Perspectives on Microbiome Therapeutics in Infectious Diseases: A Comprehensive Approach Beyond Immunology and Microbiology

Abstract

Although global life expectancy has increased over the past 20 years due to advancements in managing infectious diseases, one-fifth of people still die from infections. In response to this ongoing threat, significant efforts are underway to develop vaccines and antimicrobial agents. However, pathogens evolve resistance mechanisms, complicating their control. The COVID-19 pandemic has underscored the limitations of focusing solely on the pathogen-killing strategies of immunology and microbiology to address complex, multisystemic infectious diseases. This highlights the urgent need for practical advancements, such as microbiome therapeutics, that address these limitations while complementing traditional approaches. Our review emphasizes key outcomes in the field, including evidence of probiotics reducing disease severity and insights into host-microbiome crosstalk that have informed novel therapeutic strategies. These findings underscore the potential of microbiome-based interventions to promote physiological function alongside existing strategies aimed at enhancing host immune responses and pathogen destruction. This narrative review explores microbiome therapeutics as next-generation treatments for infectious diseases, focusing on the application of probiotics and their role in host-microbiome interactions. While offering a novel perspective grounded in a cooperative defense system, this review also addresses the practical challenges and limitations in translating these advancements into clinical settings.

Keywords: cooperative defense system; infectious disease; microbiome therapeutics; resistance defense; tolerance defense.

Figure 1

Establishing the Fundamentals of Infection-Microbiome Based on Resistance and Tolerance Defense in Microbiome-Integrated Cooperative Defense. By incorporating the microbiome perspective, this figure advances from the traditional immuno-microbiological view of resistance defense to a cooperative defense perspective that integrates tolerance defense, leading to a more comprehensive understanding. (A) The foundational concept of the infection-disease severity response model is that a higher pathogen burden correlates with increased disease severity, while a reduced burden corresponds to an improved health state. In this model, disease severity (Y-axis) inversely correlates with infection intensity (X-axis). In traditional immunology and microbiology, therapeutic strategies have largely focused on suppressing pathogen burden through antimicrobial agents and immune responses—An infection-resistant defense approach. However, in the case of infectious diseases, there is an increasing emphasis on tolerance defense, which, along with the perspective of cooperative defense, mitigates the physiological damage caused by infections. At this point, if tolerance defense is enhanced by microbiome therapeutics, the slope of the response norm graph flattens, indicating less severe physiological impacts despite pathogen presence. (B) The microbiome is closely linked to human health and disease. Within this context, a balanced microbiome (eubiosis) characterizes healthy individuals, indicating that a higher eubiotic state correlates with a healthier status. This connection aligns with the concept of tolerance defense in infectious diseases. (C) As the understanding of the microbiome expands, a fundamental approach to infectious diseases becomes possible. Dysbiosis, or microbial imbalance, is increasingly seen as a source of opportunistic pathogen proliferation and heightened pathogen burden. Here, an increased eubiotic state is associated with resistance defense. Microbiome therapeutics influence the improvement from dysbiosis to eubiosis while simultaneously leading to the enhancement of both resistance defense and tolerance defense. (D) In summary, the infection-disease severity response model, when connected to the eubiotic characteristics of the microbiome, provides a more fundamental understanding. Lower infection levels and better health are associated with a more eubiotic microbial state, while higher infection levels and poorer health correlate with dysbiosis. This interpretation suggests how these interconnected elements provide a novel perspective for the treatment of infectious diseases. Thus, microbiome therapeutics possess complex characteristics that encompass both traditional resistance and recent tolerance defense mechanisms, which can be understood through a cooperative defense system. This establishes a foundation for the “Microbiome-Integrated Infection-Disease Severity Response Model,” offering insights into the interactions among these variables and guiding the development of microbiome-based therapies.

Figure 2

Development Process of Microbiome Therapeutics for Infectious Diseases Based on Reverse Translational Research. The figure illustrates a stepwise framework for the development of microbiome therapeutics targeting infectious diseases. It begins with the identification of biomarker strains through NGS analysis of healthy individuals and infected patients. The identified strains are then isolated using culturomics from clinical samples. This is followed by efficacy and safety testing, conducted in vitro and in vivo, to evaluate their therapeutic potential. The process concludes with the standard drug development pipeline, including Good Laboratory Practice (GLP) toxicity testing, as well as clinical trials and regulatory approval based on Good Manufacturing Practice (GMP) to ensure safety and efficacy. This framework highlights the systematic approach based on reverse translational research to develop microbiome-based treatments.