The potential importance of the built-environment microbiome and its impact on human health.

There is increasing evidence that interactions between microbes and their hosts not only play a role in determining health and disease but also in emotions, thought, and behavior. Built environments greatly influence microbiome exposures because of their built-in highly specific microbiomes coproduced with myriad metaorganisms including humans, pets, plants, rodents, and insects. Seemingly static built structures host complex ecologies of microorganisms that are only starting to be mapped. These microbial ecologies of built environments are directly and interdependently affected by social, spatial, and technological norms. Advances in technology have made these organisms visible and forced the scientific community and architects to rethink gene-environment and microbe interactions respectively. Thus, built environment design must consider the microbiome, and research involving host-microbiome interaction must consider the built-environment. This paradigm shift becomes increasingly important as evidence grows that contemporary built environments are steadily reducing the microbial diversity essential for human health, well-being, and resilience while accelerating the symptoms of human chronic diseases including environmental allergies, and other more life-altering diseases. New models of design are required to balance maximizing exposure to microbial diversity while minimizing exposure to human-associated diseases. Sustained trans-disciplinary research across time (evolutionary, historical, and generational) and space (cultural and geographical) is needed to develop experimental design protocols that address multigenerational multispecies health and health equity in built environments.

The hygiene hypothesis, the COVID pandemic, and consequences for the human microbiome.

The COVID-19 pandemic has the potential to affect the human microbiome in infected and uninfected individuals, having a substantial impact on human health over the long term. This pandemic intersects with a decades-long decline in microbial diversity and ancestral microbes due to hygiene, antibiotics, and urban living (the hygiene hypothesis). High-risk groups succumbing to COVID-19 include those with preexisting conditions, such as diabetes and obesity, which are also associated with microbiome abnormalities. Current pandemic control measures and practices will have broad, uneven, and potentially long-term effects for the human microbiome across the planet, given the implementation of physical separation, extensive hygiene, travel barriers, and other measures that influence overall microbial loss and inability for reinoculation. Although much remains uncertain or unknown about the virus and its consequences, implementing pandemic control practices could significantly affect the microbiome. In this Perspective, we explore many facets of COVID-19-induced societal changes and their possible effects on the microbiome, and discuss current and future challenges regarding the interplay between this pandemic and the microbiome. Recent recognition of the microbiome's influence on human health makes it critical to consider both how the microbiome, shaped by biosocial processes, affects susceptibility to the coronavirus and, conversely, how COVID-19 disease and prevention measures may affect the microbiome. This knowledge may prove key in prevention and treatment, and long-term biological and social outcomes of this pandemic.

Role of the microbiome in human development.

The host-microbiome supraorganism appears to have coevolved and the unperturbed microbial component of the dyad renders host health sustainable. This coevolution has likely shaped evolving phenotypes in all life forms on this predominantly microbial planet. The microbiota seems to exert effects on the next generation from gestation, via maternal microbiota and immune responses. The microbiota ecosystems develop, restricted to their epithelial niches by the host immune system, concomitantly with the host chronological development, providing early modulation of physiological host development and functions for nutrition, immunity and resistance to pathogens at all ages. Here, we review the role of the microbiome in human development, including evolutionary considerations, and the maternal/fetal relationships, contributions to nutrition and growth. We also discuss what constitutes a healthy microbiota, how antimicrobial modern practices are impacting the human microbiota, the associations between microbiota perturbations, host responses and diseases rocketing in urban societies and potential for future restoration.

Human gut microbiome viewed across age and geography.

Gut microbial communities represent one source of human genetic and metabolic diversity. To examine how gut microbiomes differ among human populations, here we characterize bacterial species in fecal samples from 531 individuals, plus the gene content of 110 of them. The cohort encompassed healthy children and adults from the Amazonas of Venezuela, rural Malawi and US metropolitan areas and included mono- and dizygotic twins. Shared features of the functional maturation of the gut microbiome were identified during the first three years of life in all three populations, including age-associated changes in the genes involved in vitamin biosynthesis and metabolism. Pronounced differences in bacterial assemblages and functional gene repertoires were noted between US residents and those in the other two countries. These distinctive features are evident in early infancy as well as adulthood. Our findings underscore the need to consider the microbiome when evaluating human development, nutritional needs, physiological variations and the impact of westernization.

