From environmental perception to reproductive allocation: the microbiome–membrane–mitochondria axis in poultry

Abstract

Reproductive performance has traditionally been interpreted through the physiology of reproductive organs, endocrine regulation, and genetics. Although these approaches have substantially advanced poultry production, they do not fully explain why reproduction consistently reflects the overall physiological condition of the organism. This review proposes an integrative conceptual framework in which reproductive success emerges from the coordinated activity of the entire host–microbiome ecosystem, not from the reproductive system alone. We examine current evidence supporting the concept that the intestinal microbiome functions as a major ecological and metabolic partner that can contribute to whole-organism homeostasis through effects on intestinal barrier integrity, immunometabolism, endocrine signaling, microbial metabolite production, and mitochondrial bioenergetics. In this model, microbially derived signals, including short-chain fatty acids, bile acid metabolites, tryptophan derivatives, polyamines, vitamins, extracellular vesicles, and microbial-associated molecular patterns, form an extensive communication network linking the intestinal ecosystem with distant tissues.

Central to this model is the recognition of mitochondria as major bioenergetic and signaling integrators within the host–microbiome system. Beyond ATP production, mitochondria participate in redox homeostasis, immune activation, metabolic adaptation, endocrine responses, steroidogenesis, and cellular quality control, thereby integrating microbial, nutritional, immune, and environmental signals into cellular responses. Diverse stressors, including dysbiosis, heat stress, pathogens, mycotoxins, oxidative stress, nutritional imbalance, and chronic inflammation, converge upon mitochondrial and immunometabolic pathways that can alter systemic resource allocation and reproductive resilience. Reproductive performance is therefore considered here as an emergent, condition-dependent physiological outcome rather than as a hierarchically superior biological function. The intestinal microbiome does not directly regulate reproduction; instead, it contributes to the systemic conditions that can support reproductive investment, whereas microbial communities within the reproductive tract may interact more directly with reproductive tissues and gametes. The revised framework further emphasizes reciprocal communication: endocrine and reproductive states can reshape metabolism, immunity, intestinal physiology, mitochondrial function, and microbial ecology. Finally, maternal programming and optimization of host–microbiome interactions are considered as potential strategies for strengthening reproductive resilience across generations.

Introduction

Reproductive performance has traditionally been interpreted through the biology of the reproductive system. Gonadal development, endocrine regulation, gametogenesis, fertilization, embryogenesis, and reproductive genetics have collectively established the foundation of modern poultry reproductive physiology. These advances have substantially improved fertility, hatchability, and production efficiency, contributing to major progress in the global poultry industry. Nevertheless, this organ-centered perspective does not fully explain a fundamental biological observation shared across virtually all animal species: reproduction occurs only when the organism perceives that the internal and external conditions are compatible with long-term biological investment.

From an evolutionary perspective, every living organism continuously allocates finite biological resources among four competing physiological priorities: survival, maintenance, growth, and reproduction. Because biological energy is inherently limited (Lane, 2005), organisms integrate information regarding nutritional status, immune activation, environmental conditions, endocrine signals, metabolic reserves, and microbial interactions before determining how available resources should be distributed. Under favorable conditions, energy allocation supports growth, reproduction, and long-term fitness. Conversely, during periods of stress or physiological disturbance, resources are preferentially redirected toward survival and restoration of homeostasis, often at the expense of reproductive performance (Hochachka and Somero, 2002; Demas, 2004).

Across taxa, organisms face the common challenge of allocating finite resources among survival, somatic maintenance, growth, and reproduction. These allocations are not governed by a universal fixed hierarchy. Rather, they vary with physiological state, environmental conditions, reproductive stage, life-history strategy, and prospects for future survival. Under many adverse conditions, investment shifts toward maintenance and defense, whereas in other contexts reproductive effort may be maintained or increased despite reduced future survival prospects. Reproductive allocation is therefore best understood as dynamic and context dependent.

Seen through this evolutionary lens, reproduction should not be viewed as an isolated physiological process governed exclusively by reproductive organs. It represents the final biological expression of an integrated network that coordinates metabolism, immunity, endocrine regulation, neural communication, cellular energetics, and environmental adaptation. Reproduction is therefore an emergent property of whole-organism homeostasis.

The intestinal microbiome has emerged as one of the most influential components of this integrated biological network. Once regarded primarily as a collection of commensal microorganisms involved in digestion, the microbiome is now recognized as a dynamic metabolic and immunological partner that contributes to host physiology. Through continuous production of microbial metabolites, regulation of intestinal barrier integrity, immune education, endocrine modulation, and maintenance of metabolic homeostasis, intestinal microorganisms influence biological processes extending far beyond the gastrointestinal tract (Tellez et al., 2006; Oakley et al., 2014).

The concepts of the holobiont and hologenome provide a useful ecological and physiological framework for considering host–microbiome interactions, but their interpretation as a single evolutionary individual or unit of selection remains debated. Here, we use the term holobiont primarily as a functional descriptor of the host together with its associated microbial communities, without assuming that all components share a unified evolutionary trajectory. This functional association substantially expands host biochemical capacity: whereas the chicken genome contains approximately 17,000 protein-coding genes, an integrated chicken-gut catalog contains approximately 16.6 million nonredundant genes (Feng et al., 2021). This contrast illustrates the extensive metabolic repertoire contributed by microbial communities without requiring the host and microbiota to be treated as a single evolutionary entity.

Among the multiple systems integrating microbial signals, mitochondria occupy a central position. Beyond their classical role as cellular ATP producers, mitochondria function as dynamic regulators of immunometabolism, redox homeostasis, calcium signaling, apoptosis, innate immunity, and cellular adaptation to stress. Their bacterial evolutionary origin further positions mitochondria at the interface between microbial metabolism and host physiology, allowing them to integrate environmental, nutritional, immune, and metabolic information into coordinated cellular responses (Margulis, 1970; O’Neill et al., 2016).

The bacterial origin of mitochondria remains central to the present framework because endosymbiosis linked microbial ancestry with eukaryotic bioenergetics and created an enduring evolutionary connection between microbial metabolism and host cellular physiology (Margulis, 1970).

This integrative perspective also provides a unifying explanation for why apparently unrelated stressors frequently produce remarkably similar physiological consequences. Heat stress, dysbiosis, pathogen exposure, mycotoxins, nutritional imbalances, oxidative stress, chronic inflammation, environmental challenges, and endocrine disturbances differ substantially in their initiating causes. Nevertheless, they converge upon common biological responses characterized by increased energetic demand, disruption of immunometabolic homeostasis, mitochondrial dysfunction, and redistribution of biological resources toward survival. Under many such conditions, reproductive investment can decline, not because reproductive organs necessarily fail independently, but because defense, repair, and restoration of homeostasis can impose competing metabolic and energetic demands (Ruff et al., 2020; Tellez-Isaias et al., 2023; Nuningtyas et al., 2026).

We therefore propose that the intestinal microbiome should not be viewed as another direct regulator of reproductive physiology. It functions instead as a fundamental ecological component of an evolutionarily conserved biological system that continuously shapes the internal conditions required for reproduction to occur. By influencing immunometabolic homeostasis, mitochondrial function, endocrine balance, adaptive resilience, and systemic energy allocation, the microbiome contributes to creating the biological context in which reproductive success becomes possible.

This review develops an integrative conceptual framework describing how the intestinal microbiome influences reproductive performance in poultry through coordinated regulation of biological homeostasis, mitochondrial function, immunometabolism, adaptive resilience, and energy allocation. By integrating evidence from microbiology, physiology, immunology, metabolism, reproductive biology, and evolutionary science, we propose that successful reproduction should be understood not as the isolated function of the reproductive system, but as the emergent consequence of a healthy, resilient, and biologically integrated organism.

The host–microbiome system: a functional ecological framework

The physiological complexity of multicellular organisms cannot be fully understood by considering the host genome alone. Animals develop in continuous association with diverse microbial communities that can expand metabolic capacity, influence immune development, regulate nutrient utilization, and shape physiological adaptation. These interactions range from transient ecological associations to long-standing host–microbe partnerships and should not be assumed to represent universal co-evolution or a single level of evolutionary selection (McFall-Ngai et al., 2013; Tellez, 2014a).

The holobiont and hologenome concepts formalized this systems-level perspective by emphasizing that host phenotype can be influenced by both host and microbial functions (Bosch and Miller, 2016). Their evolutionary interpretation remains actively debated; accordingly, in this review the holobiont is used as a functional and ecological framework rather than as evidence that host and microbiota necessarily constitute a single evolutionary individual. Nutrients, microorganisms, metabolites, and other ecological signals can influence gene expression, metabolism, immune function, and reproductive physiology through interacting regulatory networks (Bordenstein and Theis, 2015).

This concept extends far beyond poultry. Fish, amphibians, reptiles, birds, mammals, insects, and even social organisms such as termites and honeybees all depend upon intimate interactions with microbial communities that regulate digestion, immunity, metabolism, development, and adaptation to environmental change. While the specific microbial composition differs considerably among species, the biological principles governing these interactions are remarkably conserved.

