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Groundbreaking research on the universality and diversity of microorganisms is now challenging the life sciences to upgrade fundamental theories that once seemed untouchable. To fully appreciate the change that the field is now undergoing, one has to place the epochs and foundational principles of Darwin, Mendel, and the modern synthesis in light of the current advances that are enabling a new vision for the central importance of microbiology. Animals and plants are no longer heralded as autonomous entities but rather as biomolecular networks composed of the host plus its associated microbes, i.e., \"holobionts.\" As such, their collective genomes forge a \"hologenome,\" and models of animal and plant biology that do not account for these intergenomic associations are incomplete. Here, we integrate these concepts into historical and contemporary visions of biology and summarize a predictive and refutable framework for their evaluation. Specifically, we present ten principles that clarify and append what these concepts are and are not, explain how they both support and extend existing theory in the life sciences, and discuss their potential ramifications for the multifaceted approaches of zoology and botany. We anticipate that the conceptual and evidence-based foundation provided in this essay will serve as a roadmap for hypothesis-driven, experimentally validated research on holobionts and their hologenomes, thereby catalyzing the continued fusion of biology's subdisciplines. At a time when symbiotic microbes are recognized as fundamental to all aspects of animal and plant biology, the holobiont and hologenome concepts afford a holistic view of biological complexity that is consistent with the generally reductionist approaches of biology.

Pregnant women represent a high-risk population for severe/critical COVID-19 and mortality. However, the maternal-fetal immune responses initiated by SARS-CoV-2 infection, and whether this virus is detectable in the placenta, are still under investigation. Here we show that SARS-CoV-2 infection during pregnancy primarily induces unique inflammatory responses at the maternal-fetal interface, which are largely governed by maternal T cells and fetal stromal cells. SARS-CoV-2 infection during pregnancy is also associated with humoral and cellular immune responses in the maternal blood, as well as with a mild cytokine response in the neonatal circulation (i.e., umbilical cord blood), without compromising the T-cell repertoire or initiating IgM responses. Importantly, SARS-CoV-2 is not detected in the placental tissues, nor is the sterility of the placenta compromised by maternal viral infection. This study provides insight into the maternal-fetal immune responses triggered by SARS-CoV-2 and emphasizes the rarity of placental infection. As pregnant women are considered vulnerable to SARSCoV-2 infection, it is important to investigate the actual risks involved. The authors show here that, while a T cell-dominant inflammatory response is observed at the maternal-foetal interface, the virus remains undetectable in the placenta but triggers specific immune responses in the neonatal (umbilical cord blood) circulation.

Recent molecular studies concluded that the endometrium has a resident microbiota dominated by Lactobacillus spp. and is therefore similar to that of the vagina. These findings were largely derived from endometrial samples obtained through a transcervical catheter and thus prone to contamination. Herein, we investigated the molecular microbial profiles of mid-endometrial samples obtained through hysterectomy and compared them with those of the cervix, vagina, rectum, oral cavity, and controls for background DNA contamination. Microbial profiles were examined through 16S rRNA gene qPCR and sequencing. Universal bacterial qPCR of total 16S rDNA revealed a bacterial load exceeding that of background DNA controls in the endometrium of 60% (15/25) of the study subjects. Bacterial profiles of the endometrium differed from those of the oral cavity, rectum, vagina, and background DNA controls, but not of the cervix. The bacterial profiles of the endometrium and cervix were dominated by Acinetobacter , Pseudomonas , Cloacibacterium , and Comamonadaceae. Both 16S rRNA gene sequencing and Lactobacillus species-specific ( L . iners & L crispatus ) qPCR showed that Lactobacillus was rare in the endometrium. In conclusion, if there is a microbiota in the middle endometrium, it is not dominated by Lactobacillus as was previously concluded, yet further investigation using culture and microscopy is necessary.