Phylogenetic and ecological factors impact the gut microbiota of two Neotropical primate species.

Recent studies suggest that variation in diet across time and space results in changes in the mammalian gut microbiota. This variation may ultimately impact host ecology by altering nutritional status and health. Wild animal populations provide an excellent opportunity for understanding these interactions. However, compared to clinical studies, microbial research targeting wild animals is currently limited, and many published studies focus only on a single population of a single host species. In this study we utilize fecal samples from two species of howler monkey (Alouatta pigra and A. palliata) collected at four sites to investigate factors influencing the gut microbiota at three scales: taxonomic (host species), ecosystemic (forest type), and local (habitat disturbance/season). The results demonstrate that the effect of host species on the gut microbiota is stronger than the effect of host forest type, which is stronger than the effect of habitat disturbance or seasonality. Nevertheless, within host species, gut microbiota composition differs in response to forest type, habitat disturbance, and season. Variations in the effect size of these factors are associated both with host species and environment. This information may be beneficial for understanding ecological and evolutionary questions associated with Mesoamerican howler monkeys, as well as determining conservation challenges facing each species. These mechanisms may also provide insight into the ecology of other species of howler monkeys, non-human primates, and mammals.

Natural variant of the Helicobacter pylori CagA oncoprotein that lost the ability to interact with PAR1.

Helicobacter pylori strains carrying the cagA gene are associated with severe disease outcomes, most notably gastric cancer. CagA protein is delivered into gastric epithelial cells by a type IV secretion system. The translocated CagA undergoes tyrosine phosphorylation at the C-terminal EPIYA motifs by host cell kinases. Tyrosine-phosphorylated CagA acquires the ability to interact with and activate SHP2, thereby activating mitogenic signaling and inducing cell morphological transformation (hummingbird phenotype). CagA also interacts with PAR1b via the CM sequence, resulting in induction of junctional and polarity defects. Furthermore, CagA-PAR1b interaction stabilizes the CagA-SHP2 complex. Because transgenic mice systemically expressing CagA develop gastrointestinal and hematological malignancies, CagA is recognized as a bacterium-derived oncoprotein. Interestingly, the C-terminal region of CagA displays a large diversity among H. pylori strains, which influences the ability of CagA to bind to SHP2 and PAR1b. In the present study, we investigated the biological activity of v225d CagA, an Amerindian CagA of H. pylori isolated from a Venezuelan Piaroa Amerindian subject, because the variant CagA does not possess a canonical CM sequence. We found that v225d CagA interacts with SHP2 but not PAR1b. Furthermore, SHP2-binding activity of v225d CagA was much lower than that of CagA of H. pylori isolated from Western countries (Western CagA). v225d CagA also displayed a reduced ability to induce the hummingbird phenotype than that of Western CagA. Given that perturbation of PAR1b and SHP2 by CagA underlies the oncogenic potential of CagA, the v225d strain is considered to be less oncogenic than other well-studied cagA-positive H. pylori strains.

Fecal transplant from vaginally seeded infants decreases intraabdominal adiposity in mice.

Exposing C-section infants to the maternal vaginal microbiome, coined "vaginal seeding", partially restores microbial colonization. However, whether vaginal seeding decreases metabolic disease risk is unknown. Therefore, we assessed the effect of vaginal seeding of human infants on adiposity in a murine model. Germ-free mice were colonized with transitional stool from human infants who received vaginal seeding or control (placebo) seeding in a double-blind randomized trial. There was a reduction in intraabdominal adipose tissue (IAAT) volume in male mice that received stool from vaginally seeded infants compared to control infants. Higher levels of isoleucine and lower levels of nucleic acid metabolites were observed in controls and correlated with increased IAAT. This suggests that early changes in the gut microbiome and metabolome caused by vaginal seeding have a positive impact on metabolic health.

