel upward through the cervix to reach the fetal membranes. For example, the presence of Mycoplasma spp., Ureaplasma spp., and Candida spp. and Candida spp., in the vagina is associated with PTB.3 Hematogenous infection occurs when bacteria travel through the blood stream from another site in the body and then traverse the placenta at the maternal–fetal interface.2
Although foreign bacteria are important causes of PTB, current research in this area is building on the observation that, far from being sterile, the human body is home to millions of microorganisms.4 Collectively, all of the bacterial genomes present in or on our body surfaces are known as the human microbiome, and each body niche has its own resident microbes. These bacteria contribute to human health in many ways, such as providing resistance to pathologic infection, breaking down nutrients, and educating the immune system.4, 5 In addition to contributing to physiology, microbiome communities respond to physiology. Pregnancy is a period of major physiological changes,6 such as immunological shifts and the vascular remodeling and metabolic changes needed to promote exchange of nutrients, gases, and wastes with the developing fetus.7 Thus, the microbial community structure in various maternal niches has the potential to shift during pregnancy.6 Although many of these changes may benefit or cause no harm to the mother and fetus, we are beginning to learn that dysbiosis of the maternal microbiomes is associated with adverse pregnancy outcomes such as PTB.
Here, we review human microbiome studies that define the microbiomes in key maternal niches and identify associations with both term and preterm birth. Additionally, we describe common technical, analytical, and statistical approaches used to conduct maternal microbiome studies. Rigorous studies together with curated microbiome data will provide an in-depth understanding of the maternal microbiomes and their impact on pregnancy and, hopefully, identify new therapeutic strategies to decrease the incidence and burden of PTB.
Section snippets
Maternal intestinal microbiome changes during pregnancy
A healthy gastrointestinal tract, dominated by Bacteroidetes and Firmicutes, contains numerous beneficial microbes that generate vitamins, break down complex foods, and synthesize products that can keep potentially harmful microbes at bay8 (Fig.). Because the intestinal microbiome regulates critical metabolic processes, diseases, such as obesity and allergy, may arise when the community structure is abnormal.9
Koren et al.10 used stool samples to characterize the maternal gut microbiome during
Cervical and uterine microbiomes
Vaginal microbes associated with PTB most likely reach the uterus by traveling through the cervix (Fig.). Thus, more and more studies are beginning to address how microbes inhabiting this particular niche contribute to the PTB outcome. During the 2nd trimester of pregnancy, in women with a short cervix, the preponderance of specific Lactobacillus species correlates with the gestational age at delivery—increased vaginal Lactobacillus iners is associated with preterm birth and L. crispatus is
Placental microbiome
Although the placenta was long thought to be germ-free, multiple histological and high-throughput sequencing studies have suggested that the placenta harbors its own microbiome31 (Fig.). For example, our group used a variety of staining methods to demonstrate the presence of intracellular microbes in the basal plate (the maternal–fetal interface) of term and preterm placentas.32 Aagaard et al. used 16S sequencing and whole-genome shotgun sequencing to profile bacteria in term and preterm-cross
Methodology of pregnancy microbiome research
The human maternal microbiome studies using high-throughput sequencing have revealed promising associations between microbial composition and health and PTB and have provided a wealth of sequencing datasets, some of which has been made publically available. The majority of associations noted thus far between maternal microbiomes and PTB are qualitative, which is a critical first step. A second priority is to develop the most complete and concise methodology for performing high-throughput
Prospectus
The majority of associations noted thus far between microbiomes and PTB are qualitative. Long term, the goal of this field will be to identify unique bacteria or bacterial communities that can be targeted to prevent PTB. In such work, it will be important to consider the ecological dynamics of bacterial species and their interactions with the host environment. Currently, infection- and inflammation-related therapies to reduce PTB focus on either targeting the causal microbes, which requires
Acknowledgments
We thank Dr. Deborah Frank for editing. This work was supported by a Preventing Prematurity Initiative grant from the Burroughs Wellcome Fund, a Prematurity Research Initiative Investigator award 21-FY13-28 from the March of Dimes, NIH grant R01HD091218 (to IUM), and NIH grant 2T32GM007067-42 (supporting LAP).
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