Comparative biology should therefore focus not on identifying identical microbial communities across species, but on understanding the conserved physiological functions performed by those microbial ecosystems. Evolution has generated countless microbial compositions capable of performing similar metabolic tasks. Functional redundancy may therefore represent a more fundamental property of microbial ecosystems than taxonomic stability itself. Recent metagenomic studies further support this concept by demonstrating that microbial ecosystems can maintain highly conserved metabolic outputs despite considerable taxonomic variation, reinforcing the idea that functional capacity is often a more robust predictor of host physiology than microbial composition itself (Jiang et al., 2026).

This distinction is particularly important when interpreting poultry microbiome studies. Investigations frequently emphasize changes in bacterial abundance or diversity; however, microbial composition alone provides only a partial description of ecosystem function. Distinct microbial communities may produce remarkably similar metabolic outputs, whereas apparently similar taxonomic profiles may differ substantially in functional capacity. Understanding the microbiome therefore requires shifting attention from who is present toward what biological functions are being performed (Stanley et al., 2014; Pan and Yu, 2014).

This functional perspective also helps explain why the intestinal microbiome exerts such profound systemic effects. Microbial communities act not only through bacterial colonization; they continuously generate a broad diversity of biologically active molecules, including short-chain fatty acids, bile acid metabolites, amino acid derivatives, polyamines, vitamins, extracellular vesicles, microbial-associated molecular patterns, and numerous signaling compounds that influence distant organs. In this sense, the microbiome functions less as a static microbial population than as a highly dynamic biochemical and informational interface between the external environment and host physiology (Nicholson et al., 2012; Krautkramer et al., 2021).

From an evolutionary standpoint, the emergence of eukaryotic life itself illustrates the extraordinary power of biological cooperation. The endosymbiotic theory proposed by Lynn Margulis fundamentally transformed our understanding of cellular evolution by demonstrating that mitochondria originated from free-living bacteria that established stable intracellular symbiosis with ancestral host cells. This evolutionary event expanded cellular bioenergetic capacity, enabling the emergence of multicellularity, tissue specialization, complex immune systems, advanced nervous systems, and ultimately the remarkable biological diversity observed today (Margulis, 1970).

The evolutionary history of mitochondria provides one relevant context for considering how microbial-derived signals intersect with host cellular physiology. Mitochondria retain numerous structural, biochemical, and genetic characteristics reflecting their bacterial ancestry, positioning them as a unique evolutionary bridge between microbial metabolism and host cellular physiology. The dialogue occurring between intestinal microorganisms and host mitochondria should not be viewed as communication between unrelated biological systems, but rather as interactions among evolutionarily connected partners sharing a common biological origin (Margulis, 1970).

This perspective complements traditional host-centered physiology by emphasizing reciprocal exchanges of nutrients, metabolites, immune mediators, endocrine signals, and metabolic information between the host and its associated microbial communities. These interactions can contribute to physiological homeostasis without requiring the host and microbiota to be treated as a single evolutionary individual.

Perhaps the most important implication of this framework is that evolution has never optimized individual organs independently. Instead, life has evolved highly conserved regulatory networks that enable organisms to maintain functional integration while continuously adapting to changing environmental conditions. Every living organism—from bacteria to plants and animals—faces the same fundamental biological challenge: allocating limited resources among survival, maintenance, growth and reproduction in an ever-changing environment. Although the molecular mechanisms differ among species, the underlying biological objective remains conserved. In multicellular organisms, these conserved regulatory principles are no longer executed by the host alone but emerge from the coordinated activity of the host and its associated microbial ecosystem (Hochachka and Somero, 2002; Noble, 2012).

Within this context, the intestinal microbiome should not be regarded solely as an accessory component of digestive physiology. Its metabolic and immunological activities can contribute to host metabolic flexibility, immune education, ecological stability, and adaptive capacity. The remarkable productive advances achieved through modern genetics, nutrition, health, and management have optimized the physiology of the host organism. However, the microbial ecosystem that complements and extends host biological function has received comparatively little attention despite contributing substantially greater metabolic diversity than the host genome alone (Tellez et al., 2006; Ducatelle et al., 2023).

Recognizing the functional integration of host physiology and microbial ecology broadens how reproductive biology can be interpreted. A key question is how host–microbiome interactions contribute to the physiological conditions associated with successful reproduction.

Answering this question requires understanding the molecular language through which microbial ecosystems communicate with distant host tissues. Those signaling mechanisms constitute the foundation upon which systemic homeostasis, mitochondrial function, immunometabolic regulation, and ultimately reproductive success are built.

Microbial signals connecting the gut with distant tissues

The recognition of the host and its intestinal microbiome as an integrated biological system immediately raises a fundamental physiological question: how do microorganisms confined to the intestinal lumen influence organs that may be anatomically distant from the gastrointestinal tract? Accumulating evidence indicates that this communication depends not on the physical migration of microorganisms themselves, but on the continuous exchange of biologically active molecules capable of influencing cellular metabolism, immune responses, endocrine regulation, and tissue function throughout the organism (Nicholson et al., 2012; Krautkramer et al., 2021).

Far from being an isolated digestive ecosystem, the intestinal microbiome represents a major biochemical factory. Through the fermentation of dietary substrates, transformation of host-derived compounds, and synthesis of numerous metabolites, intestinal microorganisms continuously generate an extensive repertoire of signaling molecules that enter the circulation or influence local neural, endocrine, and immune pathways. Together, these molecules constitute a complex biological language through which the microbial ecosystem communicates with the host.

The biological significance of these signals lies not in their individual activities but in their coordinated integration. Much like hormones, cytokines, or neurotransmitters, microbial metabolites rarely function independently. They operate within highly interconnected regulatory networks whose collective effects influence systemic physiology. Understanding microbiome biology therefore requires shifting from a reductionist view centered on individual bacterial species toward a systems perspective focused on functional communication.

Among the best-characterized microbial metabolites are the short-chain fatty acids (SCFAs), principally acetate, propionate, and butyrate, generated during bacterial fermentation of dietary fiber and other fermentable substrates. Beyond serving as energy substrates for intestinal epithelial cells, SCFAs regulate epithelial integrity, strengthen tight junctions, modulate mucosal immunity, influence endocrine secretion, and participate in systemic metabolic regulation. SCFAs also affect mitochondrial oxidative metabolism through multiple signaling pathways, influencing ATP production, redox balance, and cellular adaptation to changing energetic demands. SCFAs should therefore be viewed not merely as fermentation products but as central mediators linking microbial metabolism with host bioenergetics (Koh et al., 2016; Louis and Flint, 2017).

Microbial metabolites derived from tryptophan metabolism provide another important example. Intestinal microorganisms transform dietary tryptophan into a diverse array of bioactive metabolites, particularly indole derivatives, that function as signaling molecules rather than simply metabolic end products. Many of these compounds activate aryl hydrocarbon receptor (AhR)-dependent pathways, providing a direct molecular mechanism through which dietary substrates and microbial metabolism are translated into host cellular responses. Activation of AhR influences mucosal immune homeostasis, epithelial renewal, barrier integrity, antimicrobial defense, and inflammatory regulation, illustrating how environmental information originating in the diet can be sensed and converted into coordinated physiological programs (Hooper, 2011). Importantly, tryptophan metabolism is not controlled by the microbiome alone. Within host tissues, tryptophan is also metabolized predominantly through the kynurenine pathway, whose activity is closely linked to immune activation, inflammatory signaling, oxidative stress, redox balance, and mitochondrial metabolism. During inflammatory conditions, altered partitioning of tryptophan between microbial and host metabolic pathways may therefore change both the availability of AhR-active microbial metabolites and the production of host-derived kynurenine metabolites, with important consequences for immune tolerance and cellular bioenergetics. Tryptophan thus represents an illustrative example of how diet, microbial ecology, membrane and intracellular receptor signaling, immune function, and mitochondrial metabolism become functionally interconnected. Rather than acting as an isolated nutrient, tryptophan becomes part of an information network through which the host–microbiome ecosystem continuously interprets environmental and metabolic conditions and adjusts cellular physiology accordingly (Agus et al., 2018).

Furthermore, another important branch of tryptophan metabolism involves serotonin (5-hydroxytryptamine, 5-HT), an evolutionarily ancient signaling molecule with remarkably diverse physiological functions in all living forms of our planet. In vertebrates, most peripheral serotonin is produced within the gastrointestinal tract, predominantly by enterochromaffin cells, where its synthesis and release are strongly influenced by the intestinal microbial environment. Experimental studies have demonstrated that gut microorganisms and their metabolites can stimulate enterochromaffin-cell serotonin biosynthesis, including through microbial metabolites and SCFA-dependent regulation of TPH1, the rate-limiting enzyme in mucosal 5-HT synthesis (Reigstad et al., 2015; Yano et al., 2015). Gut-derived serotonin extends far beyond its classical association with neurotransmission, contributing to intestinal motility and secretion, epithelial and vascular function, immune regulation, inflammatory signaling, and systemic metabolic homeostasis. Importantly, evidence in chickens supports the existence of this microbiome–tryptophan–serotonin interface. Dietary tryptophan supplementation in broilers increased serotonin concentrations while modifying intestinal microbial populations and attenuating physiological indicators of transportation stress (Bello et al., 2018). More recently, heat stress was shown to induce coordinated temporal changes in enteric serotonin concentrations and the taxonomic and functional composition of the chicken cecal microbiome, further supporting serotonergic signaling as a component of host–microbiome communication in poultry (Lyte et al., 2024; Lyte et al., 2025). Consequently, dietary tryptophan does not follow a single metabolic trajectory. Its partitioning among microbial indole production and AhR signaling, host kynurenine metabolism, and serotonin biosynthesis creates a metabolic intersection through which diet and microbial ecology can be translated into immune, neuroendocrine, metabolic, and potentially reproductive signals.

