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Human microbiome

The human microbiome refers to the collective community of microorganisms—including , , fungi, viruses, and microbial eukaryotes—and their associated genetic material that inhabit various sites on and within the , forming a dynamic ecological system that influences host physiology. This microbiome, often described as the "second genome" of the , comprises an estimated 39 trillion microbial cells, roughly comparable in number to the approximately 30 trillion human cells, with the majority residing in the . Key body sites hosting distinct microbial communities include the gut, oral cavity, , , and urogenital tract, each shaped by local environmental factors such as , oxygen levels, and nutrient availability. These microbial populations establish symbiotic relationships with the host from birth, evolving through developmental stages to support essential functions like nutrient metabolism, digestion of complex carbohydrates into , and modulation of the via colonization resistance against pathogens. For instance, dominated by phyla such as Firmicutes and Bacteroidetes aid in breaking down dietary fibers and producing vitamins, while and oral microbiomes contribute to barrier protection and local immune . Disruptions in microbiome composition, known as , have been linked to a range of diseases, including , , , and even neurological disorders, highlighting the microbiome's role in maintaining eubiosis—a balanced state conducive to . Over the past decade, research investments exceeding US$1.7 billion have advanced understanding through initiatives like the Human Microbiome Project, which has cataloged microbial diversity and functional genes across healthy populations using high-throughput sequencing. Recent frameworks emphasize the as an "adaptive genome" in continuous crosstalk with the , influencing phenotypic variations and through mechanisms like epigenetic modifications and production (e.g., acids and trimethylamine N-oxide). This interplay positions the as a potential therapeutic target, with emerging interventions such as fecal transplantation and showing promise in restoring balance, though challenges remain in translating these findings to .

Definition and Overview

Terminology and History

The human microbiome refers to the collective genetic material of the microorganisms residing in and on the , encompassing , , fungi, viruses, and other microbes that interact with the host. This term is distinct from the , which denotes the actual community of microorganisms themselves within a specific niche, such as the gut or . Together, the host and its associated form a , a unified biological entity where the microbes contribute to the host's , , and . Key terminology in microbiome research includes the metagenome, which represents the aggregate of all microbial genomes in a given environment, enabling comprehensive analysis of microbial functions beyond individual isolates. describes an imbalance or disruption in the microbial community structure, often linked to states through loss of or overgrowth of opportunistic pathogens, while eubiosis denotes a stable, healthy microbial that supports . These concepts underscore the dynamic nature of microbial-host interactions. The study of the human microbiome traces back to the 17th century, when first observed and described microorganisms, including those in oral scrapings and fecal samples, using his rudimentary microscopes. Throughout the , research relied primarily on culture-based techniques to isolate and characterize microbes, revealing associations between specific bacteria and health conditions but limited by the inability to cultivate most microbial species. A pivotal shift occurred in the early 2000s with the advent of molecular methods, such as 16S rRNA gene sequencing, which allowed for culture-independent profiling of microbial diversity. This culminated in the launch of the Human Microbiome Project (HMP) by the in 2007, which characterized the metagenomes of 300 healthy adults across 18 body sites to establish a reference dataset for normal microbial variation. The field's evolution reflects a broader from the 19th-century germ theory, which portrayed microbes primarily as pathogens causing disease, to a symbiotic perspective recognizing their essential roles in host nutrition, immunity, and development. This transition was facilitated by Carl Woese's 1977 proposal of the of life—Bacteria, , and Eukarya—based on ribosomal RNA , which revolutionized microbial classification and highlighted the vast uncultured diversity of microbes. These advancements have positioned the as a critical component of , moving beyond isolation to integrated ecological and genomic studies.

Microbial Abundance and Diversity

The human microbiome encompasses an immense number of microbial cells, with approximately 3.8 × 10^{13} bacterial cells in a typical (as of 2016 estimates), slightly exceeding the estimated 3.0 × 10^{13} cells (refined in 2023 depending on age and sex), yielding a of about 1.3:1. This estimate, derived from systematic quantification of microbial densities across sites, has been refined in subsequent studies during the , accounting for variations in mass and microbial localization. In addition to , the contributes approximately 10^{13} viral particles, adding substantial complexity to the overall microbial load. The of the microbiome far exceeds that of , with the collective microbial community encoding an estimated 10 million unique genes in the gut alone—over 500 times the approximately 20,000 protein-coding genes in the . This expanded gene repertoire enables functions critical to host physiology, such as nutrient metabolism, that the alone cannot support. Recent studies have cataloged thousands of bacterial across the , with over 3,000 identified in the gut alone; individuals typically harbor several hundred , though deep sequencing reveals greater variation. In the gut, which harbors the majority of these microbes, the bacterial composition is dominated by the phyla Firmicutes and Bacteroidetes, which together account for roughly 90% of the community. Microbial diversity is quantified through metrics that capture both within-sample (alpha) and between-sample (beta) variation. Alpha diversity assesses community richness and evenness, commonly using the Shannon index, defined as H = -\sum p_i \ln p_i, where p_i represents the relative abundance of species i. Higher Shannon values indicate greater diversity, reflecting ecological stability in microbial assemblages. Beta diversity measures compositional differences across samples, often via the Bray-Curtis dissimilarity index, which ranges from 0 (identical communities) to 1 (completely distinct), highlighting factors like diet or health status that drive variation. A hallmark of the microbiome's functional diversity lies in its carbohydrate-active enzymes (CAZymes), which facilitate the breakdown of complex indigestible by s. The encodes thousands of CAZyme genes, outnumbering the genome's limited repertoire (fewer than 20 relevant enzymes) by more than 100-fold and enabling efficient extraction from dietary fibers. This enzymatic abundance underscores the microbiome's role as an extended metabolic organ, with CAZyme profiles varying by microbial taxa and environmental cues.