Phylogeographic evidence of cognate recognition site patterns and transformation efficiency differences in H. pylori: theory of strain dominance.

BACKGROUND: Helicobacter pylori has diverged in parallel to its human host, leading to distinct phylogeographic populations. Recent evidence suggests that in the current human mixing in Latin America, European H. pylori (hpEurope) are increasingly dominant at the expense of Amerindian haplotypes (hspAmerind). This phenomenon might occur via DNA recombination, modulated by restriction-modification systems (RMS), in which differences in cognate recognition sites (CRS) and in active methylases will determine direction and frequency of gene flow. We hypothesized that genomes from hspAmerind strains that evolved from a small founder population have lost CRS for RMS and active methylases, promoting hpEurope's DNA invasion. We determined the observed and expected frequencies of CRS for RMS in DNA from 7 H. pylori whole genomes and 110 multilocus sequences. We also measured the number of active methylases by resistance to in vitro digestion by 16 restriction enzymes of genomic DNA from 9 hpEurope and 9 hspAmerind strains, and determined the direction of DNA uptake in co-culture experiments of hspAmerind and hpEurope strains. RESULTS: Most of the CRS were underrepresented with consistency between whole genomes and multilocus sequences. Although neither the frequency of CRS nor the number of active methylases differ among the bacterial populations (average 8.6 ± 2.6), hspAmerind strains had a restriction profile distinct from that in hpEurope strains, with 15 recognition sites accounting for the differences. Amerindians strains also exhibited higher transformation rates than European strains, and were more susceptible to be subverted by larger DNA hpEurope-fragments than vice versa. CONCLUSIONS: The geographical variation in the pattern of CRS provides evidence for ancestral differences in RMS representation and function, and the transformation findings support the hypothesis of Europeanization of the Amerindian strains in Latin America via DNA recombination.

Microbial seeding in early life.

Early-life microbial colonization plays a key role in future health. In this issue of Cell Host & Microbe, Bogaert et al. unravel the complexities of mother-infant microbial seeding by examining multiple maternal and infant niches. Importantly, they describe "auxiliary" seeding pathways that may partially compensate when seeding patterns are perturbed.

A vitamin D deficient diet increases weight gain and compromises bone biomechanical properties without a reduction in BMD in adult female mice.

Vitamin D contributes to the development and maintenance of bone. Evidence suggests vitamin D status can also alter energy balance and gut health. In young animals, vitamin D deficiency (VDD) negatively affects bone mineral density (BMD) and bone microarchitecture, and these effects may also occur due to chronic ethanol intake. However, evidence is limited in mature models, and addressing this was a goal of the current study. Seven-month-old female C57BL/6 mice (n = 40) were weight-matched and randomized to one of four ad libitum diets: control, alcohol (Alc), vitamin D deficient (0 IU/d), or Alc+VDD for 8 weeks. A purified (AIN-93) diet was provided with water or alcohol (10 %) ad libitum. Body weight and food intake were recorded weekly, and feces were collected at 0, 4, and 8 weeks. At the age of 9 months, intestinal permeability was assessed by oral gavage of fluorescein isothiocyanate-dextran. Thereafter, bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. The microarchitecture of the distal femur was assessed by micro-computed tomography and biomechanical properties were evaluated by cyclic reference point indentation. VDD did not affect BMD or most bone microarchitecture parameters, however, the polar moment of inertia (p < 0.05) was higher in the VDD groups compared to vitamin D sufficient groups. VDD mice also had lower whole bone water content (p < 0.05) and a greater average unloading slope (p < 0.01), and energy dissipated (p < 0.01), indicating the femur displayed a brittle phenotype. In addition, VDD caused a greater increase in energy intake (p < 0.05), weight gain (p < 0.05), and a trend for higher intestinal permeability (p = 0.08). The gut microbiota of the VDD group had a reduction in alpha diversity (p < 0.05) and a lower abundance of ASVs from Rikenellaceae, Clostridia_UCG-014, Oscillospiraceae, and Lachnospiraceae (p < 0.01). There was little to no effect of alcohol supplementation on outcomes. Overall, these findings suggest that vitamin D deficiency causes excess weight gain and reduces the biomechanical strength of the femur as indicated by the higher average unloading slope and energy dissipated without an effect on BMD in a mature murine model.