A complementary dimension of host–microbiome communication is provided by microbial endocrinology, which examines the capacity of microorganisms to produce, recognize, and respond to neuroendocrine signals originating from either the host or the microbial community. Particularly relevant are the stress-associated catecholamines epinephrine and norepinephrine, which can be sensed by enteric bacteria and used as environmental cues to modify growth, motility, colonization, and virulence-associated gene expression. In several Gram-negative enteric pathogens, membrane-associated two-component signaling systems, including QseC-dependent pathways, participate in the detection and integration of host catecholamine signals with bacterial quorum-sensing networks (Bearson and Bearson, 2008). In Escherichia coli and Salmonella, exposure to epinephrine or norepinephrine has been associated with altered expression of genes controlling motility, invasion, and other virulence-related functions, although additional QseC-independent mechanisms also contribute to catecholamine responsiveness (Clarke et al., 2006; Moreira et al., 2010). These observations reveal an important biological consequence of stress: neuroendocrine signals generated by the host can become environmental information for microorganisms inhabiting the intestine. Thus, the intestinal membrane interface is bidirectional. Just as host cells sense microbial metabolites and molecular signals, microorganisms can sense changes in host physiology and adjust their own phenotype accordingly. This interkingdom chemical communication provides a mechanistic link through which physiological stress may alter microbial behavior and potentially increase susceptibility to enteric disease (Lyte et al., 2018).

The importance of the intestinal ecological context in determining susceptibility to enteric infection is further illustrated by an earlier study from our laboratory. Morales-Barrera et al. (2016) evaluated the consequences of administering the broad-spectrum fluoroquinolone enrofloxacin to neonatal poultry for five consecutive days before subsequent challenge with Salmonella Enteritidis or Salmonella Heidelberg. Rather than increasing resistance to infection, enrofloxacin treatment increased subsequent susceptibility to Salmonella. In broiler chicks, treatment with enrofloxacin increased S. Enteritidis cecal colonization and organ invasion compared with untreated controls. In turkey poults, administration of enrofloxacin at 50 mg/kg, five times the recommended dose, markedly depleted lactic acid bacteria, altered the cecal microbial community, increased intestinal permeability, and increased susceptibility to subsequent S. Heidelberg colonization. In striking contrast, poults receiving the lactic acid bacteria-based probiotic FloraMax-B11 under the same five-day administration schedule showed significantly reduced S. Heidelberg colonization and maintained a microbial community characterized by greater representation of Firmicutes and Bacteroidetes and lower Proteobacteria. These findings demonstrate that susceptibility to an enteric pathogen is determined not only by the presence of the pathogen itself, but also by the ecological state of the microbial community encountered at the time of exposure. In the developing intestine, broad microbial depletion may remove organisms contributing to colonization resistance and create ecological opportunities for subsequent pathogen establishment, whereas reinforcement of beneficial microbial populations can increase resistance to invasion. Viewed together with microbial endocrinology, these observations support a broader principle: physiological and environmental perturbations can modify the informational and ecological landscape of the intestine, thereby influencing microbial behavior, barrier integrity, and ultimately host susceptibility to disease (Morales-Barrera et al., 2016; Lucca et al., 2020).

The intestinal microbiome also profoundly modifies the composition and biological activity of bile acids. Originally synthesized in the liver as detergents facilitating lipid digestion, primary bile acids are extensively transformed by intestinal microorganisms into secondary bile acids with important endocrine and metabolic functions. Through activation of receptors such as FXR and TGR5, bile acid metabolites regulate glucose homeostasis, lipid metabolism, mitochondrial function, inflammatory responses, and energy expenditure. Bile acids have therefore emerged as key mediators connecting microbial ecology with systemic metabolic adaptation (Ridlon et al., 2006; Wahlström et al., 2016).

Additional microbial metabolites further expand this communication network. Polyamines, including spermidine and spermine, participate in epithelial renewal, cellular proliferation, autophagy, mitochondrial maintenance, and antioxidant defense (Minois et al., 2011). Microbial synthesis of vitamins, particularly B vitamins and vitamin K, contributes essential cofactors supporting mitochondrial enzymatic activity and intermediary metabolism. Numerous microbial products also influence host production of serotonin, γ-aminobutyric acid (GABA), dopamine precursors, and other neuroactive compounds, illustrating the intimate relationship between intestinal microorganisms and neuroendocrine regulation.

Communication between microorganisms and host tissues is not mediated exclusively through soluble metabolites. Components of bacterial cell walls, including lipopolysaccharides (LPS), peptidoglycans, flagellin, lipoteichoic acids, and other microbial-associated molecular patterns (MAMPs), continuously interact with pattern-recognition receptors expressed by epithelial cells and immune cells. Under physiological conditions, controlled recognition of these microbial signals contributes to immune education and maintenance of mucosal tolerance (Table 1). However, disruption of intestinal barrier integrity permits increased systemic exposure to these molecules, promoting chronic low-grade inflammation, oxidative stress, and profound alterations in immunometabolic homeostasis (Akira et al., 2006; Medzhitov, 2007; Awad et al., 2017).

Table 1.

Functional microbial signals linking the gut microbiome to host homeostasis, mitochondrial function, and reproductive performance.

Microbial signal	Primary source	Primary biological targets	Primary bioenergetic effects	Potential reproductive relevance / evidence status
Short-chain fatty acids	Dietary fiber fermentation	Gut epithelium, liver, immune cells	ATP generation, oxidative phosphorylation, and redox regulation	Candidate systemic mediator; direct ovarian delivery and causal effects remain incompletely established in poultry
Tryptophan metabolites	Microbial amino acid metabolism	AhR, immune system, nervous system	Immunometabolic regulation, mitochondrial adaptation	Plausible endocrine/immunometabolic mediator; direct ovarian mechanisms remain incompletely established in poultry
Secondary bile acids	Microbial bile acid transformation	FXR, TGR5	Lipid oxidation, mitochondrial metabolism	Plausible systemic metabolic mediator; poultry reproductive causality remains to be established
Polyamines	Microbial metabolism	Rapidly proliferating tissues	Mitophagy, cellular stress adaptation, and oxidative protection	Potential cellular-protection mechanism; direct poultry reproductive evidence is limited
Vitamins and cofactors	Microbial synthesis	Multiple tissues	Mitochondrial enzymatic reactions	Supports host metabolism; direct reproductive effects depend on tissue exposure and physiological context
Neuroactive metabolites	Microbial metabolism	Enteric and central nervous systems	Neuroendocrine regulation	Potential reciprocal neuroendocrine signaling; direct poultry reproductive pathways require validation
MAMPs (LPS, peptidoglycan, flagellin)	Bacterial structural components	Innate immune system	Inflammatory signaling, ROS production	Indirect reproductive relevance through inflammatory and metabolic pathways
Extracellular vesicles	Bacterial secretion	Multiple tissues	Intercellular information transfer and systemic signaling	Hypothesized long-distance signaling; poultry reproductive targets remain unverified
Functional Microbial Communities	Entire gut ecosystem	Multiple host systems	Functional redundancy and ecosystem resilience	Ecosystem-level association; reproductive effects are context dependent

Abbreviations: AhR, aryl hydrocarbon receptor; FXR, farnesoid X receptor; TGR5, Takeda G protein-coupled receptor 5; HPG, hypothalamic–pituitary–gonadal axis; MAMPs, microbe-associated molecular patterns; ROS, reactive oxygen species. Entries in the final column indicate potential or context-dependent reproductive relevance unless direct poultry evidence is explicitly established; they should not be interpreted as proof that a microbial metabolite reaches the ovary or directly alters follicular mitochondria.

More recently, bacterial extracellular vesicles have emerged as an additional mechanism of long-distance biological communication. These nanosized membrane structures transport proteins, lipids, enzymes, signaling molecules, and nucleic acids, providing microbial communities with a mechanism for delivering complex molecular cargo to host cells beyond the intestinal lumen. By protecting their contents from extracellular degradation and facilitating interactions with epithelial, immune, and potentially distant tissues, bacterial extracellular vesicles may extend microbial communication beyond soluble metabolites and MAMPs. Although research in poultry remains limited, these vesicles represent a promising mechanism through which intestinal microbial communities may influence systemic physiology without requiring direct bacterial translocation (Gill et al., 2019; Jones et al., 2025).

