Beyond the gut microbe: Rethinking infection, microbiome harmony, and the one-health continuum

Abstract

Emerging microbial discoveries have transformed infectious-disease science, yet detection alone does not equate to pathogenicity. Human health is mediated by complex microbiomes, and dysbiosis can convert commensals into opportunists, a concept captured by the “pathobiome”. Across infectious-disease literature, gaps remain in integrating ecological context, host response, longitudinal data, and one-health perspectives. Misinterpretation of culture or sequencing results drives antimicrobial misuse, resistance, and ecological harm. We propose an eight-principle framework to distinguish pathogen from non-pathogen: (1) Clinical localization; (2) Temporal host response; (3) Exclusion of alternative sources; (4) Ecological context; (5) Host susceptibility; (6) Contamination assessment; (7) Transparent reporting of methods and quantitative thresholds; and (8) Ethical use of diagnostic technology. Adoption of this framework to any specialty, including gut, promotes accurate infection identification, stewardship, and transparency. Expanding perspective from the individual microbiome to planetary health, this approach aligns discovery with ecological and ethical responsibility, transforming infectious-disease practice from reactionary treatment to preservation of microbial harmony.

Key Words: Microbiome; Pathobiome; Diagnostic stewardship; One Health; Pathogen identification

Core Tip: Advances in culture and sequencing have expanded microbial detection, but presence does not equal pathogenicity. Many infections reflect disruption of the human microbiome rather than invasion by a novel pathogen. Misinterpretation of isolates drives antimicrobial misuse, resistance, and ecological harm. This opinion proposes an eight-question, clinically grounded framework to distinguish pathogens from non-pathogens by integrating host site and response, ecological context, contamination assessment, and transparent reporting. Applying this approach aligns infectious-disease practice with diagnostic stewardship, one health principles, and preservation of microbial harmony from individual patients to planetary health.

INTRODUCTION

Various infectious disease (ID) journals have been instrumental in identifying novel microorganisms, resistance mechanisms, and outbreak dynamics. The advent of high-throughput culture-independent diagnostics, metagenomics, and multi-omics technologies has expanded our ability to detect microbial life, including previously uncultivable bacteria, viruses, fungi, and non-bacterial communities[1,2]. Disease emergence is increasingly understood as a function of complex microbial community interactions and environmental influences rather than single pathogens in isolation, reinforcing the pathobiome paradigm[3,4]. Non-bacterial components of the gut microbiome, including fungi and viruses, play crucial roles in shaping mucosal immunity and modulating interactions with enteric pathogens, necessitating a broader, kingdom-inclusive view of host-microbe dynamics[5,6]. Yet detection alone is no longer sufficient to define infection. The pivotal question before us is: When does a detected organism truly represent a pathogen, and when is it part of the natural microbiome or a reflection of broader ecological imbalance? In an era where culture and sequencing can detect almost any microbial fragment, redefining infection through a microbiome-ecological lens is imperative. Microbial detection without contextualization, risks misclassification, unnecessary treatment, and disruption of human and environmental microbial ecosystems[2,7]. An ecological approach to infection emphasizes that outcomes are shaped by dynamic interactions between pathogens and commensal microbiota within a regulated host ecosystem, rather than by isolated microbial effects[8,9].

FROM PATHOGEN TO PATHOBIOME

Humans coexist with trillions of microbes forming an intricate network essential for metabolism, immune regulation, and barrier integrity. Disruptions by antimicrobials, immune perturbation, environmental change, or hospital exposure can shift this equilibrium, allowing commensals or colonizers to behave as opportunists. This ecological transition from symbiosis to pathogenicity defines the pathobiome concept, where disease emerges not from invasion by a foreign organism, but from imbalance within a community[1,3]. For example, Clostridioides difficile infection often follows antibiotic-induced depletion of commensals, highlighting how the same species may be harmless or pathogenic depending on ecological context[10]. Similarly, translocation of Enterococcus or Candida species can occur in immunocompromised hosts without a new pathogen being introduced[11,12]. Such observations highlight that culture positivity or metagenomic detection demands careful clinical, ecological, and temporal interpretation rather than reflex antimicrobial therapy. Reactivation of latent infections further exemplifies this principle: Tuberculosis may recrudesce during corticosteroid or biologic therapy[13]. Reactivation of latent tuberculosis in immunosuppressed states highlights the critical role of host immune integrity in maintaining microbial latency and preventing progression to active disease[14,15]. Similarly, herpesviruses such as cytomegalovirus re-emerge after immune suppression, demonstrating intricate immunoregulatory and immune evasion mechanisms that enable lifelong persistence with periodic reactivation, reflecting a finely balanced host-virus interaction[16-18]. And hepatitis B can flare during immunosuppressive therapies, including targeted anticancer treatments, highlights the critical role of immune control in maintaining viral latency and preventing clinical disease; hence, not due to new acquisition, but disruption of host-microbe equilibrium[19-21]. Such observations highlight that culture positivity or metagenomic detection demands careful clinical, ecological, and temporal interpretation rather than reflex therapy.