Partial convergence of the human vaginal and rectal maternal microbiota in late gestation and early post-partum.

The human vaginal and fecal microbiota change during pregnancy. Because of the proximity of these perineal sites and the evolutionarily conserved maternal-to-neonatal transmission of the microbiota, we hypothesized that the microbiota of these two sites (rectal and vaginal) converge during the last gestational trimester as part of the preparation for parturition. To test this hypothesis, we analyzed 16S rRNA sequences from vaginal introitus and rectal samples in 41 women at gestational ages 6 and 8 months, and at 2 months post-partum. The results show that the human vaginal and rectal bacterial microbiota converged during the last gestational trimester and into the 2nd month after birth, with a significant decrease in Lactobacillus species in both sites, as alpha diversity progressively increased in the vagina and decreased in the rectum. The microbiota convergence of the maternal vaginal-anal sites perinatally might hold significance for the inter-generational transmission of the maternal microbiota.

Time to rethink academic publishing: the peer reviewer crisis.

There is concern that the time taken to publish academic papers in microbiological science has significantly increased in recent years. While the data do not specifically support this, evidence suggests that editors are having to invite more and more reviewers to identify those willing to perform peer review.

Maternal Bacterial Engraftment in Multiple Body Sites of Cesarean Section Born Neonates after Vaginal Seeding-a Randomized Controlled Trial.

Children delivered by elective, prelabor Cesarean section (C-section) are not exposed to the birth canal microbiota and, in relation to vaginally delivered children, show altered microbiota development. Perturbed microbial colonization during critical early-life windows of development alters metabolic and immune programming and is associated with an increased risk of immune and metabolic diseases. In nonrandomized studies, vaginal seeding of C-section-born neonates partially restores their microbiota colonization to that of their vaginally delivered counterparts, but without randomization, confounding factors cannot be excluded. In a double-blind, randomized, placebo-controlled trial, we determined the effect of vaginal seeding versus placebo seeding (control arm) on the skin and stool microbiota of elective, prelabor C-section-born neonates (n = 20) at 1 day and 1 month after birth. We also examined whether there were between-arm differences in engraftment of maternal microbes in the neonatal microbiota. In relation to the control arm, vaginal seeding increased mother-to-neonate microbiota transmission and caused compositional changes and a reduction in alpha diversity (Shannon Index) of the skin and stool microbiota. The neonatal skin and stool microbiota alpha diversity when maternal vaginal microbiota is provided is intriguing and highlights the need of larger randomized studies to determine the ecological mechanisms and effects of vaginal seeding on clinical outcomes. IMPORTANCE Children delivered by elective C-section are not exposed to the birth canal and show altered microbiota development. Impairing microbial colonization during early life alters metabolic and immune programming and is associated with an increased risk of immune and metabolic diseases. In a double-blind, randomized, placebo-controlled trial, we determined the effect of vaginal seeding on the skin and stool microbiota of elective C-section born neonates and found that vaginal seeding increased mother-to-neonate microbiota transmission and caused compositional changes and a reduction in the skin and stool microbiota diversity. The reduction of neonatal skin and stool microbiota diversity when maternal vaginal microbiota is provided is intriguing and highlights the need of larger randomized studies to determine the ecological mechanisms and effects of vaginal seeding on clinical outcomes.

Development of the human gastrointestinal microbiota and insights from high-throughput sequencing.