The existence of a placental microbiota is debated. The human placenta has historically been considered sterile and microbial colonization was associated with adverse pregnancy outcomes. Yet, recent DNA sequencing investigations reported a microbiota in typical human term placentas. However, this detected microbiota could represent background DNA or delivery-associated contamination. Using fifteen publicly available 16S rRNA gene datasets, existing data were uniformly re-analyzed with DADA2 to maximize comparability. While Amplicon Sequence Variants (ASVs) identified as Lactobacillus , a typical vaginal bacterium, were highly abundant and prevalent across studies, this prevalence disappeared after applying likely  DNA contaminant removal to placentas from term cesarean deliveries. A six-study sub-analysis targeting the 16S rRNA gene V4 hypervariable region demonstrated that bacterial profiles of placental samples and technical controls share principal bacterial ASVs and that placental samples clustered primarily by study origin and mode of delivery. Contemporary DNA-based evidence does not support the existence of a placental microbiota. Importance Early-gestational microbial influences on human development are unclear. By applying DNA sequencing technologies to placental tissue, bacterial DNA signals were observed, leading some to conclude that a live bacterial placental microbiome exists in typical term pregnancy. However, the low-biomass nature of the proposed microbiome and high sensitivity of current DNA sequencing technologies indicate that the signal may alternatively derive from environmental or delivery-associated bacterial DNA contamination. Here we address these alternatives with a re-analysis of 16S rRNA gene sequencing data from 15 publicly available placental datasets. After identical DADA2 pipeline processing of the raw data, subanalyses were performed to control for mode of delivery and environmental DNA contamination. Both environment and mode of delivery profoundly influenced the bacterial DNA signal from term-delivered placentas. Aside from these contamination-associated signals, consistency was lacking across studies. Thus, placentas delivered at term are unlikely to be the original source of observed bacterial DNA signals.

The list of pharmacological agents that can modify the gut microbiome or be modified by it continues to grow at a high rate. The greatest amount of attention on drug-gut microbiome interactions has been directed primarily at pharmaceuticals used to treat infection, diabetes, cardiovascular conditions and cancer. By comparison, drugs of abuse and addiction, which can powerfully and chronically worsen human health, have received relatively little attention in this regard. Therefore, the main objective of this study was to characterize how selected synthetic psychoactive cathinones (aka \"Bath Salts\") and amphetamine stimulants modify the gut microbiome. Mice were treated with mephedrone (40 mg/kg), methcathinone (80 mg/kg), methamphetamine (5 mg/kg) or 4-methyl-methamphetamine (40 mg/kg), following a binge regimen consisting of 4 injections at 2h intervals. These drugs were selected for study because they are structural analogs that contain a β-keto substituent (methcathinone), a 4-methyl group (4-methyl-methamphetamine), both substituents (mephedrone) or neither (methamphetamine). Mice were sacrificed 1, 2 or 7 days after treatment and DNA from caecum contents was subjected to 16S rRNA sequencing. We found that all drugs caused significant time- and structure-dependent alterations in the diversity and taxonomic structure of the gut microbiome. The two phyla most changed by drug treatments were Firmicutes (methcathinone, 4-methyl-methamphetamine) and Bacteriodetes (methcathinone, 4-methyl-methamphetamine, methamphetamine, mephedrone). Across time, broad microbiome changes from the phylum to genus levels were characteristic of all drugs. The present results signify that these selected psychoactive drugs, which are thought to exert their primary effects within the CNS, can have profound effects on the gut microbiome. They also suggest new avenues of investigation into the possibility that gut-derived signals could modulate drug abuse and addiction via altered communication along the gut-brain axis.

All animals harbor beneficial microbes. One way these microbes can benefit their animal hosts is by increasing the diversity and efficacy of communication signals available to the hosts. The fermentation hypothesis for mammalian chemical communication posits that bacteria in the scent glands of mammals generate odorous metabolites used by their hosts for communication and that variation in host chemical signals is a product of underlying variation in the bacterial communities inhabiting the scent glands. An effective test of this hypothesis would require accurate surveys of the bacterial communities in mammals’ scent glands and complementary data on the odorant profiles of scent secretions—both of which have been historically lacking. Here we use next-generation sequencing to survey deeply the bacterial communities in the scent glands of wild spotted and striped hyenas. We show that these communities are dominated by fermentative bacteria and that the structures of these communities covary with the volatile fatty acid profiles of scent secretions in both hyena species. The bacterial and volatile fatty acid profiles of secretions differ between spotted and striped hyenas, and both profiles vary with sex and reproductive state among spotted hyenas within a single social group. Our results strongly support the fermentation hypothesis for chemical communication, suggesting that symbiotic bacteria underlie species-specific odors in both spotted and striped hyenas and further underlie sex and reproductive state-specific odors among spotted hyenas. We anticipate that the fermentation hypothesis for chemical communication will prove broadly applicable among scent-marking mammals as others use the technical and analytical approaches used here.