An especially intriguing dimension of this communication is the capacity of bacterial extracellular vesicles to transport small RNAs and other nucleic acids that may participate in interkingdom signaling. Celluzzi and Masotti (2016) proposed that bacterial RNAs delivered to host cells could interact with regulatory pathways involved in gene expression and epigenetic control, suggesting that the microbial “other genome” may communicate with the regulatory machinery of the host genome. Although the physiological magnitude and in vivo relevance of this mechanism remain to be fully established, the concept expands host–microbiome communication beyond metabolic and immune signaling to include the potential exchange of regulatory information. In this framework, the microbiome functions not only as a source of metabolites and molecular signals, but as a dynamic informational interface capable of influencing how host cells interpret environmental conditions and regulate their functional phenotype (Celluzzi and Masotti, 2016).

The effectiveness of microbial communication ultimately depends upon preservation of intestinal barrier integrity. The intestinal epithelium functions as both a physical barrier separating luminal microorganisms from host tissues and a dynamic regulatory interface that selectively permits nutrient absorption while restricting uncontrolled passage of microbial products. Tight junction proteins, mucus layers, antimicrobial peptides, secretory immunoglobulins, and resident immune cells collectively maintain this functional barrier. When barrier integrity is preserved, microbial communication remains tightly regulated and supports physiological homeostasis. Conversely, increased intestinal permeability profoundly alters the quality and magnitude of microbial signals reaching systemic circulation, fundamentally changing the host's immunometabolic state (Yegani and Korver, 2008; Awad et al., 2017).

A stronger reproductive focus also requires distinguishing the intestinal microbiome from microbial communities residing within the reproductive tract. In chickens, microbial communities have been detected along the oviduct, including regions directly involved in fertilization and egg formation, and overlap between intestinal and reproductive-tract microbiota has been reported (Lee et al., 2019; Shterzer et al., 2020). These local communities are anatomically positioned to interact more directly with reproductive tissues than the intestinal microbiome. Evidence from mammals further illustrates the principle: short-chain fatty acids detected in cervico-vaginal mucus can activate sperm signaling and modify sperm migration through OR51E2-dependent mechanisms (Teveroni et al., 2022). This mammalian mechanism should not be assumed to operate identically in birds, but it demonstrates why local reproductive-tract microbiomes must be distinguished from the systemic effects attributed to the intestinal microbiome.

Evidence for the male avian reproductive-tract and semen microbiome remains much more limited, representing an important research gap. Nevertheless, the reproductive relevance of microbial ecology in birds may extend beyond the gut and genital tract. The uropygial or preen gland contains microbial communities that can contribute to odor-associated chemical profiles; in songbirds, preen-gland microbiota covary with major histocompatibility complex genotype, and preen-oil chemistry has been implicated in mate recognition and reproductive communication (Grieves et al., 2021). These observations derive largely from wild birds and should not be extrapolated directly to poultry fertility, but they broaden the reproductive microbiome concept and identify additional avian-specific mechanisms deserving investigation.

This distinction reinforces a functional interpretation of microbiome data. Traditional investigations have largely focused on describing taxonomic composition, emphasizing which bacterial species increase or decrease under different conditions. Although taxonomic information provides valuable ecological insights, it may not explain physiological outcomes. Similar microbial communities may exhibit strikingly different metabolic activities, whereas taxonomically distinct ecosystems often generate comparable functional outputs through metabolic redundancy. Biological function should therefore increasingly become the primary focus of microbiome investigation (Stanley et al., 2014; Pan and Yu, 2014).

In the model developed here, microbial metabolites represent more than isolated biochemical products. Together, they constitute an integrated information network through which the intestinal microbiome continuously informs the host about nutrient availability, microbial ecology, environmental conditions, and physiological status. The host does not respond to individual metabolites in isolation; rather, it integrates thousands of simultaneous microbial signals into coordinated systemic adaptations.

The next question is which cellular system integrates this extraordinary diversity of microbial information into coherent physiological responses?

Increasing evidence suggests that mitochondria occupy precisely this position. As descendants of ancient bacterial endosymbionts, mitochondria are uniquely positioned to integrate microbial-derived metabolic signals with host energy metabolism, redox regulation, innate immunity, endocrine signaling, and cellular adaptation. Understanding how mitochondria perform this integrative function represents the central theme of the next section (Margulis, 1970; Nicholson et al., 2012).

Mitochondria as the integrative bioenergetic hub of the holobiont

The molecular dialogue between the intestinal microbiome and the host converges upon a fundamental biological question: how are thousands of simultaneous microbial, nutritional, endocrine, immune, and environmental signals integrated into coordinated physiological responses? Although numerous tissues participate in this process, increasing evidence indicates that mitochondria occupy a unique position as the principal bioenergetic and signaling platform through which the organism continuously evaluates its physiological state and adjusts cellular function accordingly.

The work of Lynn Margulis established the bacterial endosymbiotic origin of mitochondria and transformed understanding of the evolution of complex cellular bioenergetics (Margulis, 1970). In the framework developed here, mitochondria are considered major bioenergetic and signaling integrators rather than autonomous decision-makers. Their functions in metabolism, redox signaling, calcium homeostasis, innate immunity, apoptosis, endocrine responses, and cellular adaptation place them at an important intersection between microbial-derived signals and reproductive physiology.

For decades, mitochondria were regarded primarily as intracellular organelles responsible for ATP production through oxidative phosphorylation. While bioenergetics remains their most recognized function, this classical view has expanded. Mitochondria are now understood as highly dynamic organelles coordinating intermediary metabolism, reactive oxygen species (ROS) signaling, calcium homeostasis, innate immunity, apoptosis, cellular differentiation, and metabolic adaptation. Mitochondria are not passive energy generators; they function as sophisticated biological integrators capable of translating multiple environmental and intracellular signals into coordinated physiological responses (Sies et al., 2017).

From an evolutionary perspective, this integrative role is perhaps unsurprising. Mitochondria originated from ancient α-proteobacteria that established a stable endosymbiotic relationship with ancestral eukaryotic cells approximately two billion years ago. This endosymbiotic event expanded cellular bioenergetic capacity and enabled multicellularity, tissue specialization, complex immune systems, advanced nervous systems, and reproductive strategies requiring enormous energetic investment. Each mitochondrion therefore retains both structural and functional characteristics reflecting its bacterial ancestry, positioning these organelles at the interface between microbial metabolism and host physiology.

Environmental perception is not exclusive of multicellular organisms or specialized nervous systems. Prokaryotic members of the intestinal microbiome continuously sense nutrients, oxygen tension, pH, osmolarity, microbial signals, host-derived molecules, and potential threats through membrane-associated receptors, transporters, chemotaxis systems, ion gradients, and signal-transduction networks. Experimental evidence for the capacity of extracellular signals to reshape cellular phenotype was provided by Lipton et al. (1991) using human dermal microvessel endothelial cells. The authors demonstrated that differentiated endothelial cells could transition among epithelial-like, transitional, and mesenchymal phenotypes in response to changes in their extracellular signaling environment, including modulation by cyclic AMP, without requiring cell division. Importantly, cells maintained sufficient phenotypic plasticity to reverse aspects of this transition when signaling conditions were restored. These observations provided early experimental evidence that cellular phenotype is not determined solely by genomic identity, but is dynamically influenced by information received from the extracellular environment and translated through intracellular signaling pathways involving second messengers, calcium-dependent signaling, protein kinases, and cytoskeletal reorganization (Lipton et al., 1991; Lipton et al., 1992). Mitochondria add a third, evolutionarily connected membrane system. Derived from an ancestral bacterial endosymbiont, mitochondria retain a double-membrane architecture in which the outer membrane participates in signaling, organelle dynamics, innate immune communication, and apoptosis, whereas the inner membrane maintains the electrochemical gradient required for oxidative phosphorylation, ATP synthesis, metabolite transport, and redox regulation. Thus, microbial membranes, the host plasma membrane, and mitochondrial membranes constitute interconnected biological interfaces through which environmental information is detected, transmitted, and translated into metabolic, immune, endocrine, and energetic responses (Tellez, 2014a).

The functional continuity among these membrane systems also creates a shared vulnerability. Because cellular and mitochondrial membranes are enriched in oxidation-sensitive lipids and membrane proteins, persistent inflammation and excessive production of reactive oxygen and nitrogen species can initiate lipid peroxidation, alter membrane fluidity and permeability, disrupt receptors and transport systems, dissipate mitochondrial membrane potential, impair electron transport, and amplify danger signaling. Oxidative injury therefore does not damage a single organelle in isolation. It progressively compromises microbial ecology, epithelial sensing and barrier function, intracellular signaling, mitochondrial bioenergetics, and ultimately the capacity of the organism to maintain homeostasis and allocate energy toward reproduction (Niki et al., 2005; Sies et al., 2017; Petrone-Garcia et al., 2021).

In other words, the microbial membrane perceives the local ecosystem. The plasma membrane interprets the extracellular environment. The mitochondrial membranes interpret its energetic and redox consequences. Together, these evolutionarily connected interfaces contribute to how biological systems sense conditions, adapt, and participate in resource allocation within broader endocrine, immune, neural, and metabolic networks.