Microbial Composition

Bacteria

Bacteria constitute the predominant component of the human microbiome, comprising over 90% of microbial cells across body sites such as the gut, where they perform essential functions in nutrient metabolism and immune modulation. In the , bacterial communities are highly diverse, with densities reaching up to 10^11 cells per gram of fecal matter, dominated by species adapted to low-oxygen environments. The taxonomic structure of the human bacterial microbiome is characterized by a few major phyla that account for the majority of sequences in metagenomic surveys. Firmicutes and Bacteroidetes together represent over 90% of gut bacteria in healthy adults, followed by Actinobacteria, Proteobacteria, and Verrucomicrobia at lower abundances. Within these phyla, key genera include and (Firmicutes), which are involved in lactic and fermentation, respectively; (Actinobacteria), a prominent early colonizer in infants aiding in milk oligosaccharide breakdown; and (Bacteroidetes), which excels in complex carbohydrate utilization. These genera exhibit site-specific variations, with more prevalent in the upper gut and enriched in the colon. Bacterial physiology in the microbiome is largely , particularly in the oxygen-depleted gut , where of undigested carbohydrates produces (SCFAs) such as , propionate, and butyrate, which serve as energy sources for host epithelial cells and modulate . A representative pathway is the of glucose by acetogenic like certain species, yielding , , and gas: \text{C}_6\text{H}_{12}\text{O}_6 \rightarrow 2 \text{CH}_3\text{COOH} + 2 \text{CO}_2 + 4 \text{H}_2 Antibiotic resistance genes (ARGs) are widespread among , conferring adaptive advantages in environments exposed to compounds; metagenomic analyses indicate their presence in many sequenced bacterial genomes, particularly those from the gut, with higher prevalence linked to prior exposure. These genes often encode efflux pumps, beta-lactamases, and aminoglycoside-modifying enzymes, facilitating via plasmids and integrons. Interactions between and bacteriophages (viruses targeting ) dynamically shape microbiome composition through , which selectively reduces dominant populations and promotes . counter this via adaptive immune systems like -Cas, which acquire phage DNA spacers to cleave invading viral genomes; in the gut, CRISPR acquisition events modulate phage abundances, with a significant portion of spacers (up to 41%) matching known phages in the virome. A notable example of bacterial specialization is Bacteroides thetaiotaomicron, a core gut symbiont proficient in degrading host-indigestible from diet and ; its encodes 261 carbohydrate-active enzymes (CAZymes), including hydrolases and polysaccharide lyases, organized into polysaccharide utilization loci (PULs) that enable sequential breakdown and import of breakdown products. This capacity underscores bacteria's role in expanding the host's metabolic repertoire beyond the human 's limitations.

Archaea, Fungi, and Viruses

In the human microbiome, archaea represent a minor but ecologically significant component, primarily residing in the gastrointestinal tract. The dominant archaeon is Methanobrevibacter smithii, a methanogenic species that constitutes approximately 0.1–4% of the total microbial community in the gut, depending on individual variation and methanogen prevalence. This low abundance belies its functional importance, as M. smithii consumes hydrogen (H₂) and carbon dioxide (CO₂) produced by bacterial fermentation, converting them to methane (CH₄) via the reaction $4H_2 + CO_2 \rightarrow CH_4 + 2H_2O. By removing excess H₂, it enhances the efficiency of bacterial fermentation, allowing for greater production of short-chain fatty acids that the host can absorb for energy, thereby aiding overall caloric harvest from the diet. The fungal component of the human microbiome, known as the mycobiome, is similarly sparse, comprising less than 1% of the total microbial load but influencing host immunity and microbial interactions. In the gut, the mycobiome is predominantly composed of phyla, with species (e.g., ) and species (e.g., ) as the most abundant genera across age groups and populations. These fungi contribute to immune training by engaging receptors on host immune cells, particularly through β-glucans in their cell walls, which trigger innate immune responses and enhance long-term protection against pathogens. Fungal-bacterial antagonism further shapes community dynamics; for instance, biofilms resist invasion by bacterial competitors like through metabolic interference and structural barriers, promoting fungal persistence in polymicrobial environments. Viruses in the human microbiome, collectively termed the virome, are non-cellular entities that vastly outnumber microbial cells, with an estimated 10⁹–10¹⁰ virus-like particles per gram of fecal content in the gut. The virome is overwhelmingly dominated by bacteriophages (>90%), which target bacterial and regulate community structure, while eukaryotic viruses constitute a smaller and include latent herpesviruses that infect cells. Temperate bacteriophages often integrate as prophages into bacterial genomes, enabling of traits such as antibiotic resistance and virulence factors, which influences microbiome and -pathogen interactions. This prophage-mediated exchange underscores the virome's role in maintaining microbial diversity and adaptability within the gut ecosystem.

Anatomical Distribution

Gastrointestinal Tract

The gastrointestinal tract harbors the majority of the human microbiome, accounting for approximately 99% of its total microbial biomass. This dense microbial community plays a central role in , metabolism, and host , with the highest concentrations residing in the distal regions. The tract's microbial populations exhibit distinct site-specific compositions influenced by anatomical, physiological, and environmental factors, creating a gradient of diversity and density from proximal to distal segments. In the small intestine, microbial density remains relatively low, ranging from approximately 10^4 to 10^7 cells per milliliter, reflecting the rapid transit time, high oxygen levels, and antimicrobial defenses such as bile acids and peristalsis that limit proliferation. This region is predominantly aerobic or microaerobic, supporting oxygen-tolerant taxa like Proteobacteria and facultative anaerobes. In contrast, the colon hosts a far higher density of 10^11 to 10^12 cells per gram of content, fostering a strictly anaerobic environment dominated by fermentative bacteria. The colonic microbiota is primarily composed of Firmicutes and Bacteroidetes phyla in a ratio of approximately 1:1 in healthy adults, enabling efficient breakdown of complex carbohydrates into short-chain fatty acids. Approximately 10^14 microbial cells are excreted daily via feces, representing the continuous turnover of this vast population. Environmental gradients along the tract further shape microbial communities. The pH shifts from around 6 in the —neutralized by —to 5.5–6.5 in the colon, where produces organic acids that maintain this mildly acidic milieu. acids, released from the into the , undergo microbial transformation in the colon; primary bile acids are converted to secondary forms by taxa such as species, which exhibit properties that inhibit potential pathogens and modulate community structure. These gradients, combined with availability and oxygen depletion, drive ecological niches that favor specialized microbial consortia. The gut microbiome demonstrates remarkable stability, with a core set of taxa persisting over years in healthy individuals, reflecting resilient ecological dynamics and host-specific factors. Longitudinal studies have shown that dominant phylotypes remain consistent across decades, despite minor fluctuations from or transient perturbations. This stability is exemplified by enterotypes—discrete community clusters identified in large-scale metagenomic analyses—primarily defined by dominance of (prevalent in Western diets), (linked to high-fiber intake), or genera, as described in the seminal 2011 study by Arumugam et al. These enterotypes highlight the gut's functional partitioning and long-term compositional robustness.