Rough-skinned newts (Taricha granulosa) use tetrodotoxin (TTX) to block voltage-gated sodium (Nav) channels as a chemical defense against predation. Interestingly, newts exhibit extreme population-level variation in toxicity attributed to a coevolutionary arms race with TTX-resistant predatory snakes, but the source of TTX in newts is unknown. Here, we investigated whether symbiotic bacteria isolated from toxic newts could produce TTX. We characterized the skin-associated microbiota from a toxic and non-toxic population of newts and established pure cultures of isolated bacterial symbionts from toxic newts. We then screened bacterial culture media for TTX using LC-MS/MS and identified TTX-producing bacterial strains from four genera, including Aeromonas, Pseudomonas, Shewanella, and Sphingopyxis. Additionally, we sequenced the Nav channel gene family in toxic newts and found that newts expressed Nav channels with modified TTX binding sites, conferring extreme physiological resistance to TTX. This study highlights the complex interactions among adaptive physiology, animal-bacterial symbiosis, and ecological context. Rough-skinned newts produce tetrodotoxin or TTX, a deadly neurotoxin that is also present in some pufferfish, octopuses, crabs, starfish, flatworms, frogs, and toads. It remains a mystery why so many different creatures produce this toxin. One possibility is that TTX did not evolve in animals at all, but rather it is made by bacteria living on or in these creatures. In fact, scientists have already shown that TTX-producing bacteria supply pufferfish, octopus, and other animals with the toxin. However, it was not known where TTX in newts and other amphibians comes from. TTX kills animals by blocking specialized ion channels and shutting down the signaling between neurons, but rough-skinned newts appear insensitive to this blockage, making it likely that they have evolved defenses against the toxin. Some garter snakes that feed on these newts have also evolved to become immune to the effects of TTX. If bacteria are the source of TTX in the newts, the emergence of newt-eating snakes resistant to TTX must be putting evolutionary pressure on both the newts and the bacteria to boost their anti-snake defenses. Learning more about these complex relationships will help scientists better understand both evolution and the role of beneficial bacteria. Vaelli et al. have now shown that bacteria living on rough-skinned newts produce TTX. In the experiments, bacteria samples were collected from the skin of the newts and grown in the laboratory. Four different types of bacteria from the samples collected produced TTX. Next, Vaelli et al. looked at five genes that encode the channels normally affected by TTX in newts and found that all them have mutations that prevent them from being blocked by this deadly neurotoxin. This suggests that bacteria living on newts shape the evolution of genes critical to the animals’ own survival. Helpful bacteria living on and in animals have important effects on animals’ physiology, health, and disease. But understanding these complex interactions is challenging. Rough-skinned newts provide an excellent model system for studying the effects of helpful bacteria living on animals. Vaelli et al. show that a single chemical produced by bacteria can impact diverse aspects of animal biology including physiology, the evolution of their genes, and their interactions with other creatures in their environment.

Symbiotic microbes can benefit their animal hosts by enhancing the diversity of communication signals available to them. The fermentation hypothesis for chemical recognition posits that 1) fermentative bacteria in specialized mammalian scent glands generate odorants that mammals co-opt to communicate with one another and 2) that variation in scent gland odors is due to underlying variation in the structure of bacterial communities within scent glands. For example, group-specific social odors are suggested to be due to members of the same social group harboring more similar bacterial communities in their scent glands than do members of different social groups. We used 16S rRNA gene surveys to show that 1) the scent secretions of spotted hyenas are densely populated by fermentative bacteria whose closest relatives are well-documented odor producers and that 2) these bacterial communities are more similar among hyenas from the same social group than among those from different groups.