In this model, mitochondria are viewed not simply as cellular powerhouses but as major bioenergetic integrators. They respond to information originating from microbial metabolites, nutrient availability, endocrine mediators, inflammatory cytokines, oxygen tension, and environmental stressors. Through these interactions, mitochondrial metabolism contributes to cellular energetic efficiency and to the physiological processes through which resources are allocated among competing functions.

ATP production represents only one dimension of mitochondrial biology. Cellular energy must be continuously balanced with biosynthetic demands, antioxidant defense, immune activation, tissue repair, and reproductive investment. Mitochondria coordinate these competing processes through tightly regulated metabolic networks involving the tricarboxylic acid cycle, oxidative phosphorylation, fatty acid oxidation, amino acid metabolism, and numerous anabolic pathways. In this sense, ATP should not be viewed simply as the universal energy currency of the cell but as the energetic expression of the organism's overall physiological condition.

Mitochondrial ROS are not exclusively damaging metabolic by-products. Under physiological conditions, controlled ROS production functions as an essential signaling mechanism regulating gene expression, cellular differentiation, immune activation, antioxidant responses, and metabolic adaptation. Only when ROS generation exceeds antioxidant capacity does oxidative stress develop, leading to lipid peroxidation, protein oxidation, DNA damage, and impairment of mitochondrial function. The biological consequences of ROS therefore depend fundamentally upon context, magnitude, and duration instead of their mere presence (Zhang et al., 2016; Sies et al., 2024).

The intimate relationship between mitochondrial function and immunity is increasingly evident in immunometabolism. Activation of innate and adaptive immune responses requires profound metabolic reprogramming, with mitochondria serving as central regulators of inflammatory signaling, cytokine production, inflammasome activation, and antimicrobial defense. During periods of infection or tissue injury, substantial energetic resources are redirected toward immune function. Mitochondrial metabolism consequently reflects the balance between physiological maintenance and defensive responses (O’Neill et al., 2016; Muri and Kopf, 2021).

Mitochondria likewise coordinate intracellular calcium signaling, apoptosis, autophagy, and cellular quality control. Mitochondrial biogenesis, fusion, fission, mitophagy, and the mitochondrial unfolded protein response (UPRmt) collectively maintain a healthy mitochondrial network capable of adapting to changing metabolic demands. These quality-control mechanisms are particularly important in tissues characterized by high energetic requirements, including the ovary, oviduct, skeletal muscle, liver, immune organs, and developing embryo. Preservation of mitochondrial integrity therefore represents a prerequisite for sustained physiological performance (Youle and Narendra, 2011; Ni et al., 2015; Melber and Haynes, 2018; Zhan et al., 2024; Couty et al., 2026).

Within reproductive tissues, mitochondrial function is especially critical. Oocyte maturation, follicular growth, steroid hormone synthesis, ovulation, albumen secretion, shell formation, embryogenesis, and early post-hatch development all require exceptionally high rates of ATP production accompanied by precise regulation of redox homeostasis. The reproductive system therefore represents one of the most energy-demanding physiological functions of the organism. Small disturbances in mitochondrial efficiency may consequently produce disproportionately large effects on reproductive performance (Nys and Guyot, 2011; Sah and Mishra, 2018; Kirillova et al., 2021).

Mitochondria also have a direct mechanistic role in reproductive endocrinology because steroidogenesis begins with delivery of cholesterol to the inner mitochondrial membrane and its conversion to pregnenolone, the precursor of downstream steroid hormones. This provides a direct link between mitochondrial integrity and gonadal endocrine function. Experimental evidence in mammalian Leydig cells shows that lipopolysaccharide-associated inflammation and reactive oxygen species can disrupt mitochondrial membrane potential, reduce steroidogenic proteins, and suppress testosterone production (Allen et al., 2004). Comparable mechanistic evidence remains limited in poultry; therefore, this pathway is presented as comparative support rather than proof that intestinal endotoxin directly regulates avian gonadal steroidogenesis.

The membrane component of the framework is also relevant to male reproductive physiology through the blood–testis barrier (BTB), a specialized Sertoli-cell interface that maintains the microenvironment required for spermatogenesis. An effective BTB has been demonstrated in the domestic fowl (Osman et al., 1980; Bergmann and Schindelmeiser, 1987). More recent chicken studies show that inflammatory and oxidative insults can reduce junctional proteins and disrupt BTB integrity, with associated testicular injury and impaired steroidogenic or reproductive function (Hou et al., 2022; Li et al., 2024). These findings do not establish that intestinal permeability directly disrupts the avian BTB, but they support the mechanistic plausibility that systemic inflammation and oxidative stress generated during barrier dysfunction could influence testicular homeostasis.

The microbiome continuously influences many of these mitochondrial processes. SCFAs, bile acid metabolites, polyamines, microbial vitamins, amino acid derivatives, and other microbial products modulate mitochondrial respiration, substrate utilization, redox balance, and inflammatory signaling. Conversely, dysbiosis, increased intestinal permeability, endotoxemia, and chronic inflammation alter mitochondrial metabolism through persistent activation of innate immune pathways and sustained oxidative stress. Microbial ecology and mitochondrial physiology therefore should not be viewed as independent systems but as continuously interacting components of a highly integrated biological network (Krautkramer et al., 2021; Levy et al., 2017).

This integrative perspective offers a coherent explanation for a phenomenon frequently observed in animal production. Heat stress, enteric disease, nutritional imbalance, mycotoxin exposure, social stress, aging, pathogen challenge, and environmental disturbances differ substantially in their initiating causes. Nevertheless, all eventually converge upon remarkably similar mitochondrial responses characterized by altered ATP production, increased oxidative stress, inflammatory activation, metabolic reprogramming, and reduced energetic efficiency. The remarkable diversity of external stressors therefore produces a surprisingly limited repertoire of intracellular responses, with mitochondrial pathways representing one important point of convergence (Senas-Cuesta et al., 2023; Petrone-Garcia et al., 2021; Tellez et al., 2014b).

We therefore propose that mitochondria represent an important cellular interface through which microbial, nutritional, immune, endocrine, and environmental signals converge on bioenergetic and redox physiology. Rather than independently governing organism-level priorities, mitochondrial responses participate in broader endocrine, neural, immune, and metabolic networks that coordinate adaptation. Under favorable conditions, these networks can support growth, maintenance, and reproduction; under adverse conditions, they may favor defense and restoration of homeostasis.

This concept leads naturally to a broader question: how do interacting endocrine, immune, neural, metabolic, and cellular networks redistribute resources as physiological conditions change? Addressing this question requires distinguishing mitochondrial signal integration from organism-level regulation of resource allocation.

One conceptual distinction deserves particular emphasis. Mitochondria integrate the intracellular energetic, metabolic, inflammatory, and redox consequences of many extracellular signals, but this integration should not be interpreted as autonomous physiological decision-making.

Unlike the plasma membrane, which continuously senses changes in the extracellular environment through nutrient transporters, receptors, microbial metabolites, hormones, cytokines, and danger-associated molecules, mitochondria continuously monitor the intracellular consequences of those signals. Mitochondria do not detect the external stimulus itself; they evaluate its energetic, metabolic, inflammatory, and redox impact on cellular physiology.

In this sense, the plasma membrane and mitochondria represent complementary biological interfaces. The plasma membrane senses and transduces extracellular signals, whereas mitochondrial metabolism responds to the intracellular energetic and redox consequences generated by those signals. Together with endocrine, immune, and neural networks, these interfaces contribute to adaptive cellular reprogramming.

This distinction provides an important conceptual framework for understanding systemic physiological regulation. Thousands of microbial metabolites, endocrine mediators, nutrients, inflammatory cytokines, reactive oxygen species, calcium signals, oxygen availability, and metabolic intermediates converge upon mitochondrial metabolism. Mitochondria integrate these signals rather than responding to each one independently, combining their collective energetic consequences into a coordinated cellular response.

This response extends far beyond ATP production. Mitochondria participate in redox signaling, calcium homeostasis, innate immunity, apoptosis, mitochondrial quality control, and cellular metabolism. In this context, the Cell Danger Response can be interpreted as one manifestation of broader stress-associated metabolic reprogramming. When intracellular conditions become unfavorable for continued investment in growth or reproduction, mitochondrial and cytosolic signaling pathways can shift metabolism toward defense, repair, antioxidant protection, and restoration of homeostasis. This adaptive transition need not indicate failure of the reproductive system; rather, it reflects coordinated cellular responses to biological stress (Naviaux, 2014).

At the organismal level, mitochondrial responses interact with endocrine communication, immune signaling, neural regulation, and tissue-specific metabolism. Reproduction should therefore not be interpreted as a process regulated independently by reproductive organs, nor as the downstream output of mitochondrial control, but as an emergent physiological outcome of coordinated reproductive and systemic regulation.

The intestinal microbiome is one contributor within this reciprocal regulatory network. By modulating nutrient availability, microbial metabolite production, epithelial integrity, immune activation, and systemic inflammation, the microbiome can influence the intracellular environment to which mitochondria respond. Conversely, host endocrine and metabolic states can reshape intestinal physiology and microbial ecology. The intestinal microbiome therefore contributes to, but does not unilaterally control, the conditions associated with reproductive function.

