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

Silverstein and Mysorekar Microbiome (2021) 9:7 https://doi.org/10.1186/s40168-020-00968-w COMMENTARY Open Access Group therapy on in utero colonization: seeking common truths and a way forward Rachel B. Silverstein1 and Indira U. Mysorekar1,2* Abstract 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. Keywords: Decidua, Pregnancy, Placenta, Extravillous trophoblasts, Microbiome, Low biomass microbial communities, Ralstonia, Micrococcus, Kitome Bacteria R Us The human body is home to a variety of microbes, including bacteria, archaea, fungi, microbial eukaryotes, and viruses/phages. Our bacterial friends are in an overall 1:1 stoichiometric relationship with human cells. Thus, understanding how we have co-evolved and how we affect each other remains of the greatest importance. The microbes around us have the power to modulate not only our external environment, such as the soil and food we consume, but also have a profound impact on the internal environment of the human beings they inhabit. It comes as no surprise therefore that the state of pregnancy, with its accompanying metabolic and immunological changes, alters the microbiota at a variety of body sites including the gut, oral mucosa, vaginal * Correspondence: 1 Department of Obstetrics and Gynecology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA 2 Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110, USA mucosa. Several studies have even linked microbial community alterations to being affected by maternal conditions such as diabetes [1, 2], excess gestational weight gain [3], or eczema [4], with others suggesting links between the microbiota and clinical outcomes such as low birth weight [5] and preterm birth [6–8]. Advancements in technologies and methodologies to identify the components of the microbiota, including cultureindependent methods, next-generation sequencing and bioinformatics have begun to provide a clearer picture of the types and niches inhabited by microbes and the types of microbial communities within us [9, 10]. Despite humans being half bacteria and half human in terms of the number of cells, bacteria are unevenly distributed across our body sites with high density in our gut, mouth, skin, nose, and vagina. Next-generation sequencing approaches have evolved to be highly sensitive, which has allowed for the identification of other sites such as the urine, uterus, penile urethra, lower airway, © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Silverstein and Mysorekar Microbiome (2021) 9:7 within tumors, and the maternal-fetal interface/placenta as harboring low biomass microbial communities [11] (Fig. 1). Group therapy: relationships are all about patterns—therapy is about analyzing the patterns together In this commentary, we focus on two of these body sites: the maternal-fetal interface, which includes the maternal decidua and the placenta, and the fetus itself, particularly the fetal gut. The maternal-fetal interface is made up of the maternal decidua and fetally derived placenta. The placenta comprises fetal cytotrophoblast cells, which follow villous and extravillous pathways. In the villous pathway, mononuclear cytotrophoblasts fuse, creating multinucleated syncytiotrophoblasts that establish villi surrounded by maternal blood and aid in the provision of nutrients and gas exchange with fetal cells. Cytotrophoblasts also follow the extravillous pathway and differentiate into interstitial and endovascular extravillous trophoblast cells, which remodel the spiral arteries and invade into the maternal decidua to be surrounded by a large population of maternal immune cells including decidual Natural Killer cells, macrophages, T cells, and dendritic cells [12]. The developing fetal gut is divided into three segments: the foregut (esophagus/duodenum/ liver and gallbladder), midgut (lower duodenum/ileum/ ascending colon), and hindgut (descending colon, rectum, anal canal). A number of studies over the past decade have hammered on whether this interface contains any bacteria or a low-biomass community. Or put more bluntly, there is a ‘controversy in the field’ resulting in two rather strong stances: that the womb is a sterile niche and any microbial signals must be contamination or that there is a bona fide microbiome at this interface. Unless otherwise noted, the terms microbes or microbiota focus on the bacterial component. We discuss a number of these studies below. In addition, there has been considerable Page 2 of 7 discussion with the broader community and in the media about this topic [13, 14]. We highlight studies that present morphological evidence of microbes in the placenta and fetal gut. Given the distinct landscape differences between placental villi and maternal decidua, and betwe (...truncated)