Frontiers | Modulating the human gut microbiome-host system: a new drug discovery paradigm

Modulating the human gut microbiome-host system: a new drug discovery paradigm

• Gonzalo Colmenarejo ^*

• Cheminformatics & Artificial Intelligence Group, IMDEA Nutrition, Madrid, Spain

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Abstract

The human gut microbiome-host system represents a recently unleashed chemo-biological realm of crucial importance in human biology and health. So much so that new therapeutic approaches targeting it are emerging to prevent and treat a broad range of conditions, including inflammatory, metabolic, and cardiovascular diseases, infectious disorders, cancer, and neurodegeneration. From a drug discovery standpoint, this paradigm offers several distinctive advantages: it introduces novel therapeutic modalities (such as fecal microbiota transplantation, probiotics, prebiotics, and postbiotics), expands the biological search space to include the gut metagenome, unlocks new chemical space through microbial metabolites, and enables gut-localized pharmacokinetics with the potential to reduce systemic exposure and off-target effects. However, realizing this therapeutic potential critically depends on establishing causal links between specific microbiome features, microbial metabolites, and disease phenotypes. Achieving such causality requires the integration of diverse experimental and computational approaches across multiple scales, including epidemiological and clinical studies, metagenomics and longitudinal multi-omic profiling, gnotobiotic animal models, strain isolation and cultivation, biochemical and molecular analyses, and synthetic biology—supported by Artificial Intelligence, Bioinformatics, and Cheminformatics. In this Perspective, we provide a concise overview of this rapidly evolving field. We review the gut microbiome–host system and the principal tools used to interrogate it, with an emphasis on approaches that enable causality inference. We further evaluate current strategies for therapeutic intervention and conclude with an assessment of key achievements to date, as well as the major challenges and opportunities that will shape the future of microbiome-based drug discovery.

Introduction

The search for new drug discovery and development paradigms has been spurred in the last two decades by a convergence of structural challenges. These include: the observed high attrition rates to bring a new drug to the clinic (Sun et al., 2022; Waring et al., 2015); the limited exploitation of the human proteome due to the unknown or poorly characterized functions of a large fraction of its constituents (Oprea et al., 2018; Perdigão et al., 2015; Santos et al., 2017); the difficulty of designing effective modulators for many so-called “undruggable” proteins within the traditional orally bioavailable small-molecule paradigm (Duffy et al., 2022; Hopkins and Groom, 2002; Xie et al., 2023); and the risk of successive “patent cliffs” with increasing costs for drug discovery (Drug Discovery News, 2026; Hemphill and Sampat, 2012). This situation is being addressed through different strategies, that include systematic efforts to functionally annotate and characterize understudied proteins (Kelleher et al., 2023; Orgaz et al., 2024; Sánchez-Ruiz and Colmenarejo, 2022; Sharma et al., 2024), the development of new chemical modalities beyond the classical “rule-of-five” space (; Valeur et al., 2017), drug repurposing initiatives (Pinzi et al., 2024; Tanoli et al., 2025), and innovative drug delivery technologies (Mitchell et al., 2021; Uzakova et al., 2026).

However, an alternative (although not excluding from the previous) approach comes from the discovery of whole new areas of human biology that open the door to unprecedented new ways to cure diseases. A prominent example is the human microbiome, whose central role in human biology—particularly within the gastrointestinal tract, the gut microbiome—has become increasingly evident (; Gilbert et al., 2018; Lynch and Oluf, 2016; Proctor et al., 2019; Turnbaugh et al., 2007). The recognition that microbial cells in the gut engage in extensive mutualistic and commensal interactions with the host has led to a conceptual shift, in which humans and mammals in general are viewed as “composite organisms” or “holobionts” (Dietert and Dietert, 2012).

Research into the human gut microbiome has revealed its involvement in a broad range of diseases across multiple therapeutic areas, including metabolic diseases, inflammation, neurodegeneration, cardiovascular diseases (CVD), cancer, and infectious diseases (; ; Guggeis et al., 2025; Khalil et al., 2024; Lavelle and Sokol, 2020; Lynch and Oluf, 2016; Needham et al., 2020; Uzakova et al., 2026; Wu et al., 2021; Zhang et al., 2025). These insights have catalyzed the emergence of a new field in drug discovery aiming at the design of drugs targeting the human gut microbiome-host system (; ; Elkrief et al., 2025; Karn et al., 2023; Liu W. et al., 2025; Nuzzo and Brown, 2020; O’Toole et al., 2017; Thomas et al., 2008; Woo et al., 2023). The distinctive characteristics of this system necessitate the adoption of fundamentally novel concepts and methodologies in drug discovery. Notably, the therapeutic target space is expanded to include the microbial proteome, which is estimated to be roughly two orders of magnitude larger than the human proteome (Grice and Segre, 2012). In addition, its confinement to the intestinal tract enables the possibility of a localized drug delivery, potentially reducing systemic exposure, off-target effects, and toxicity (McCoubrey et al., 2023). Moreover, microbial metabolites—key mediators in the host-microbiome communication—show alternative structures that differ from those of endogenous human metabolites, thereby expanding the accessible chemical space for mimetic small molecule modulators and calling for new physicochemical design principles (Gil-Pichardo et al., 2023).