Reproductive investment depends on the interaction of energetic reserves, endocrine state, immune activity, environmental conditions, life-history context, and reproductive stage. Once reproduction is underway, reproductive physiology can itself reorganize metabolism, nutrient partitioning, behavior, and potentially microbial ecology.

Immunometabolic homeostasis and energy allocation: why reproduction is a biological investment

If mitochondria are considered major bioenergetic integrators within the host–microbiome system, a fundamental physiological question follows: how are available energetic resources distributed among competing biological functions? Every multicellular organism continuously faces this challenge. Because energy availability is finite, physiological systems cannot simultaneously maximize growth, immune defense, tissue repair, stress adaptation, and reproduction. Biological performance therefore depends not only on the amount of energy available but also on how that energy is allocated under constantly changing environmental conditions.

Traditionally, immunity and reproduction have been investigated as largely independent physiological systems. However, growing evidence indicates that these processes are intimately connected through shared metabolic pathways. Activation of one biological function inevitably influences the energetic resources available for others. Immunometabolism has consequently emerged as the discipline that explains how metabolic pathways coordinate immune function and, conversely, how immune activation reshapes systemic metabolism (O’Neill et al., 2016; Hotamisligil, 2017).

The intestinal microbiome occupies a central position within this regulatory network (Dietert, 2016). Under physiological conditions, microbial communities contribute to maintenance of epithelial integrity, production of bioactive metabolites, regulation of immune tolerance, and optimization of nutrient utilization. Together, these processes minimize the energetic cost required to maintain homeostasis. In contrast, dysbiosis increases epithelial permeability, facilitates systemic exposure to microbial products, amplifies inflammatory signaling, and substantially elevates the energetic demands associated with immune activation and tissue repair (Ducatelle et al., 2023; Levy et al., 2017).

This transition from homeostasis to inflammation represents one of the most important energetic shifts in biology. Immune activation is not metabolically neutral. Proliferation of immune cells, synthesis of cytokines, production of antimicrobial molecules, acute-phase protein synthesis, oxidative burst, tissue repair, and activation of antioxidant defenses all require substantial amounts of ATP and metabolic substrates. Chronic inflammation consequently functions as a persistent energetic drain that continuously competes with other physiological priorities (Demas, 2004).

Recent advances in immunometabolism have demonstrated that activated immune cells undergo profound metabolic reprogramming. Rapid inflammatory responses frequently rely upon increased glycolysis despite the presence of oxygen, whereas resolution of inflammation and tissue repair require restoration of mitochondrial oxidative metabolism. These coordinated metabolic transitions illustrate that immunity cannot be understood independently of cellular bioenergetics. Immune function and mitochondrial metabolism instead constitute two inseparable components of the same adaptive physiological system (Vander Heiden et al., 2009; O’Neill et al., 2016).

Endocrine regulation further integrates resource allocation throughout the organism. The hypothalamic–pituitary–gonadal (HPG) axis promotes and sustains reproductive physiology, whereas stress-responsive endocrine pathways, including corticosterone signaling, modify nutrient partitioning, immune activity, behavior, and cellular metabolism. Importantly, these relationships are reciprocal rather than unidirectional: reproductive endocrine state can itself reshape metabolism and immunity, and stress hormones can modify intestinal physiology and microbial ecology.

These endocrine systems do not operate independently of the intestinal microbiome. Microbial metabolites can influence enteroendocrine signaling, bile acid receptors, glucose homeostasis, appetite regulation, and inflammatory pathways, whereas host endocrine signals can modify the intestinal environment experienced by microbial communities. In chickens, experimental corticosterone administration altered intestinal bacterial community structure and increased the abundance of Clostridium perfringens, providing direct poultry evidence that endocrine stress signals can reshape the gut ecosystem (Zaytsoff et al., 2020). Thus, the microbiome–endocrine relationship is better represented as a feedback network than as a pathway terminating at the HPG axis.

Within this integrated network, mitochondrial metabolism responds to changes in immune activation, oxidative stress, nutrient availability, oxygen supply, hormonal signals, and microbial metabolites. These responses modify ATP production, substrate utilization, redox balance, and metabolic efficiency, thereby contributing to the broader physiological adjustments that accompany changing environmental and reproductive conditions.

This perspective refines how reproductive biology should be interpreted. Reproduction is energetically demanding, but its relationship with survival and maintenance is not governed by a fixed hierarchy. Energetic status, body reserves, endocrine signals, immune activity, environmental conditions, reproductive stage, and life-history context jointly influence whether reproductive investment can be initiated and sustained. Once reproduction has commenced, reproductive hormones can themselves reorganize metabolism, nutrient partitioning, behavior, and energy use to support reproductive demands.

Avian reproductive stages illustrate this reciprocal reorganization. During pre-lay and egg production, females undergo marked changes in nutrient partitioning to support yolk deposition, albumen synthesis, and shell formation (Nys and Guyot, 2011; Sah and Mishra, 2018). In other avian life-history contexts, incubation can involve reduced feeding and greater reliance on endogenous reserves, as demonstrated in fasting or largely fasting incubating waterfowl (Criscuolo et al., 2002). Such changes in diet, endocrine state, metabolism, and behavior can also alter the intestinal environment and may reshape microbial ecology, reinforcing the bidirectional nature of the proposed framework.

Reproductive suppression during chronic disease, heat stress, nutritional deficiency, environmental challenge, or persistent inflammation can reflect adaptive resource reallocation, although the magnitude and direction of this response depend on context. Conversely, reproductive investment may be maintained under some adverse conditions, particularly when future reproductive opportunities are limited. Reduced reproductive performance should thus be interpreted within a dynamic life-history framework rather than as either inevitable reproductive failure or a universal prioritization of survival (Demas, 2004). Consistent with this context-dependent interpretation, a recent meta-analysis across birds found no general within-species trade-off between reproduction and survival under natural variation, although experimentally elevated reproductive effort could reveal survival costs (Winder et al., 2025).

This dynamic framework helps interpret numerous observations in poultry production. Heat stress can reduce egg production, enteric disease can impair fertility, mycotoxins can decrease hatchability, chronic inflammation can compromise reproductive persistence, and nutritional imbalance can diminish embryonic viability. These challenges can increase the energetic and metabolic costs of defense, repair, and homeostasis, thereby constraining reproductive investment; however, the magnitude and direction of the response depend on reproductive stage, physiological reserves, endocrine state, and environmental context (Ruff et al., 2020; Tellez-Isaias et al., 2023; Nuningtyas et al., 2026).

In this framework, reproductive performance is interpreted as an emergent and condition-dependent physiological outcome. Successful reproduction reflects interactions among reproductive organs, intestinal integrity, microbial ecology, mitochondrial function, endocrine regulation, immune activity, nutritional state, and energetic reserves, without assigning reproduction a hierarchical position above other essential biological functions.

This perspective also explains why improvements in genetics, nutrition, health management, and environmental control have collectively transformed modern poultry production over recent decades. Each of these advances has reduced the energetic burden associated with maintaining homeostasis, thereby increasing the proportion of biological resources available for growth and reproduction. The intestinal microbiome represents the next major frontier within this field. Optimization of the host–microbiome ecosystem may complement traditional management strategies and further reduce the energetic cost of maintaining physiological stability, allowing greater biological investment in productive and reproductive performance (Ricke et al., 2022; Ducatelle et al., 2023).

Ultimately, reproduction should be viewed not as the direct outcome of isolated endocrine or gonadal mechanisms, but as the integrated expression of a resilient biological system capable of maintaining energetic balance despite continuous environmental challenges.

An immediate consequence of this framework is that virtually every environmental stressor capable of disrupting microbiome composition, intestinal integrity, immune homeostasis, or mitochondrial function should converge upon remarkably similar physiological outcomes. Understanding this convergence requires examining how diverse stressors activate common adaptive pathways that temporarily prioritize survival over long-term biological investment. This concept forms the basis of the next section.

From adaptation to maladaptation: stress, cell danger response, and loss of reproductive resilience

The integrated framework developed throughout this review suggests that reproductive performance reflects interactions among reproductive organs and broader systemic physiology, including host–microbiome relationships. A related implication follows: virtually any environmental or biological stressor capable of disrupting systemic homeostasis should ultimately influence reproductive performance through common adaptive mechanisms.

This concept helps explain why diverse stressors in experimental and commercial poultry production repeatedly produce similar physiological outcomes, including impaired reproductive persistence, reduced fertility, decreased egg quality, lower hatchability, compromised embryonic development, and diminished offspring performance.

Traditionally, each of these stressors has been investigated as an independent pathological entity. However, increasing evidence suggests that they are better viewed as different initiating events converging upon a limited number of highly conserved adaptive responses. Regardless of the initial insult, disruption of intestinal microbial ecology frequently represents one of the earliest biological consequences. Altered microbial composition, reduced production of beneficial metabolites, increased intestinal permeability, and greater systemic exposure to microbial-derived inflammatory molecules collectively initiate a cascade of physiological events extending far beyond the gastrointestinal tract (Awad et al., 2017; Tellez-Isaias et al., 2023).

