Frontiers in Microbiology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 8, 2025

Introduction"The instinct of each species is good for itself but has never, as far we can judge, been produced the exclusive others" (1). Why, then, do humans and other mammals benefit from their microbes?Evolutionary theory predicts that natural selection act at organizational levels higher than gene or individual—such on groups even species—provided selective advantages group outweigh evolutionary conflicts. Darwin suggested "on family, not individual," "for sake gaining a serviceable end" This idea was later formalized kin (2). Even distantly related organisms align goals, demonstrated by longstanding partnership between eukaryotic cells mitochondria (3).Microbes are an integral part animal plant hosts, fulfilling essential physiological roles, such enabling access to otherwise unavailable nutrients, training immune system, supporting mucosal development, providing protection. Some microbes vertically transmitted parents offspring. The numerous examples performing vital functions macrobial hosts makes it tempting assume residing within our bodies—particularly in guts—evolved share common interests potential conflicts (4–7). Supporting this assumption, several reports suggest selected harboring "good" these thrive helping example, contributing over 95% organism's genetic repertoire (7–9). But group-level necessary sufficient mechanism explain why microbiomes hosts?Microbes certainly influence host's chances survival reproductive success (10,11) reasons would reduce own fitness form evolutionarily aligned with microbial populations—an condition selection—are easily explained (12,13). For during 25-year human generation, gut undergo more 50,000 generations (assuming conservative four-hour generation time), competing thousands species. Roughly half bacterial biomass colon lost daily replaced new growth (14,15). Before reproduces, any trait unfavorable microbe's likely be eliminated. Moreover, relatively open regularly exposed diverse environmental microbes. Vertical transmission accounts only small fraction microbiome. About twenty consistently shared among most adults (16). How, evolution shaped diverse, rapidly evolving ecosystem individual health?One might argue microbes, host mitigates conflicts, encouraging sacrifice some benefit. However, evolve, genotypes similar needs emerge exploit host-provided without incurring costs—an example tragedy commons (17). These benefits all compatible whether they contribute well-being, creating imbalance contributors free riders. A rider, could bacterium feeds mucin glycans provided while invading tissue potentially causing severe illness.Why, microbes? recent model Sharp & Foster suggests one way overcome conundrum evolve mechanisms actively control limit opportunities evade (18). require enforcement policing maintain cooperation (19). In view, "beneficial" ability healthy state. words, favor microbiome engineers—or, accurately, tinkerers (20)—who make use various methods reach landscape sustain include responses ranging rudimentary inflammation diarrhea sophisticated driven adaptive system. From perspective, theory—the study how systems regulate themselves achieve desired outcomes—parallels host-microbial interactions, suggesting be, definition, host-controllable microbiomes.Will large complex stable?In 1970s, writing Nature, Robert May proposed stability ecosystems complexity increases, particularly number strength interactions grow (21). analyzed simplified Generalized Lotka-Volterra (GLV) explore concept. simulates random communities where population sizes constrained resource availability (represented negative self-interactions) mutual positive influences another's growth. According GLV model, assembled predicted remain stable when sufficiently weak strong confined few (Figure 1). GLV-like models commonly applied microbiomes, stability/complexity trade-offs assumed hold (22,23). May's introducing controller—an agent directs system toward predetermined objective, through energy expenditure—is continuously stabilize unstable reshape stability-complexity Figure 1. Fraction controller 10,000 simulations. Random were simulated increasing interaction strengths numbers Each dot represents hundred simulations colored according resulted Dark blue dots indicate cases 100 unstable, dark red stable. white transition zone intermediate stability. results show adding controller—here idealized device senses microbiome's current composition adjusts rates guide composition—significantly increases range microbiomes. Stability, defined here following original refers returns equilibrium after perturbation based signs eigenvalues Jacobian matrix point. Increased diversity generally associated gut. patients suffering pathogen invasions, inflammation, colitis, inflammatory bowel disease, colorectal cancer reduced alpha compared controls. Similarly, factors aging, obesity, Western diet, urbanization also linked decline (24). Diversity necessarily cause microbiome, rather consequence indirect evidence control. effectively drives state, which, state occur absence (due, constraints). case, impaired, declines. biological