Skin and Respiratory Tract

The human skin microbiome varies significantly across body sites, categorized primarily by moisture levels, sebum production, and environmental exposure, which collectively shape microbial community structure and function. Moist regions, such as the axillae and inguinal creases, harbor high microbial densities of approximately 10^6 to 10^7 colony-forming units (CFU) per cm², dominated by Gram-positive bacteria including Corynebacterium and Staphylococcus species that thrive in humid conditions. These sites support a relatively low diversity of microbes adapted to moisture, contributing to barrier defense against external pathogens. In contrast, dry areas like the forearms exhibit lower densities, ranging from 10^2 to 10^4 CFU/cm², with a more diverse assemblage including Staphylococcus epidermidis, Micrococcus, and Propionibacterium (now classified as Cutibacterium) species, reflecting exposure to desiccating air and transient colonization. Sebaceous sites, such as the face and upper back, feature moderate densities of 10^5 to 10^6 CFU/cm² and are characterized by lipophilic microbes like Cutibacterium acnes and the fungus Malassezia, which utilize sebum lipids for growth and maintain a stable, low-diversity community. Fungal elements, particularly Malassezia in sebaceous areas, complement bacterial populations in lipid-rich environments. Environmental factors, including surface of 4.5 to 5.5, profoundly influence microbial selection by favoring acid-tolerant such as coagulase-negative staphylococci and corynebacteria while inhibiting neutral-pH-preferring pathogens like . This acidity, derived from free fatty acids in sebum and , enhances the 's protective . Overall, these site-specific microbiomes play a critical role in preventing , modulating , and supporting epithelial integrity through competitive exclusion and production. The microbiome exhibits a of microbial abundance and composition from the upper airways to the lower lungs, reflecting constant seeding, clearance mechanisms, and varying physiological conditions. In the upper airways, including the , communities are dominated by and genera within the phyla Firmicutes and Bacteroidetes, with nasal sites showing distinct profiles enriched in and compared to the more diverse oropharynx. These upper regions serve as reservoirs, with higher facilitating immune priming and resistance. Transitioning to the lungs, microbial decreases markedly to 10^3 to 10^5 bacteria per gram of tissue in healthy individuals, primarily comprising , , and species that arrive via microaspiration from the oropharynx. This low- ecosystem maintains through and immune surveillance, with communities showing an inside-out distribution where oral immigrants predominate but are selectively filtered. Environmental influences, such as oxygenation levels that increase distally toward the alveoli, favor aerobic and facultative bacteria like and , while promoting a gradient of decreasing microbial density from the proximal oropharynx to distal alveoli due to enhanced clearance and immune activity. in the respiratory often arises from disrupted transient from the oral , leading to overgrowth of pathobionts and impaired barrier defense in conditions like . These dynamic communities underscore the respiratory tract's role as an exposure-driven interface, contrasting with more stable internal ecosystems by relying on continuous microbial turnover for health.

Urogenital and Reproductive Tract

The urogenital microbiome encompasses the urinary tract, including the and , where microbial communities exhibit low , typically ranging from 10² to 10⁴ colony-forming units per milliliter in healthy individuals. In females, these communities are frequently dominated by species, such as L. crispatus, alongside Gardnerella, contributing to a stable, protective environment against pathogens. However, indwelling urinary catheters disrupt this balance, leading to shifts toward Proteobacteria dominance, particularly Enterobacteriaceae like and , which can promote formation and infection risk. The vaginal microbiome is distinctly Lactobacillus-dominated in reproductive-age women, with key species including L. crispatus and L. iners that ferment glycogen-derived glucose into (glucose → 2 ), maintaining a low below 4.5 essential for barrier integrity and inhibition. This metabolic activity supports eubiosis, where concentrations can reach approximately 1% (w/v). Ravel et al. classified vaginal microbial profiles into five community state types (s) using 16S rRNA sequencing of samples from 396 women: CST I (L. crispatus-dominated, 26%), CST II (L. gasseri, 6%), CST III (L. iners, 34%), CST V (L. jensenii, 5%), and the more diverse CST IV (27%) with reduced and elevated anaerobes like and Gardnerella, correlating with higher (around 5.3) and increased susceptibility. Protective mechanisms extend to (H₂O₂) production by certain strains, which generates effects under aerobic conditions, reducing colonization by uropathogens and sexually transmitted agents. In the reproductive tract, the placenta has been reported in some early studies to harbor a low-biomass , with estimates of around 0.002 mg bacterial DNA per gram of tissue primarily comprising nonpathogenic Firmicutes, Proteobacteria, Tenericutes, Bacteroidetes, and Fusobacteria, resembling oral microbial signatures; however, these findings are subject to methodological concerns including , and the existence of a resident placental remains highly debated. The maintains a similarly sparse community during , but postpartum shifts occur, marked by increased microbial diversity and potential immune modulation that may elevate risks like postpartum hemorrhage. Fetal acquisition remains debated, with the "sterile womb" hypothesis supported by anatomical barriers and negative cultures in healthy pregnancies, while molecular detections in and suggest possible in utero seeding, though often attributed to in low-biomass analyses. Recent studies as of 2025 using advanced methods have confirmed no detectable microorganisms in from healthy pregnancies throughout , reinforcing challenges in prior detections. from uncomplicated term pregnancies typically shows no detectable microbial community, though some molecular studies report signals that are contested. Viruses, including bacteriophages, are present at levels across urogenital and reproductive sites, influencing bacterial dynamics without dominating the overall composition.

Other Sites

The oral cavity hosts one of the most diverse microbial communities in the , encompassing approximately 700 prokaryotic taxa as cataloged in the Human Oral Microbiome Database. Predominant genera such as and facilitate early adhesion and metabolic cross-feeding, contributing to in this niche. Microbial composition varies significantly across sub-sites; for example, biofilms are enriched in anaerobes like Fusobacterium and Porphyromonas, while saliva supports a more transient, aerobic community dominated by species, reflecting differences in oxygen availability and nutrient flow. These biofilms exhibit high bacterial densities, typically ranging from 10^8 to 10^9 cells per gram of plaque, enabling robust interspecies interactions within structured matrices. The maintains a distinct, lower-diversity compared to the oral site, primarily dominated by Corynebacterium species and Dolosigranulum pigrum, which promote commensal colonization and in healthy states. Pathological shifts, such as in chronic rhinosinusitis, often involve reduced abundance of these aerobes and proliferation of anaerobes like Prevotella and Fusobacterium, altering local and production. In the , particularly the , the exhibits low , with Bacteroidetes phyla comprising a significant portion alongside Firmicutes and Proteobacteria, influenced by 's properties. These communities deconjugate primary bile acids via enzymes like bile hydrolase, modulating host and potentially contributing to . Such low-density populations contrast with the higher microbial gradients observed in the , highlighting site-specific adaptations to harsh chemical environments. Notably, the oral microbiome influences distant sites through daily swallowing of approximately 1.5 × 10^{12} , seeding the gut and potentially altering its in dysbiotic states.