In this sequence, loss of intestinal barrier integrity marks a critical transition by changing the quality of host–microbiome communication. The organism no longer maintains immunological tolerance and metabolic cooperation; it begins responding to persistent danger-associated signals requiring continuous immune activation (Awad et al., 2017; Baxter et al., 2017).

The resulting chronic inflammatory state imposes substantial energetic demands upon the organism. Hence, dysbiosis progressively redistributes biological energy toward maintenance of homeostasis (Tellez-Isaias et al., 2023).

At the cellular level, mitochondria occupy the central position within this adaptive response. Because mitochondrial metabolism continuously integrates inflammatory signals, oxidative stress, nutrient availability, endocrine regulation, and microbial-derived metabolites, these organelles function as highly sensitive indicators of physiological disturbance. Mitochondria do more than respond to damage; they actively coordinate cellular adaptation by modifying ATP production, redox signaling, substrate utilization, and numerous metabolic pathways essential for survival (Bar-Ziv et al., 2020; Sies et al., 2017).

This adaptive mitochondrial response closely resembles the Cell Danger Response (CDR) proposed by Naviaux, in which mitochondria temporarily shift cellular physiology away from growth and long-term biological investment toward protection, defense, and repair. Although originally developed within human medicine, the conceptual framework of the Cell Danger Response provides a valuable biological model for understanding how diverse environmental challenges may produce remarkably similar physiological consequences across species (Naviaux, 2014, 2020).

The Cell Danger Response should not be interpreted as inherently pathological. It describes an adaptive metabolic program in which cellular resources can be redirected toward protection, defense, and repair. In reproductive biology, the consequences of such reprogramming are context dependent: sustained stress may constrain reproductive investment, but reproductive effort is not universally subordinated to survival across all life-history conditions (Naviaux, 2014, 2020).

Problems arise when adaptive responses fail to be resolved. Persistent dysbiosis, chronic inflammation, repeated environmental stress, nutritional inadequacy, or continuous exposure to damaging stimuli may maintain the organism in a prolonged state of metabolic defense. Under these conditions, mitochondrial function progressively deteriorates, oxidative stress accumulates, inflammatory signaling becomes self-sustaining, and biological resilience gradually declines. What initially represented a protective adaptation ultimately becomes chronic maladaptation (Naviaux, 2020; Tellez-Isaias et al., 2023).

This distinction between adaptation and maladaptation provides a coherent explanation for numerous chronic disorders affecting productive animals. The transition is rarely abrupt. Physiological resilience instead progressively decreases as the energetic cost of maintaining homeostasis continues to increase. Eventually, functions requiring sustained biological investment, including growth, productive persistence, reproductive efficiency, embryonic development, and offspring quality, become increasingly compromised.

In the framework developed here, dysbiosis should therefore not be interpreted merely as an alteration in microbial composition. It represents the disruption of an ecological partnership that normally contributes to minimizing the energetic cost of maintaining physiological homeostasis. The biological consequences emerge not because individual bacterial species are lost or gained, but because the efficiency of the host–microbiome ecosystem itself progressively deteriorates.

Reproductive impairment should therefore not be regarded as an isolated consequence of reproductive-organ dysfunction. It can be a sensitive indicator that systemic homeostasis and resilience are being challenged, but the reproductive response to stress remains dependent on reproductive stage, energetic reserves, endocrine state, and life-history context.

This interpretation naturally leads to the next question. Can the resilience of this integrated biological system be strengthened before chronic maladaptation develops? Addressing this question requires understanding how maternal physiology, microbial ecology, mitochondrial integrity, and early-life interventions shape long-term biological resilience across generations.

Building resilience: maternal programming and modulation of the host–microbiome ecosystem

If reproductive performance reflects broader physiological resilience, strengthening that resilience before biological dysfunction develops becomes a logical priority.

For decades, interventions in animal production have largely focused on correcting disease after physiological disturbances have already occurred. Although these approaches remain essential, increasing evidence suggests that additional biological benefits may be achieved by promoting resilience before chronic dysregulation becomes established. This preventive perspective shifts attention away from treating isolated pathological events toward optimizing the biological system responsible for maintaining homeostasis itself.

Hence, maternal physiology assumes central importance. Reproduction represents more than the transmission of nuclear DNA from one generation to the next. The maternal organism also provides mitochondria, nutrients, hormones, antibodies, antioxidants, immune mediators, and an array of metabolic signals that collectively shape embryonic development and influence physiological performance long after hatch. Maternal health should consequently be viewed as the first environmental condition experienced by the developing offspring (Gong et al., 2023).

The maternal intestinal microbiome occupies a central position within this developmental environment. Through continuous production of microbial metabolites, regulation of systemic inflammation, modulation of nutrient availability, and maintenance of metabolic homeostasis, maternal microbial communities may contribute indirectly to the physiological environment associated with ovarian function, egg formation, and embryonic development through effects on metabolites, nutrient availability, and systemic inflammatory tone. Although the precise mechanisms remain incompletely understood in poultry, accumulating evidence indicates that maternal microbial ecology contributes substantially to the biological environment within which reproductive success is established (Shterzer et al., 2020; Ricke et al., 2022).

Direct poultry evidence supports a functional relationship between intestinal microbial ecology and ovarian physiology, although the molecular pathway remains incompletely defined. Cao et al. (2023) transplanted fecal microbiota from high-laying-rate broiler breeders into low-laying-rate recipients and reported increased egg-laying rate, higher circulating 17β-estradiol and anti-Müllerian hormone, reduced proinflammatory cytokines, improved intestinal barrier-related outcomes, and changes in ovarian function. This intervention provides unusually direct avian evidence that manipulation of the intestinal microbial ecosystem can coincide with reproductive and ovarian responses. However, FMT does not by itself identify the specific microbial metabolites, endocrine mediators, or cellular pathways responsible for those effects. Similarly, synbiotic modulation has been associated with improved ovarian function in aged laying hens (Liu et al., 2026). Together, these studies support a functional gut–ovary association while leaving its molecular architecture unresolved.

A critical unresolved question is which microbiota-derived metabolites reach the avian ovary at physiologically relevant concentrations and whether they directly alter follicular mitochondrial function. SCFAs, bile-acid derivatives, tryptophan metabolites, polyamines, and other microbiota-associated molecules are plausible candidate mediators, but direct poultry evidence establishing intestinal origin, circulating exposure, ovarian uptake, cellular targets, and mitochondrial effects remains limited. Resolving this gap will require studies that integrate microbial functional analysis with targeted and untargeted metabolomics, endocrine measurements, ovarian signaling, mitochondrial phenotyping, and reproductive outcomes; isotope-tracing approaches may be particularly informative for establishing metabolite origin and tissue delivery.

Mitochondrial inheritance provides a particularly important dimension of maternal programming because the oocyte supplies essentially the entire mitochondrial population from which embryonic development begins. Unlike the nuclear genome, which combines genetic information from both parents, mitochondrial DNA and the organelles that contain it are inherited predominantly through the maternal lineage. Hence, the mother transmits not only genetic information and the biochemical components of the egg, but also the bioenergetic machinery upon which the earliest stages of development depend. The functional state of this mitochondrial population, including respiratory capacity, redox balance, ATP-generating efficiency, mitochondrial DNA integrity, and quality-control mechanisms, therefore represents a biological legacy established before fertilization and carried into the developing embryo. This distinction is especially relevant to the framework proposed here. If mitochondria function as integrators of nutritional, inflammatory, endocrine, microbial, and environmental information, then the mitochondria deposited into the oocyte may reflect, at least in part, the cumulative physiological environment in which oocyte development occurred. Maternal nutrition, oxidative stress, inflammation, metabolic status, and microbial ecology may therefore influence offspring biology not only through nutrients, hormones, immune mediators, and other egg components, but also through their effects on the mitochondrial system inherited by the embryo. Maternal programming can thus be viewed as a biological bridge between generations: the physiological environment experienced by the mother contributes to shaping the bioenergetic starting conditions from which the next generation begins (Lane, 2005). In other words, maternal physiological disturbances capable of compromising mitochondrial function may therefore influence offspring performance long before the chick encounters its own environmental challenges (Dumollard et al., 2007; Kirillova et al., 2021).

Microbial programming also begins remarkably early in life. Although the existence of a fully established embryonic microbiome remains controversial, hatchlings encounter a dynamic microbial environment immediately before, during, and after hatch. The reproductive tract, eggshell, nesting environment, hatchery conditions, litter, feed, water, and maternal microbial communities collectively contribute to the initial ecological succession that shapes development of the intestinal microbiome during the first days of life. Because this period coincides with rapid maturation of immune, metabolic, and intestinal functions, early microbial colonization may exert disproportionately large long-term physiological effects (Ding et al., 2017; Lee et al., 2019; Nyholm, 2020).