Little was known about the development of the gastrointestinal (GI) tract microbiota, until recently, because of difficulties in obtaining sufficient sequence information from enough people or time points. Now, with decreased costs of DNA sequencing and improved bioinformatic tools, we can compare GI tract bacterial communities among individuals, of all ages from infancy to adulthood. Some key recent findings are that the initial bacterial community, even in the GI tract, depends strongly on delivery mode; that the process of early development of the microbiota is highly unstable and idiosyncratic; that the microbiota differs considerably among children from different countries; and that older adults have substantially different GI tract communities than younger adults, indicating that the GI tract microbiota can change throughout life. We relate these observations to different models of evolution including the evolution of senescence and suggest that probiotics be selected based on patient age. Studies of the microbiota in older people might tell us which probiotics could increase longevity. Drug metabolism varies among individuals with different microbial communities, so age- and region-specific clinical trials are required to ensure safety and efficacy.

Can maternal-child microbial seeding interventions improve the health of infants delivered by Cesarean section?

Maternal-child microbial seeding interventions expose Cesarean-section (C-section)-delivered infants to the maternal microbiome they bypass during Cesarean delivery. It is theorized such interventions restore the microbiome and normalize immune development to reduce the occurrence of C-section-associated inflammatory conditions. Here we discuss the rationale, evidence, and controversies surrounding such interventions.

A randomized controlled trial of the effects of whole grains versus refined grains diets on the microbiome in pregnancy.

Dietary whole grain consumption has been postulated to have metabolic benefits. The purpose of this study was to compare a pregnancy diet containing 75% of total carbohydrates as refined grains with a diet of 75% of total carbohydrates as whole grains for pregnancy outcomes and effects on the microbiome. Gestational weight gain, glucose tolerance and newborn outcomes were measured on 248 enrolled compliant women from whom a subset of 103 women consented to give 108 vaginal and 109 anal swabs. The data presented here are limited to the patients from whom the vaginal and anal swabs were obtained in order to study the microbiome. A microbiome-16SrRNA survey-was characterized in these samples. Samples and measurements were obtained at the first obstetrical visit, before beginning a prescribed diet (T1-baseline) and after 17-32 weeks on the prescribed diet (T3). Food frequency questionnaires and total plasma alkylresorcinols were used as a measure of whole grain consumption. There were no dietary differences in maternal weight gain, birth weight, or glucose tolerance test. Mothers consuming the whole grains diet showed a trend of gestational decrease in vaginal bacterial alpha diversity, with increasing Lactobacillus-dominance. No significant difference was observed for the anal microbiome. The results suggest that diet modulations of the vaginal microbiome during gestation may have important implications for maternal and neonatal health and in the intergenerational transfer of maternal microbiome. Trial registration: ClinicalTrials.gov Identifier: NCT03232762.

Limited microbiome differences in captive and semi-wild primate populations consuming similar diets.

Gut microbial communities are shaped by a myriad of extrinsic factors, including diet and the environment. Although distinct human populations consistently exhibit different gut microbiome compositions, variation in diet and environmental factors are almost always coupled, making it difficult to disentangle their relative contributions to shaping the gut microbiota. Data from discrete animal populations with similar diets can help reduce confounds. Here, we assessed the gut microbiota of free-ranging and captive rhesus macaques with at least 80% diet similarity to test the hypothesis that hosts in difference environments will have different gut microbiomes despite a shared diet. Although we found that location was a significant predictor of gut microbial composition, the magnitude of observed differences was relatively small. These patterns suggest that a shared diet may limit the typical influence of environmental microbial exposure on the gut microbiota.

Context-aware dimensionality reduction deconvolutes gut microbial community dynamics.

The translational power of human microbiome studies is limited by high interindividual variation. We describe a dimensionality reduction tool, compositional tensor factorization (CTF), that incorporates information from the same host across multiple samples to reveal patterns driving differences in microbial composition across phenotypes. CTF identifies robust patterns in sparse compositional datasets, allowing for the detection of microbial changes associated with specific phenotypes that are reproducible across datasets.