Methods of Study

Sampling and Sequencing Techniques

Sampling protocols for the human microbiome vary by anatomical site to minimize and capture representative microbial communities. For and oral sites, swabbing with sterile flocked swabs moistened in saline or is standard, allowing non-invasive collection while targeting surface-associated microbes. In the , fecal samples are collected directly into sterile containers, often snap-frozen to preserve microbial integrity. For the , particularly the lungs, via endotracheal tubes or (BAL) using sterile saline and retrieval provides access to lower airway communities, though BAL may introduce oral contaminants if not performed carefully. In the urogenital tract, bladder lavage involves catheter-based saline and to sample luminal contents, reducing external compared to voided . To control for across methods, researchers incorporate mock communities—defined mixtures of known microbial strains—processed alongside samples to assess extraction and sequencing biases, as well as extraction blanks and environmental controls. DNA extraction from microbiome samples requires robust lysis to access diverse cell types, particularly Gram-positive bacteria with thick peptidoglycan walls. Mechanical disruption via bead-beating, using 0.1-mm zirconia beads in a homogenizer for 5-10 minutes, effectively lyses these cells and is integrated into commercial kits. The QIAamp DNA Stool Mini Kit (Qiagen), for instance, combines bead-beating with chemical lysis and silica-based purification to yield high-quality DNA from fecal or other complex samples, minimizing host DNA interference and inhibitors like humic acids. Kits emphasizing bead-beating, such as the PowerLyzer PowerSoil DNA Isolation Kit, outperform gentler methods in recovering Gram-positive taxa like Firmicutes, ensuring comprehensive community representation. Sequencing techniques begin with targeted or untargeted approaches to profile microbial diversity and function. For taxonomic profiling, 16S rRNA gene amplicon sequencing amplifies the V4 hypervariable region using Earth Microbiome Project (EMP)-standardized primers 515F (5'-GTGCCAGCMGCCGCGGTAA-3') and 806R (5'-GGACTACHVGGGTWTCTAAT-3'), followed by paired-end sequencing on platforms like Illumina MiSeq, yielding ~250 bp reads per amplicon for operational taxonomic unit (OTU) assignment. This method is cost-effective for high-throughput bacterial identification but underrepresents some taxa due to primer biases. For functional insights, shotgun metagenomics sequences total DNA without amplification, typically using Illumina HiSeq or NovaSeq platforms with 150 bp paired-end reads at depths of 5-10 Gb per sample, enabling gene cataloging and strain-level resolution in human gut microbiomes. The Human Microbiome Project (HMP) established standardized protocols for sampling 18 body sites across 300 healthy adults, including posterior auricular skin swabs, anterior nares, and vaginal lavages, to generate a reference dataset of microbial profiles and promote reproducibility. Post-2020 advancements in long-read sequencing, such as PacBio's HiFi circular consensus reads (up to 20 kb), have improved assembly of unculturable microbes in human samples by resolving repetitive regions and full-length genes, enhancing taxonomic accuracy beyond short-read limitations.

Metagenomic and Phylogenetic Analyses

Metagenomic analyses involve the computational reconstruction and characterization of microbial communities from high-throughput sequencing data, enabling the identification of uncultured organisms and their functional potential without relying on targeted markers. These approaches address limitations in sampling, such as biases that can skew representation of certain taxa, by providing a more comprehensive view of community diversity. Phylogenetic analyses complement this by inferring evolutionary relationships among microbes, aiding in strain-level resolution and tracking of microbiome dynamics over time or across hosts. In metagenomic assembly, short reads from are pieced together into longer contigs using de novo assemblers like MEGAHIT, which employs a for efficient handling of large datasets and has been widely adopted for its speed and accuracy in reconstructing microbial genomes from complex samples. Once assembled, open reading frames are predicted using tools such as , which identifies protein-coding genes with high sensitivity by modeling bacterial gene features like Shine-Dalgarno sequences. Functional annotation follows, mapping predicted genes to databases like for pathway reconstruction or for orthologous group classification, revealing metabolic capabilities such as carbohydrate degradation pathways prevalent in the gut microbiome. For targeted analyses of bacterial diversity, 16S rRNA gene sequencing remains a cornerstone, with pipelines like QIIME2 facilitating end-to-end processing from raw reads to taxonomic profiles. Denoising steps employ algorithms such as DADA2, which models sequencing errors to generate amplicon sequence variants (ASVs)—more precise units than traditional operational taxonomic units (OTUs) that cluster sequences at 97% similarity, thus reducing artificial inflation of diversity estimates. Taxonomy is then assigned against reference databases like , which curates high-quality aligned sequences, or Greengenes, offering a comprehensive 16S phylogeny for classification down to level in most cases. analysis via 16S identifies approximately 90% of bacterial taxa in microbiomes, though it misses rare or novel lineages; post-2018 advances in untargeted have uncovered previously unknown phyla, such as Candidatus Absconditabacter, expanding our understanding of microbial . Phylogenetic methods further refine these profiles by constructing evolutionary to delineate relationships among taxa. Maximum likelihood-based tools like RAxML enable robust of phylogenies from concatenated marker genes or whole genomes, accommodating models of substitution to account for evolutionary rates across the tree. For strain tracking within the human microbiome, core genome phylogeny aligns conserved genes across isolates to resolve fine-scale differences, as demonstrated in studies of populations in the gut, where it reveals transmission events and adaptation to host environments.