This developmental perspective fundamentally changes how nutritional interventions should be interpreted. Traditionally, dietary components have been evaluated primarily according to their direct effects on the host animal. However, within the host–microbiome ecosystem, numerous dietary ingredients first influence microbial ecology before their physiological consequences become evident. Soluble fiber provides an excellent example. Fermentable fiber functions not primarily as a nutrient for the bird, but as an ecological substrate sustaining microbial communities responsible for producing SCFAs and numerous other metabolites essential for systemic homeostasis. In this sense, dietary fiber nourishes the microbial ecosystem that subsequently supports host physiology (Flint et al., 2012; Koh et al., 2016; Oluseyifunmi and Olukosi, 2026).

The same perspective applies to probiotics, competitive exclusion cultures, prebiotics, synbiotics, postbiotics, phytogenic compounds, enzymes, organic acids, precision nutrition, and antioxidant supplementation. Although these interventions differ substantially in composition and mechanism, their greatest biological value may not reside in altering individual bacterial populations but in improving the functional resilience of the host–microbiome ecosystem. Successful interventions should therefore be evaluated according to their capacity to preserve intestinal barrier integrity, reduce unnecessary inflammatory activation, support mitochondrial function, maintain metabolic flexibility, and ultimately improve biological resilience (Nurmi et al., 1992; Gadde et al., 2017; Shehata et al., 2022; Senas-Cuesta et al., 2023).

This interpretation also has important implications for future microbiome research. Intervention studies have emphasized changes in microbial diversity or relative abundance of selected bacterial taxa. While such information remains valuable, taxonomic shifts alone rarely explain improvements in productive or reproductive performance. A more informative strategy may be to evaluate whether interventions restore functional outputs, including microbial metabolite production, epithelial integrity, mitochondrial bioenergetics, immunometabolic homeostasis, oxidative balance, and physiological resilience. In other words, future nutritional strategies should increasingly be evaluated according to function instead of taxonomy (Pan and Yu, 2014; Kogut, 2019).

The next frontier in poultry nutrition may not simply involve feeding the host more efficiently but rather optimizing the entire host–microbiome ecosystem. Modern poultry genetics, health programs, environmental management, and nutritional precision have dramatically improved productive efficiency over the past decades. Nevertheless, the microbial ecosystem that complements host physiology has only recently begun to receive comparable scientific attention. Integrating microbial ecology into nutritional and reproductive management may therefore represent a major remaining opportunity for improving biological performance (Ricke et al., 2022; Ducatelle et al., 2023).

Ultimately, maternal programming illustrates a broader biological principle extending throughout this review. The objective is not merely to maximize production, reproduction, or growth independently. The objective is instead to maintain a resilient biological system capable of continuously adapting to environmental challenges while preserving physiological integration. Reproductive success emerges naturally from such resilience. It cannot be sustained when resilience has already been lost.

This perspective prepares the final question addressed in this review. If reproduction represents the emergent consequence of biological resilience, how should future poultry science redefine the relationship between microbiome biology, nutrition, physiology, and animal production?

Future perspectives: from optimizing the host to optimizing the holobiont

The progress achieved by modern poultry production represents a major success in agricultural science. Continuous advances in genetics, nutrition, disease prevention, environmental management, incubation technology, and precision production have transformed the biological potential of the modern chicken. Over the past several decades, these innovations have improved growth rate, feed efficiency, reproductive performance, and overall productivity.

Despite these remarkable achievements, nearly all these advances have shared a common characteristic: they have primarily focused on optimizing the physiology of the host.

The emergence of microbiome science suggests that this host-centered paradigm is no longer sufficient to fully explain animal biology.

Every multicellular organism exists in functional partnership with its associated microbial communities. This ecosystem exchanges nutrients, metabolites, immune signals, endocrine mediators, and metabolic information that determines the organism's physiological state. The host therefore does not function independently of its microbiome; physiology instead emerges from the coordinated activity of the entire host–microbiome ecosystem (McFall-Ngai et al., 2013; Bordenstein and Theis, 2015).

Recognizing this relationship fundamentally changes the questions that future poultry science should address. Future research should move beyond asking how individual microorganisms influence isolated physiological traits and increasingly investigate how microbial ecosystems contribute to maintaining whole-organism homeostasis, biological resilience, and efficient energy allocation under commercial production conditions.

This transition requires moving beyond a predominantly taxonomic view of the microbiome. Bacterial abundance and microbial diversity provide valuable ecological information but rarely explain biological performance by themselves. The next generation of microbiome research should emphasize microbial function, metabolic outputs, ecological interactions, host responses, and physiological integration. Functional resilience will likely prove more informative than taxonomic composition alone (Stanley et al., 2014; Pan and Yu, 2014).

Nutritional science should likewise adopt a broader ecological perspective because many nutrients influence microbial ecology before host physiology. Soluble fermentable fiber exemplifies this principle by sustaining microbial communities that produce metabolites essential for intestinal integrity, immunometabolic homeostasis, mitochondrial function, and systemic physiological stability. Optimizing microbial nutrition may therefore become an essential component of optimizing host nutrition (Koh et al., 2016; Oluseyifunmi and Olukosi, 2026).

This conceptual framework also has important implications for evaluating nutritional interventions. Future probiotic, prebiotic, synbiotic, postbiotic, phytogenic, enzymatic, and precision nutrition strategies should increasingly be assessed according to their ability to strengthen functional resilience instead of simply altering microbial composition. Improvements in intestinal barrier function, mitochondrial efficiency, metabolic flexibility, oxidative balance, inflammatory regulation, reproductive persistence, and offspring performance may ultimately represent more meaningful biological endpoints than taxonomic changes alone (Gadde et al., 2017; Kogut, 2019; Shehata et al., 2022).

More broadly, this review supports a transition from reductionist physiology toward systems biology. Increasing evidence suggests that immunity, metabolism, endocrinology, mitochondrial biology, and reproduction are not independent physiological disciplines, but that these systems operate as highly interconnected components of an evolutionarily conserved regulatory network. Understanding this integration may become one of the defining challenges of animal biology during the coming decades (Kitano, 2002; Noble, 2012).

Finally, the conceptual framework proposed here does not replace classical reproductive physiology. It expands it. The intestinal microbiome should not be viewed as a direct regulator of reproduction but as a fundamental ecological partner that continuously shapes the biological conditions under which reproduction becomes physiologically possible. Through coordinated regulation of intestinal integrity, immunometabolism, endocrine signaling, mitochondrial bioenergetics, and adaptive resilience, the host–microbiome ecosystem contributes to determining how biological resources are allocated among survival, maintenance, growth, and reproduction.

Reproduction is no longer interpreted simply as the function of reproductive organs. In the end, future progress will depend less on identifying individual microbial taxa than on understanding how integrated biological systems preserve resilience under continuously changing environmental conditions.

Conclusions

For more than a century, reproductive physiology has been interpreted primarily through the biology of reproductive organs, endocrine regulation, and genetics. These disciplines have generated major advances that continue to fortify modern poultry production. However, accumulating evidence now indicates that reproductive performance cannot be fully understood in isolation from the physiological systems that maintain whole-organism homeostasis.

Throughout this review, we have proposed an integrative framework in which the intestinal microbiome functions as a central ecological component of the holobiont, continuously interacting with the immune system, endocrine networks, mitochondrial bioenergetics, and host metabolism. The microbiome does not directly control reproductive physiology; it contributes to maintaining the biological conditions that make sustained reproductive investment possible.

In this framework, mitochondria emerge as major bioenergetic and signaling integrators within a broader network that includes endocrine, immune, neural, metabolic, and reproductive regulation. Reproductive performance consequently reflects not only the functional integrity of reproductive organs but also the capacity of the organism to preserve systemic homeostasis and biological resilience despite continuous environmental challenges.

This perspective provides a unified explanation for why seemingly unrelated stressors, including dysbiosis, heat stress, pathogen exposure, mycotoxins, nutritional imbalance, oxidative injury, and chronic inflammation frequently converge upon remarkably similar reproductive outcomes. Although their initiating mechanisms differ, they ultimately alter the energetic balance required to sustain long-term biological investment (Senas-Cuesta et al., 2023; Tellez-Isaias et al., 2023; Nuningtyas et al., 2026).

We therefore propose that the intestinal microbiome should be viewed not as an isolated regulator of reproduction, but as a fundamental contributor to the evolutionarily conserved biological networks that maintain homeostasis, coordinate energy allocation, and support adaptive resilience.

Future progress in poultry science may depend not only on optimizing the genetics and physiology of the host, but also on understanding and managing host–microbiome interactions as an integrated physiological and ecological system.

In doing so, poultry science may be entering its next major biological frontier.

Declaration of generative AI and AI-assisted technologies in the manuscript preparation process

During the preparation of this work, the author used ChatGPT (OpenAI) to assist with manuscript organization and to improve language, clarity, and readability. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the published article.

Author contributions

Guillermo Tellez-Isaias: Conceptualization; literature review and investigation; development of the conceptual framework; writing – original draft; writing – review and editing; visualization; and final approval of the manuscript. The author takes full responsibility for the scientific content, interpretation, and final submitted version of the manuscript.

Disclosures

The author declares no financial or personal relationships with other people or organizations that could inappropriately influence or bias the work presented in this manuscript.