The gut microbiota is critical for host function. Among mammals, host phylogenetic relatedness and diet are strong drivers of gut microbiota structure, but one factor may be more influential than the other. Here, we used 16S rRNA gene sequencing to determine the relative contributions of host phylogeny and host diet in structuring the gut microbiotas of 11 herbivore species from 5 families living sympatrically in southwest Kenya. Herbivore species were classified as grazers, browsers, or mixed-feeders and dietary data (% C4 grasses in diet) were compiled from previously published sources. We found that herbivore gut microbiotas were highly species-specific, and that host taxonomy accounted for more variation in the gut microbiota (30%) than did host dietary guild (10%) or sample month (8%). Overall, similarity in the gut microbiota increased with host phylogenetic relatedness ( r  = 0.74) across the 11 species of herbivores, but among 7 closely related Bovid species, dietary %C4 grass values more strongly predicted gut microbiota structure ( r  = 0.64). Additionally, within bovids, host dietary guild explained more of the variation in the gut microbiota (17%) than did host species (12%). Lastly, while we found that the gut microbiotas of herbivores residing in southwest Kenya converge with those of distinct populations of conspecifics from central Kenya, fine-scale differences in the abundances of bacterial amplicon sequence variants (ASVs) between individuals from the two regions were also observed. Overall, our findings suggest that host phylogeny and taxonomy strongly structure the gut microbiota across broad host taxonomic scales, but these gut microbiotas can be further modified by host ecology (i.e., diet, geography), especially among closely related host species.

Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Multiple etiologies are associated with preterm birth; however, 25% of preterm infants are born to a mother with intra-amniotic infection, most commonly due to invasion of the amniotic cavity by Ureaplasma species. Much research has focused on establishing a link between Ureaplasma species and adverse pregnancy/neonatal outcomes; however, little is known about the taxonomy of and host response against Ureaplasma species. Here, we applied a multifaceted approach, including human samples, in vivo models, and in vitro manipulations, to study the maternal-fetal immunobiology of Ureaplasma infection during pregnancy. Furthermore, we investigated the use of clarithromycin as a treatment for this infection. Our research provides translational knowledge that bolsters scientific understanding of Ureaplasma species as a cause of adverse pregnancy/neonatal outcomes and gives strong evidence for the use of clarithromycin as the recommended treatment for women intra-amniotically infected with Ureaplasma species. Intra-amniotic infection is strongly associated with adverse pregnancy and neonatal outcomes. Most intra-amniotic infections are due to Ureaplasma species; however, the pathogenic potency of these genital mycoplasmas to induce preterm birth is still controversial. Here, we first laid out a taxonomic characterization of Ureaplasma isolates from women with intra-amniotic infection, which revealed that Ureaplasma parvum is the most common bacterium found in this clinical condition. Next, using animal models, we provided a causal link between intra-amniotic inoculation with Ureaplasma species and preterm birth. Importantly, the intra-amniotic inoculation of Ureaplasma species induced high rates of mortality in both preterm and term neonates. The in vivo potency of U. parvum to induce preterm birth was not associated with known virulence factors. However, term-derived and preterm-derived U. parvum isolates were capable of inducing an intra-amniotic inflammatory response. Both U. parvum isolates invaded several fetal tissues, primarily the fetal lung, and caused fetal inflammatory response syndrome. This bacterium was also detected in the placenta, reproductive tissues, and most severely in the fetal membranes, inducing a local inflammatory response that was replicated in an in vitro model. Importantly, treatment with clarithromycin, a recently recommended yet not widely utilized antibiotic, prevented the adverse pregnancy and neonatal outcomes induced by U. parvum . These findings shed light on the maternal-fetal immunobiology of intra-amniotic infection. IMPORTANCE Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Multiple etiologies are associated with preterm birth; however, 25% of preterm infants are born to a mother with intra-amniotic infection, most commonly due to invasion of the amniotic cavity by Ureaplasma species. Much research has focused on establishing a link between Ureaplasma species and adverse pregnancy/neonatal outcomes; however, little is known about the taxonomy of and host response against Ureaplasma species. Here, we applied a multifaceted approach, including human samples, in vivo models, and in vitro manipulations, to study the maternal-fetal immunobiology of Ureaplasma infection during pregnancy. Furthermore, we investigated the use of clarithromycin as a treatment for this infection. Our research provides translational knowledge that bolsters scientific understanding of Ureaplasma species as a cause of adverse pregnancy/neonatal outcomes and gives strong evidence for the use of clarithromycin as the recommended treatment for women intra-amniotically infected with Ureaplasma species.