Ecological and Functional Profiling

Ecological profiling of the human involves constructing co-occurrence networks to model microbial community interactions and dynamics. These networks represent taxa as nodes and statistically inferred associations, such as correlations in abundance, as edges, providing insights into community structure beyond taxonomic composition. A widely used method is SparCC (Sparse Correlations for ), which addresses the compositional biases inherent in data by estimating pseudo-correlation coefficients to infer true ecological relationships, particularly in the human gut where it has revealed habitat-specific associations among bacterial genera. Such networks highlight potential symbiotic or competitive interactions, with applications in identifying shifts during disease states like . Within these networks, taxa—microbes that disproportionately influence community stability and function—are identified using measures. , for instance, quantifies a taxon's control over interactions between others, marking high- nodes as potential s that maintain resilience, as demonstrated in gut microbiomes where taxa like exhibit elevated linked to anti-inflammatory roles. assesses connectivity, revealing hubs that drive , while evaluates influence through connections to other influential nodes; these metrics have been pivotal in studies showing taxa's role in resisting in the human . Top-down approaches further refine identification by evaluating a taxon's total impact on the broader community, enhancing predictive power for therapeutic targeting. Functional profiling complements ecological analyses by predicting metabolic capabilities from community data. PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) infers gene family abundances from 16S rRNA sequences by leveraging phylogenetic relationships and precomputed functional annotations, accurately recapturing Human Microbiome Project findings on pathways like in the gut. For deeper resolution, HUMAnN (HMP Unified Metabolic Analysis Network) processes shotgun metagenomic data to quantify pathway abundances using databases like , enabling strain-level functional attribution; it has illuminated variations in short-chain production modules across healthy and diseased states. These tools prioritize conceptual pathways over exhaustive gene lists, focusing on high-impact contributions like fermentation-related orthogroups. Diversity indices, particularly beta diversity metrics, assess community stability and variability in ecological contexts. Beta-dispersions measure dispersion around centroids in ordination space, indicating compositional homogeneity, while PERMANOVA (permutational multivariate analysis of variance) tests for significant differences attributable to factors like host diet or health status, revealing greater stability in resilient gut microbiomes. Applied to longitudinal data, these reveal temporal dynamics, such as reduced beta diversity dispersion in stable adult microbiomes compared to infants. Ecological analyses of co-occurrence networks uncover modularity, where densely connected subgroups (modules) perform specialized functions, such as fermentation clusters in the gut involving butyrate producers and hydrogen utilizers that enhance energy harvest from diet. In the 2020s, multi-omics integration has advanced this by combining metagenomics with metaproteomics to validate active modules, as seen in reviews highlighting proteomics' role in quantifying functional proteins during gut fermentation perturbations.

Functions and Interactions

Metabolic Contributions

The human gut microbiome plays a pivotal role in metabolizing otherwise indigestible dietary components, particularly complex that human enzymes cannot break down, with microbial communities degrading the majority of these compounds through processes. This degradation primarily occurs in the colon, where undigested fibers from plant sources are converted into bioactive metabolites that contribute to host nutrition. A key aspect of these fermentation pathways involves the production of (SCFAs), such as , propionate, and butyrate, which arise from the microbial breakdown of dietary fibers and resistant starches. Butyrate, in particular, is synthesized via the pathway, where two molecules of condense to form acetoacetyl-CoA, which is then reduced through crotonyl-CoA and butyryl-CoA intermediates to yield butyrate. This pathway is predominant in butyrate-producing like those in the genera and Roseburia, enabling efficient energy extraction from carbohydrates. Additionally, the microbiome synthesizes essential vitamins, including (menaquinone) by species, which produce long-chain forms critical for host and . The microbiome also facilitates energy harvest from diet, contributing approximately 10% of daily caloric needs through SCFA production from , a process that enhances host beyond what human digestion alone provides. This is supported by microbial cross-feeding interactions, such as species generating from , which butyrate-producers like Anaerostipes caccae then utilize as a to form butyrate via the acetate CoA-transferase pathway. Such interspecies exchanges optimize utilization and yields in the gut . In metabolism, gut microbes transform exogenous compounds, exemplified by inactivating the cardiac drug through reduction to cardioinactive dihydrodigoxin via a cytochrome-mediated process encoded by the . Similarly, dietary polyphenols like from berries and nuts are converted by diverse gut bacteria, including Gordonibacter species, into urolithins—bioavailable metabolites with potential properties—via sequential and ring formation. These transformations highlight the microbiome's role in modulating the and efficacy of both nutrients and pharmaceuticals.

Immune System Regulation

The human microbiome plays a pivotal role in regulating the immune system by modulating both innate and adaptive responses, thereby maintaining homeostasis and preventing excessive inflammation at barrier sites. Microbes interact with host immune cells through pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), which detect microbe-associated molecular patterns (MAMPs) to initiate signaling cascades that shape immune tolerance and activation. For instance, TLR4 specifically recognizes lipopolysaccharide (LPS), a MAMP from Gram-negative bacteria in the microbiota, triggering NF-κB activation and cytokine production while promoting tolerance to commensals when signaling is balanced. This recognition educates the immune system to distinguish harmless microbes from pathogens, preventing chronic inflammation. Dendritic cells (DCs), key antigen-presenting cells, are influenced by the microbiota to promote , particularly in the gut mucosa. Commensal bacteria-derived signals, including (SCFAs), condition DCs to adopt a tolerogenic , enhancing their production of anti-inflammatory cytokines like IL-10 and inducing regulatory T cells (Tregs). In the intestinal environment, microbiota-stimulated DCs migrate to lymphoid tissues, where they present antigens in a way that favors Treg differentiation over pro-inflammatory responses, thus maintaining mucosal homeostasis. Disruptions in this education process, such as during , can lead to impaired tolerance and heightened susceptibility to autoimmune conditions. The microbiome exerts profound effects on adaptive immunity through T-cell modulation, with specific bacterial taxa driving distinct subsets. Clostridiales species, indigenous to the gut, induce Foxp3+ Tregs by producing metabolites that activate G protein-coupled receptors on T cells, expanding the Treg pool and suppressing excessive Th1/Th17 responses to prevent . A rationally selected mixture of human-derived strains has been shown to enhance colonic Treg accumulation, underscoring their therapeutic potential in inflammatory disorders. Conversely, segmented filamentous bacteria (SFB), adherent to the small , potently promote Th17 cell differentiation via production and MHCII-dependent by DCs, bolstering defenses against extracellular pathogens while contributing to barrier protection. This selective induction highlights the microbiota's role in fine-tuning T-cell balance for host defense. Microbial contributions to barrier integrity further support immune regulation by preventing microbial translocation that could trigger . Akkermansia muciniphila, a mucin-degrading bacterium enriched in the layer, paradoxically strengthens the intestinal barrier by stimulating differentiation and production, thereby enhancing epithelial tightness and reducing permeability. In models of , supplementation with A. muciniphila restores density and integrity, mitigating inflammatory responses. This process indirectly modulates immune activation by limiting exposure to underlying immune cells. Early-life colonization by species critically influences long-term , particularly in reducing risk. Neonates colonized with exhibit elevated IL-10 production, an anti-inflammatory that dampens Th2-driven allergic responses and promotes regulatory pathways. Low IL-10 at birth in -colonized infants correlates with increased risk, emphasizing the protective role of this early imprinting. Temporal shifts in abundance during infancy further associate with altered profiles, including reduced IL-4 and IFN-γ, which mitigate to allergens. Recent investigations into the have revealed its contributions to antiviral immunity, expanding beyond bacterial influences. Post-2020 studies demonstrate that the gut virome, comprising bacteriophages and eukaryotic viruses, modulates innate antiviral responses by shaping signaling and training mucosal immunity against respiratory viruses like SARS-CoV-2. In inflammatory contexts, virome exacerbates susceptibility to viral infections, highlighting its integration with bacterial in holistic immune regulation.