This Perspective aims to provide a self-contained introduction to this rapidly evolving field of drug discovery, offering readers who are new to the area the conceptual framework necessary to understand its foundations and assess its current state. We summarize the key features of the gut microbiome–host system, review the methodologies used to infer causal relationships between the microbiome and disease, and outline the therapeutic strategies that have been pursued to date. The achievements, challenges and perspectives for the future of the field are discussed as well. The resulting curated reference set is intended to serve as a starting point for deeper exploration of specific subfields within this expansive and multidisciplinary research landscape.

The human gut microbiome-host system

The human gut microbiome is an incredibly diverse and dynamic ecosystem consisting of trillions of microorganisms, including bacteria, archaea, fungi, viruses, and protozoa (; ; Elkrief et al., 2025; Gilbert et al., 2018; Hou K. et al., 2022; Khalil et al., 2024; Lavelle and Sokol, 2020; Sender et al., 2016). Often referred to as a “human organ” or a “second genome,” this community is fundamental to understand the functioning and regulation of human biology (; Grice and Segre, 2012). In a healthy adult, the community is typically dominated by two major anaerobic bacterial phyla: Firmicutes and Bacteroidetes (Eckburg et al., 2005).

Through more than a billion years of mammalian-microbial co-evolution, the host and its microbiome have become deeply interdependent (Ferretti et al., 2025; Zaneveld et al., 2008). The gut microbiome performs a vast repertoire of functions essential to the host’s survival, including the digestion of complex dietary fibers, the synthesis of essential vitamins (such as B and K) and amino acids (like tryptophan and phenylalanine), the metabolism of xenobiotics, the maturation of the immune system, and the provision of up to 10% of the host’s daily energy requirements through energy biogenesis (; Fobofou and Savidge, 2022; Khalil et al., 2024; Lavelle and Sokol, 2020). It also acts as a primary defense against pathogens through “colonization resistance,” where commensal microbes outcompete pathogenic invaders for nutrients and produce antimicrobial substances (Hou K. et al., 2022; Miller et al., 1956).

The communication between the microbiome and the host is primarily mediated by bioactive small-molecule metabolites (<1,500 Da) that act as interkingdom signaling messengers (

Fobofou and Savidge, 2022

;

Guggeis et al., 2025

;

Lavelle and Sokol, 2020

). These molecules are generated through fermentation of dietary inputs, biotransformation of host compounds (like bile acids)

de novo

microbial synthesis, and even host-modification of microbial biotransformation products (e.g., trimethylamine N-oxide, TMAO). Microbial metabolites group in several main classes of chemotypes, with different origins and host targets. The most important ones for human health are:

• Short-Chain Fatty Acids (SCFAs): SCFAs are saturated aliphatic organic acids of up to six carbons produced through the microbial saccharolytic fermentation of indigestible dietary fibers and resistant starch. The primary SCFAs—acetate, propionate, and butyrate—typically exist in a 3:1:1 ratio in the colon (Hou H. et al., 2022; Mann et al., 2024). Butyrate is the preferred energy source for colonocytes and maintains gut barrier integrity by stabilizing the hypoxia-inducible factor that promotes barrier repairment, and by upregulating the transcription and assembly of tight junction proteins (Kaiko et al., 2016; Kelly et al., 2015; Yu, 2012). Propionate serves as a substrate for intestinal gluconeogenesis and regulates cholesterol levels in the liver, while acetate enters systemic circulation to influence appetite centrally and trigger thermogenesis in adipose tissue (; ; Frost et al., 2014). SCFAs exert their effects by activating specific G protein-coupled receptors (GPCRs), such as GPR41 (FFAR3), GPR43 (FFAR2), and GPR109A, or by acting as inhibitors of histone deacetylases (HDACs) to regulate immune cell differentiation and suppress inflammation (Mann et al., 2024; Zhang et al., 2022).

• Secondary Bile Acids and bile acid derivatives: Primary bile acids (mainly conjugated cholic and chenodeoxycholic acids, CA and CDCA, respectively) synthesized from cholesterol in the liver are secreted into the gut, where microbial bile salt hydrolases (BSH) deconjugate them into their unconjugated derivatives (; ; Thomas et al., 2008). A specialized group of bacteria further performs 7α-dehydroxylation to generate secondary bile acids, such as deoxycholic acid (DCA) and lithocholic acid (LCA); additional bacterial modifications include oxidation/epimerization, desulfation, esterification and amidation (; Guzior and Quinn, 2021). These metabolites act as hormone-like signals engaging mainly the nuclear farnesoid X receptor (FXR), pregnane X receptor (PXR), and vitamin D receptor (VDR), plus the membrane G-protein–coupled receptor TGR5 (GPBAR1) (; ; Fiorucci and Distrutti, 2015). This signaling axis regulates lipid and glucose homeostasis, insulin sensitivity, and the expansion of RORγ+ regulatory T cells in the gut ().