A SHARED CHALLENGE ACROSS THE FIELD

This challenge is systemic across ID research. Key gaps include: (1) Microbiome integration - infection models under-represent ecological and community-level interactions, limiting understanding of microbial behavior[7]; (2) Evolved definitions - pathogen vs non-pathogen, commensal vs colonizer, microbiome vs exogenous organism distinctions are inconsistently applied; (3) Pathogenicity standards - no universal criteria distinguish mere microbial presence from causative disease in high-throughput or metagenomic data; (4) Longitudinal evidence - few studies capture transitions from colonization to dysbiosis to overt disease, despite gut microbiota playing a dynamic balance between commensals and enteric pathogens[22-24]; (5) Cross-species, one-health understanding - a fragmented approach to studying human, animal, and environmental microbiomes limits understanding of ecosystem-level disease emergence, reinforcing the need for integrated One Health frameworks that connect cross-species microbial dynamics and antimicrobial resistance[25-27]; (6) Non-bacterial communities - viruses, fungi, and other non-bacterial components of the microbiome are frequently neglected, despite their ecological and pathogenic potential[2]; and (7) Ethical stewardship frameworks - over-diagnosis and over-treatment contribute to antimicrobial misuse, iatrogenic dysbiosis, and ecosystem disturbance[28,29].

Additionally, bacterial pathogenicity is not an intrinsic property alone but is defined by host-microbe interactions and the resulting damage response, emphasizing context-dependent disease expression rather than mere microbial presence[30,31]. Host determinants such as immune modulation, metabolic status, age, and prior antimicrobial exposure are insufficiently integrated into ID modelling, despite their decisive influence on microbial behavior. Biomarker-driven thresholds for intervention remain poorly standardized, further widening the gap between detection and disease attribution[32]. Biomarker-based predictive models and machine learning approaches are increasingly shaping proactive healthcare, though their clinical utility depends on careful validation, interpretability, and integration with bedside decision-making[33,34]. The result is a diagnostic-therapeutic paradox: Increasingly sensitive microbial detection tools, yet declining ecological understanding and clinical discernment.

DIAGNOSTIC STEWARDSHIP: THE COST OF MISINTERPRETATION

Misidentifying colonizers or contaminants as pathogens drives unnecessary antimicrobial exposure, accelerates resistance, and disrupts the patient’s microbiome[35]. Accurate differentiation between pathogenic infection, colonization, and contamination is essential to avoid unnecessary antimicrobial use, requiring structured clinical-microbiological correlation and evidence-based interpretation of culture-positive results[36,37]. Clinically, this manifests as secondary infections, prolonged hospitalization, and increased morbidity. In a prospective study in a tertiary care hospital in India of 275 positive urine cultures, nearly 9.5% of cases initially treated as infection were classified as non-pathogenic by a structured model, and this correct classification was associated with a reduction in average hospital stay by over 13 days and antibiotic cost savings of approximately Rupees 981 per patient, demonstrating the significant clinical and economic costs of misidentifying non-pathogens as pathogens[38]. Similarly, another structured clinico-microbiological stepwise model integrating clinical features, host factors, and outcome data demonstrates that mere detection of organisms in respiratory samples does not equate to pathogenicity, and such integrated interpretation significantly improves treatment decisions and antimicrobial stewardship[39]. On a population level, indiscriminate antimicrobial use contributes to environmental dissemination of resistance determinants. The ethical duty of clinicians and microbiologists is not merely to detect but to discern true pathogenicity. Accurate distinction between pathogen and non-pathogen is the first step toward rational therapy and effective antimicrobial stewardship[40]. Integrating microbiome data, clinical context, and longitudinal trends allows informed decisions, reducing harm while preserving essential microbial partners.