Host-Microbe Symbiosis

The host-microbe symbiosis in the human microbiome reflects a long history of co-, where microorganisms and their hosts have developed interdependent relationships that enhance survival and . Central to this dynamic is the hologenome theory, which posits that the —the host organism combined with its resident —functions as the fundamental unit of selection in , rather than the host alone. Introduced by Zilber-Rosenberg and Rosenberg, this theory emphasizes that genetic variation in the hologenome arises from both host genomic changes and shifts in microbial composition, allowing rapid through microbial flexibility. of the microbiome, particularly from mother to offspring during birth and , further reinforces this symbiosis by seeding the infant's microbial communities and shaping early immune development, ensuring the inheritance of adaptive traits that promote and resistance. Mutualistic interactions exemplify the benefits of this symbiosis, with microbial communities providing essential functions that bolster host fitness. For instance, quorum sensing via autoinducer-2 (AI-2) enables interspecies communication among gut bacteria, coordinating behaviors such as formation and production that stabilize the microbial and indirectly support host nutrition and barrier integrity. The microbiome profoundly influences host immunity, as microbial signals regulate the expression of a substantial number of immune-related genes; for example, associations between gut microbial composition and the activity of innate and adaptive immune genes highlight how symbionts calibrate host responses to maintain . These interactions underscore the microbiome's role in enhancing host resilience, with microbial contributions extending to metabolic support and defense against environmental stressors. Disruptions to this , such as induced by antibiotics, can temporarily alter the microbial balance, leading to reduced and impaired host functions, though recovery often occurs within weeks to months depending on and environmental factors. Research in the on monozygotic twins has further illuminated hologenomic , demonstrating that shared microbial strains persist into adulthood despite physical separation, indicating strong and genetic-microbial interplay in shaping individual microbiomes.

Modulation and Transmission

Developmental and Lifestyle Changes

The human microbiome undergoes profound changes throughout life, beginning at birth when the mode of delivery significantly influences initial microbial seeding. Infants born vaginally acquire a gut microbiome dominated by Lactobacillus species from the maternal vaginal microbiota, promoting early colonization by beneficial bacteria that support immune development. In contrast, cesarean section-born infants are primarily seeded with skin-associated bacteria such as Staphylococcus and Corynebacterium, leading to delayed establishment of a diverse, adult-like microbiota and potential long-term health implications like increased risk of allergies and metabolic disorders. Breastfeeding further shapes this nascent microbiome, as human milk oligosaccharides—complex carbohydrates indigestible by the infant—selectively nourish Bifidobacterium species, such as B. longum subsp. infantis, which efficiently utilize structures like 2'-fucosyllactose to produce short-chain fatty acids that enhance gut barrier function and inhibit pathogens. Weaning from breast milk to solid foods around 6 months triggers a shift toward greater microbial diversity, with the introduction of complex carbohydrates fostering the growth of fiber-degrading taxa; by age 3, the gut microbiome typically stabilizes into an adult-like configuration dominated by Firmicutes and Bacteroidetes phyla. Lifestyle factors, particularly and , continue to modulate the mature , influencing its composition and metabolic output. High-fiber diets, rich in plant , promote the proliferation of species, which excel at breaking down resistant starches and fibers to generate like propionate. Conversely, Western-style diets high in saturated fats and low in fiber enrich , a sulfite-reducing bacterium that thrives on taurine-conjugated acids, potentially exacerbating intestinal and metabolic dysfunction. Regular exercise also exerts beneficial effects, with aerobic and endurance activities increasing the abundance of , a mucin-degrader that strengthens the gut barrier and correlates with improved insulin sensitivity and reduced risk in responders to training. In aging, the gut microbiome experiences a decline in after age 60, characterized by reduced abundance of butyrate-producing Firmicutes such as prausnitzii, which contributes to chronic low-grade inflammation (inflammaging) and frailty. However, centenarians often exhibit a unique microbial signature with enrichment in Christensenellaceae family members, which are associated with enhanced metabolic efficiency and , potentially buffering age-related . Studies have shown that adherence to a can beneficially affect the in older adults by fostering fiber-fermenting communities and sustaining short-chain production, thereby mitigating frailty and cardiometabolic risks.

Person-to-Person and Environmental Transmission

The human microbiome is initially established through from mother to , primarily during birth and subsequent . In vaginal deliveries, infants acquire a substantial portion of their resembling the maternal vaginal and fecal communities, with studies estimating that approximately 58.5% of the 's early can be attributed to maternal sources across body sites. further facilitates this transfer by introducing milk-associated microbes, enhancing gut colonization with beneficial taxa like species, which promote immune maturation. Paternal contributions to the microbiome, while present through close contact, remain minimal compared to maternal seeding, accounting for a smaller cumulative strain input independent of delivery mode. Horizontal transmission occurs among individuals through close interpersonal interactions, leading to microbiome convergence within households. Family members cohabiting share up to 30% of their gut microbiome species on average, with similarity increasing over time due to shared environments and physical contact. Intimate behaviors, such as kissing, facilitate direct exchange; a 10-second kiss can transfer around 80 million between partners, influencing oral microbiota composition and potentially stabilizing shared strains over repeated interactions. These dynamics highlight how social networks drive ongoing microbial exchange beyond initial seeding. Environmental exposures also shape the microbiome by introducing diverse microbes from surroundings. Contact with household pets, particularly dogs, increases skin microbiome diversity in owners by promoting the transfer of animal-derived taxa, which can enhance overall microbial richness and potentially confer benefits like reduced risk. versus rural environments further influence this; for instance, children exposed to farm settings exhibit altered innate immune responses and maturation due to high levels of environmental lipopolysaccharides (LPS) from microbial sources, providing protection against compared to peers. In early life, the fecal-oral route plays a key role in microbiome acquisition, allowing incidental ingestion of maternal or environmental microbes to seed the gut. Recent analyses indicate that global travel contributes to homogenizing microbiomes, reducing geographic variability in microbial profiles through increased and shared exposures.