systems, active instead diversity. laboratory techniques like media dilution-to-extinction procedures, which isolate single strains, antibiotics, physical barriers, extreme pH, heat conditions similarly nature, see reducing diversity, Hawaiian bobtail squid, isolates Vibrio fischeri ocean its light organ (25). less often appreciated promote greater control.An intriguing underexplored perspective controls declining may signal loss controllability, instance, established reactors simulate gastrointestinal tract significantly stool inocula (26). Although replicate physicochemical flow gut, lack host-control mechanisms, dynamically regulated factors. Overall, viewing interconnected, island-like ecosystem—where serves patch colonized dispersal, local diversification, selection, drift (27)—becomes clearer consider processes active, energy-expending efforts target composition, functions.Beyond extends "state-space," includes populations biochemical activities. ideal scenario tight, full-state control, both abundance function population, including chemical outputs inputs. realistic involves limited, partial-state exerts varying degrees distinct aspects state-space. theoretical framework controlled targeting specific sets referred "minimal elements" (28). achieved leveraging species-species chains connecting external controllers intrinsic dynamics community still lacks empirical validation, highlights identifying elements restore dysbiotic microbiome.How helps microbiomesThe mammalian contains (29,30), categorized into microbiome-independent microbiome-dependent processes. transit time ranges two five hours intestine ten fifty-nine (31). parameters directly microbiome—favoring absorption fermentation intestine—but independent sensing features. open-loop (32)—that is, operate feedback itself. By contrast, system's features exemplifies closed-loop controller, actions dynamics. Evolving allowed fine-tune maximize large, densely populated meta-study comparing cultures fresh samples that, degrees, environment (e.g., SHIME, TIM-2) found interindividual variation inoculum primary driver (33)—i.e., outweighs pressure exerted reactor's operational design (biotope). ensures widely different, personalized communities, lifetime, continue perform despite variability.Controllability observability fundamental controlIf then need experimental elucidate control: (which state-space observe?) controllability states inputs, ideally finite time?). Numerous studies associate high consumption simple sugars low dietary fiber intake underlying debated. One possible explanation observability.Experiments synthetic substrates result history dependence, diverge taxonomic (34–36). lead deterministic compositions, (37). Put simply, multiple grown substrates, isolated same source maintained under identical (35). subset correspond communities. states. tend converge compositions metabolic profiles, regardless sources (37,38). scenario, outside reach. richness respond poorly therapeutic interventions, restriction immunotherapy (39).Controllability inherently dependent observability. Specifically, colonization events educate recognize pathogens enhance monitor Bacteroides fragilis produces immunomodulatory polysaccharide germ-free mice, trains protect against Helicobacter hepaticus, responsible colitis immunocompromised animals (40,41). Another segmented filamentous bacteria (SFB) (Candidatus Arthromitus), species-specific guts vertebrates. SFB forms millimeter-long filaments attach ileal epithelium via specialized cell called holdfast, triggering (42). species, peaks early life (43), future invasive pathogens.Interestingly, occupies spatial gradient cable bacteria, oxygen-rich anoxic lumen. morphology—long, single-layered filaments—it remains tested plays ecological role conducting electrons zones (44) sharing them (45). Ericsson colleagues observed mice exoelectrogenic fuel cells, though electrodes (46). Their showed differences electrical production exoelectrogens predictive lymphocyte trafficking unique signatures locations unusual signatures. adapting response redox gradients, observe react changes state-space.Host-microbiome dynamics: Pinocchio GeppettoOverall, incurs costs host, gathering information acting information. minimize invest reproduction. Over different timescales, arms race develops populations: efficient, cost-effective strategies, ways control—especially restricts (29). systemic counter invasion. When triggered, reactive oxygen released. opportunistic tolerating released hydrogen peroxide expressing molecular machinery allows absorb cytoplasm. There, quickly convert respiratory chain, giving advantage fermentative (47). Salmonella enterica serotype Typhimurium goes step further. Under normal conditions, detoxifies sulfide, quantities microbiota, converting thiosulfate. During thiosulfate tetrathionate, S. respires (48), feeding defense mechanisms.A healthy, symbiotic regulatory ensure beneficial function. arises impaired—whether because becomes unreachable, cues become unobservable, (effectors) ineffective. Geppetto (49); instead, attempt them. Like Pinocchio, strive—and succeed—to

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