A STRUCTURED FRAMEWORK: EIGHT PRINCIPLES TO DISTINGUISH A PATHOGEN FROM A NON-PATHOGEN

Drawing from both ecological reasoning and clinical pragmatism, the following eight-point framework merges earlier models with bedside experience. It may offer an operational tool for clinicians, microbiologists, and authors reporting new organisms: (1) Clinical localization and correlation - are there consistent clinical signs, symptoms, or radiological findings pointing to the same anatomical site as the isolate? (2) Temporal host response - has there been a measurable dysregulated immune response (fever, inflammatory markers, organ dysfunction) temporally linked to the isolate within approximately 48 hours[40]? (3) Alternative explanations excluded - have other infectious or non-infectious causes for the presentation been reasonably ruled out[38]? (4) Ecological context and normal flora - is the organism part of the body’s commensal flora at that site? If so, quantify burden, virulence factors, and displacement patterns before assigning pathogenicity[41]; Disruption of gut microbial homeostasis (i.e. dysbiosis) alters host-microbiome cross-talk, facilitating opportunistic infections through impaired immune regulation and ecological imbalance[42,43]; (5) Host predisposition and environmental enablers - immunosuppression, metabolic derangement, devices, or anatomical breaches may permit ordinarily harmless organisms to invade; interpretation must adjust for these factors[44-47]; (6) Contamination assessment - rigorously evaluate sample collection, storage, transport, and laboratory processes; repeat sampling or negative controls help verify authenticity[48]. Blood culture contamination, particularly with coagulase-negative staphylococci, can lead to diagnostic uncertainty and unnecessary antimicrobial use, highlighting the importance of stringent sampling practices and careful clinical interpretation[36,49]; (7) Reporting standards for transparency - every report of a ‘new microbe’ require detailed disclosure of sampling methods, controls, sequencing depth, and analytical pipelines, as inadequate reporting and lack of standardized controls can significantly compromise reproducibility and interpretation of microbiome data[50-52]. Transparent data allows readers to judge pathogenic significance objectively; and (8) Ethical use of diagnostic technology and artificial intelligence - automation or artificial intelligence tools must support, not replace, human clinical reasoning. Their ethical utility lies in promoting transparency, reproducibility, and restraint, preventing overdiagnosis and unjustified therapy[53]. Applied systematically, these principles allow consistent interpretation, reproducible reporting, and ethically aligned stewardship, as studied in the urinary or respiratory model[38,39].

FROM ONE HUMAN TO ONE HEALTH

Each individual microbiome interacts dynamically with environmental and animal microbial ecosystems. Antibiotic use, urbanization, climate change, and habitat disruption reshape microbial communities, influencing both individual health and population-level disease emergence[25]. Recognizing the continuum from human microbiome to planetary ecology emphasizes that preserving microbial harmony in one patient contributes to ecosystem stability. When clinicians indiscriminately eradicate commensals or colonizers, they disrupt internal ecosystems and propagate wider ecological disharmony. It’s not about one clinician-one patient issues of microbiome, from one doctor to each clinical department where he/she works, to the hospital, to each state, to each country, to the whole world, there is a connection. We must have our own stewardship at the individual level[54-57], at the department level, at the hospital/community level, at the state/country/earth level[58-61]. Infection medicine is thus ecological medicine at a micro scale, and stewardship becomes an ethical imperative extending beyond individual patients to communities, ecosystems, and planetary health.

CONCLUSION

Future infectious-disease research and journal reporting must go beyond merely naming new microbes. Detection must be contextualized with ecological relevance, host response, methodological transparency, and ethical stewardship. Adoption of the eight-principle framework enables clinicians, microbiologists, and journals to distinguish pathogens from non-pathogens, optimize therapy, and reduce ecological disruption (Figure 1). Ultimately, our mission is not just to cure infection, but to preserve harmony between humans, their microbiomes, the shared biosphere, and the broader universe, acknowledging that microbial balance is central to health at every scale.

Figure 1  Eight guiding questions for distinguishing pathogens from non-pathogens.