Therapeutic Interventions

Therapeutic interventions targeting the human microbiome aim to restore or modulate microbial communities disrupted by , which is implicated in various diseases such as recurrent infections and inflammatory conditions. These strategies include the administration of live beneficial microbes (), non-digestible substrates that promote their growth (prebiotics), and more invasive procedures like fecal transplantation (FMT). Emerging approaches, such as targeted antimicrobials and genetically engineered , offer precision in addressing specific pathogens or host-microbe imbalances. Clinical evidence supports their efficacy in select contexts, though outcomes vary by individual factors and require rigorous safety protocols. Probiotics, defined as live microorganisms that confer health benefits when administered in adequate amounts, commonly involve strains of Lactobacillus and Bifidobacterium. For instance, Lactobacillus rhamnosus GG (LGG) has demonstrated efficacy in preventing antibiotic-associated diarrhea, reducing its duration by approximately one day in randomized controlled trials. This strain's protective effects are attributed to its ability to adhere to intestinal mucosa and inhibit pathogen colonization. Similarly, Bifidobacterium species enhance gut barrier function and modulate immune responses, contributing to overall microbiome stability. Prebiotics, such as inulin and fructo-oligosaccharides (FOS), serve as fermentable fibers that selectively stimulate the growth of beneficial bacteria like bifidobacteria, leading to increased short-chain fatty acid production and improved gut health. Systematic reviews confirm that inulin-type fructans exhibit prebiotic potential by promoting microbial diversity and abundances of health-associated taxa in the human intestine. Fecal microbiota transplantation (FMT) involves transferring processed stool from a healthy donor to a recipient to restore a balanced microbiome, particularly effective against recurrent Clostridioides difficile infection (CDI). Meta-analyses of 2010s randomized controlled trials report cure rates of 80% to 90% for recurrent CDI following FMT, surpassing standard antibiotic therapies in preventing relapse. Efficacy is independent of delivery method (e.g., colonoscopy or enema) or stool preparation, though rigorous donor screening is essential to mitigate risks. As of 2023, the U.S. FDA has approved commercial products based on FMT, including Rebyota (fecal microbiota, live-jslm) in November 2022 and Vowst (fecal microbiota spores, live-brpk), the first orally administered option, in April 2023, for preventing recurrence of CDI in adults following antibiotic treatment. Protocols recommended by clinical guidelines include comprehensive questionnaires assessing risk factors for transmissible diseases, serological testing for pathogens like HIV and hepatitis, and stool assays for bacteria, parasites, and multidrug-resistant organisms to ensure donor safety and prevent adverse transmissions. Targeted antimicrobial interventions, including bacteriophage therapy, provide precise alternatives to broad-spectrum antibiotics that disrupt the . Phages are viruses that selectively lyse specific bacterial pathogens without affecting commensal microbes. In 2020s clinical trials, nebulized phage cocktails like BX004-A have shown safety and microbiological activity against chronic lung infections in patients, reducing bacterial burden in phase 2b studies. These trials highlight phages' potential for refractory infections, with no reported phage-related adverse effects, though challenges in phage stability and resistance remain. Post-2020 advancements include engineered microbes, such as CRISPR-edited strains designed for (IBD) therapy. These synthetic bacteria, often based on probiotic chassis like E. coli Nissle 1917, are modified to deliver anti-inflammatory payloads or inhibit pathogen adhesion in the gut, demonstrating targeted regulation of intestinal immunity in preclinical models. Synbiotics, combining and prebiotics, amplify these effects by enhancing microbial viability and colonization; for example, formulations with and FOS increase beneficial taxa levels and support balance in human studies. Ongoing research emphasizes strain-specific efficacy and personalized applications to optimize therapeutic outcomes.

Health Implications

Dysbiosis in Infectious Diseases

Dysbiosis in the human microbiome refers to an imbalance in microbial communities that disrupts , often creating niches for opportunistic to proliferate and cause infectious diseases. In infectious contexts, dysbiosis typically arises from external perturbations like use, which reduces microbial diversity and impairs colonization resistance, allowing pathogen overgrowth. This imbalance not only facilitates initial infections but also contributes to recurrence and severity, as seen in various body sites including the gut, , , and . A prominent example is * (CDI), where antibiotic-induced depletes protective gut bacteria, enabling toxin-producing strains to dominate and release toxins A and B that damage the colonic mucosa. This loss of diversity, particularly in Firmicutes and Bacteroidetes, allows C. difficile spores to germinate and produce symptoms like severe . Recurrence occurs in 20–30% of cases due to persistent and spore persistence, often requiring interventions like fecal microbiota transplantation (FMT) to restore balance. Pathobionts, normally commensal microbes that become pathogenic under dysbiosis conditions, exemplify how imbalances promote infections. In the gut, enteropathogenic Escherichia coli can bloom following antibiotic exposure, exploiting released host sugars and reduced competition to expand and cause enteritis. Similarly, in the vaginal microbiome, dysbiosis favors Gardnerella vaginalis overgrowth in bacterial vaginosis (BV), where Lactobacillus depletion raises vaginal pH above 4.5, creating an environment conducive to polymicrobial biofilms and symptoms like discharge and odor. Viral infections can also drive dysbiosis by altering immune responses, as in , where depletion of Th17 cells in the gut mucosa weakens barrier integrity and enables fungal overgrowth, such as , leading to opportunistic infections. On the skin, persistently colonizes about 30% of the population, and dysbiosis—often from disrupted commensal staphylococci—can promote methicillin-resistant S. aureus (MRSA) emergence and skin infections. Recent 2024 studies highlight post-COVID respiratory dysbiosis, where alters oropharyngeal diversity, potentially increasing susceptibility to secondary bacterial pneumonias through reduced protective species.

Role in Chronic and Inflammatory Conditions

The human microbiome plays a pivotal role in the of chronic and inflammatory conditions through , where shifts in microbial composition and function contribute to sustained and tissue damage. In (IBD), including and , patients exhibit reduced microbial diversity alongside a decreased abundance of Firmicutes phylum and an increased abundance of Proteobacteria, which correlates with severity and . These alterations disrupt short-chain production, impairing epithelial barrier integrity and promoting immune dysregulation. Fecal calprotectin, a marker of neutrophil-derived , is elevated in IBD and associates with microbial , serving as a non-invasive indicator of mucosal and activity. As of 2025, ongoing clinical trials explore microbiome-modulating therapies, such as next-generation , for managing long COVID-associated . In cancer, particularly , the bacterium is enriched in tumor tissues and promotes by adhering to host E-cadherin via its FadA adhesin, activating β-catenin signaling, and inducing inflammatory responses that enhance tumor growth and . This microbial interaction fosters a pro-tumorigenic microenvironment, highlighting the microbiome's contribution to oncogenesis beyond genetic mutations. Alterations in the , including the cervicovaginal DNA virome, are also linked to , where increased viral diversity and shifts away from papillomavirus dominance correlate with HPV persistence and progression to . The gut-brain axis exemplifies the microbiome's influence on chronic conditions like (IBS) and , where reduces butyrate-producing , leading to lower short-chain fatty acid levels that diminish serotonin synthesis in the gut—up to 90% of which is produced enterically—and alters signaling to exacerbate mood and visceral symptoms. These changes perpetuate a cycle of and gut dysfunction, as seen in IBS patients with comorbid . A 2023 analysis further connects low gut microbial diversity to via (LPS) endotoxemia, where increases gut permeability, allowing bacterial toxins to trigger systemic and metabolic .

Influence on Longevity and Mortality

The human gut microbiome experiences a progressive decline in with advancing age, characterized by reduced richness and evenness of microbial taxa, which compromises its resilience and functionality. This shift is linked to factors such as dietary changes and reduced , contributing to overall microbial instability during aging. A notable consequence of these alterations is diminished production of (SCFAs), such as butyrate and , due to lower abundances of fermentative like Faecalibacterium and Roseburia. Reduced SCFA levels exacerbate chronic low-grade inflammation, termed inflammaging, by impairing gut barrier integrity and promoting systemic immune dysregulation. Supplementation with SCFAs has been shown to mitigate inflammaging markers in aging models, underscoring the microbiome's role in modulating inflammatory processes. In centenarians, the gut microbiome often displays a distinct composition enriched with health-promoting taxa, including Akkermansia muciniphila and members of the Christensenellaceae family, which correlate with enhanced metabolic efficiency, reduced inflammation, and preserved gut barrier function. These microbial signatures are associated with exceptional , as observed in cohorts from various regions. In Japanese centenarians from Okinawa, a traditional plant-rich, low-calorie high in and polyphenols supports this beneficial profile by fostering SCFA-producing bacteria and overall microbial diversity, contributing to lower rates of age-related decline. A history of antibiotic exposure further disrupts the elderly , leading to persistent reductions in and shifts toward pro-inflammatory taxa, which are independently linked to increased frailty indices such as diminished and . Following death, the postmortem , or thanatomicrobiome, undergoes rapid in the gut, marked by a bloom of anaerobic putrefactive bacteria such as species, which thrive in the oxygen-deprived, nutrient-rich environment of decaying tissues. This predictable microbial progression enables forensic applications, where thanatomicrobiome composition and succession patterns can estimate the postmortem interval (PMI) with increasing accuracy through 16S rRNA sequencing. Emerging evidence from fecal microbiota transplantation (FMT) studies supports the causal of longevity-associated microbiomes; for instance, transfers from long-lived donors to mice have reduced aging biomarkers and extended healthspan in recipient models through improved microbial diversity and effects.

Research Frontiers

Population and Geographic Variations

The human gut microbiome undergoes rapid changes following migration to new environments, often aligning with the microbial profile of the host country within one year. Studies of Hmong and Karen immigrants from and to the demonstrate a shift from Prevotella-dominant communities, characteristic of high-fiber diets in their origin countries, to Bacteroides-dominant profiles typical of diets, accompanied by a loss of microbial diversity. This transition is linked to dietary alterations and environmental exposures during relocation, highlighting how person-to-person and environmental transmission influences microbiome adaptation post-migration. Geographic and lifestyle factors contribute to substantial variations in microbiome composition, with non-urbanized populations exhibiting greater diversity. For instance, the Hadza hunter-gatherers of maintain one of the most diverse gut microbiomes documented, with higher phylogenetic richness and abundance of unique taxa such as species, which are adapted to utilize from dietary sources like . In contrast, promotes homogenization of the microbiome, reducing beta-diversity—the variation between individuals—and leading to more uniform community structures across populations. Comparative analyses in reveal that urban residents have altered beta-diversity metrics, with compositional shifts driven by lifestyle changes, resulting in less distinct microbiomes compared to rural counterparts. Ancestry correlates with distinct microbiome features, including differences in enterotype prevalence between populations of African and European descent. African-descended groups, such as rural Africans and , often display higher proportions of the enterotype, associated with fiber-rich diets and greater overall diversity, while European-descended urban populations are enriched in the enterotype, reflecting processed diets and lower diversity. Indigenous Australian populations exhibit unique microbiome signatures, which may reflect heritage-specific adaptations and contribute to distinct health profiles. Extensions of the Earth Microbiome Project in 2022 underscore broader geographic patterns, revealing latitude gradients in microbial communities, including skin-associated fungi, where diversity and composition vary with climatic zones. A of EMP data further highlights global trends in microbial ecosystems, emphasizing ongoing shifts in diversity across biomes. Urbanization exacerbates these shifts, correlating with approximately 30% lower prevalence of novel microbial taxa in the gut compared to rural settings (e.g., 20% vs. 28% of individuals carrying novel taxa), as observed in Chinese populations undergoing rapid development.

Emerging Discoveries and Applications

Recent studies have uncovered novel mechanisms of cellulose digestion in the human gut microbiome, revealing that certain bacteria, such as Ruminococcus species, produce cellulosomes—multienzyme complexes that break down crystalline cellulose by targeting β-1,4 glycosidic linkages through enzymes like cellulases and endoglucanases. These structures enable efficient degradation of plant-derived fibers that humans cannot digest independently, contributing to short-chain fatty acid production for host energy and gut health. In a 2024 discovery, researchers identified cryptic diversity among cellulose-degrading Ruminococcus strains in non-ruminant humans, showing their prevalence has declined in industrialized populations due to low-fiber diets, potentially impacting fiber metabolism and overall microbiome resilience. The concept of the "sexome" has emerged to describe sex-specific microbial communities across body sites, highlighting differences influenced by hormones and anatomy. In females, the vaginal microbiome is predominantly shaped by estrogen, fostering dominance of Lactobacillus species that maintain an acidic environment for pathogen resistance. In males, the urethral microbiome features higher proportions of Proteobacteria, which can be altered by vaginal intercourse through microbial transfer, introducing diverse taxa and potentially affecting urinary tract health. These sex-specific patterns, termed the sexome, underscore implications for personalized medicine, as unique microbial signatures at genital sites could inform tailored diagnostics and therapies for reproductive and infectious conditions. Multi-omics approaches integrating and have elucidated how gut microbes convert dietary choline into N-oxide (TMAO), a metabolite strongly linked to (CVD) risk. Gut bacteria such as Gammaproteobacteria and Firmicutes produce from choline, which the host liver oxidizes to TMAO, promoting and . Elevated TMAO levels, observed in cohort studies, correlate with increased CVD events, providing a for dietary and microbial interventions to mitigate heart disease. Therapeutic applications are advancing, with post-2020 developments in cocktails targeting obesity-related . A 2025 ex vivo study demonstrated that a two-phage cocktail targeting obesogenic in simulated colons from obese individuals reshaped composition, reduced markers, and improved metabolic profiles. Similarly, phage therapies have shown promise in preclinical models by selectively depleting harmful taxa, restoring microbial balance, and alleviating obesity-associated metabolic disturbances without side effects.