• Tryptophan and Indole Derivatives: Bacteria in the colon directly degrade the essential amino acid tryptophan into a suite of indole metabolites, including indole-3-propionic acid (IPA), indole-3-aldehyde (I3A), and tryptamine (; Wikoff et al., 2009; Zhang and Davies, 2016). Many of these act as ligands for the aryl hydrocarbon receptor (AhR) and PXR, which are vital for maintaining mucosal tolerance, enhancing tight junction expression, and stimulating the release of IL-22 to protect against infections like Clostridium difficile (Illés et al., 2020; Natividad et al., 2018; Scott et al., 2020; Venkatesh et al., 2014). Conversely, dysbiotic bacteria like Morganella morganii can produce genotoxic indolimines that cause DNA damage and exacerbate inflammation (; Duan et al., 2024).

• Choline and Carnitine: Gut microbes metabolize dietary choline and L-carnitine (found in red meat and eggs) into trimethylamine (TMA), which is then oxidized in the host liver by flavin monooxygenases to TMAO (). Elevated TMAO is a potent risk factor for CVD, as it promotes atherosclerosis, platelet hyperreactivity, and thrombosis (Wang et al., 2011), through a not clear mechanism

• Phenylalanine and Tyrosine Metabolites: microbial metabolism of phenylalanine produces phenylacetylglutamine (PAGln), which enhances thrombosis potential by acting via host adrenergic receptors (Liu W. et al., 2025; Nemet et al., 2020; Zhu et al., 2023). In turn, tyrosine microbial metabolites include p-cresol and p-cresyl sulfate, both uremic toxins that impair barrier integrity and associate with chronic kidney disease progression (Ito and Yoshida, 2014).

• Histidine Metabolites: The gut microbiota metabolizes the essential amino acid histidine into mainly imidazole propionate (ImP) and histamine. ImP is generated through the microbial urocanate reductase (UrdA) and acts by activating the p38γ/p62/mTORC1 signaling axis, which contextually impairs insulin signaling and contributes to type 2 diabetes (T2D, Koh et al., 2018). Additionally, ImP has been identified as a driver of atherosclerosis, where it signals through the imidazoline-1 receptor (I1R) in myeloid cells to trigger systemic and local inflammation (Mastrangelo et al., 2025). Microbial histamine, synthesized via bacterial histidine decarboxylase, serves as a regulator of gastrointestinal functions by activating host H2 receptors to suppress intestinal inflammation (Gao et al., 2015).

• Amino Acids and Polyamines: Branched-chain amino acids (BCAAs), such as leucine, isoleucine, and valine, are both utilized and produced by the microbiome; their accumulation in blood is a strong biomarker for insulin resistance and T2D (; Vanweert et al., 2022). Additionally, microbes ferment arginine to produce polyamines (putrescine, spermidine, spermine), which are essential for epithelial proliferation and wall stability (Tsvetikova and Koshel, 2020).

The intestinal epithelium serves as the critical interface between the gut microbiota and the host, functioning as both a physical and immunological barrier. This barrier consists of a specialized layer of cells (enterocytes, Goblet cells, and Paneth cells) reinforced by tight junctions and a protective mucin layer (; Iliev et al., 2025; Mann et al., 2024; Martinez et al., 2017). Microbial metabolites can reach systemic circulation primarily through absorption across the intestinal epithelium, utilizing different transport mechanisms and circulatory routes depending on their chemical properties. The process is a critical part of the “gut–host axis,” allowing molecules produced in the gut lumen to influence distant organs such as the liver, heart, and brain. These metabolites circulate through the portal vein to the liver and then to peripheral tissues, allowing the gut microbiome to function as the body’s largest endocrine organ. In eubiosis, an state of healthy, balanced and diverse microbiome, the continuous flow of beneficial metabolites supports a robust intestinal epithelium barrier, reinforced by a protective mucin layer and tight junctions (Khalil et al., 2024; Valencia et al., 2025; Yadav and Chauhan, 2022). When this delicate balance is disrupted, a state known as dysbiosis occurs, characterized by a loss of microbial diversity and an expansion of pathobionts (typically benign microbes that become pathogenic under certain conditions). Dysbiosis can compromise the gut barrier—often termed “leaky gut”—allowing the translocation of bacteria and proinflammatory factors like lipopolysaccharides (LPS) into host circulation (Fan and Pedersen, 2021; Khalil et al., 2024; Menezes and Shah, 2024; Witkowski et al., 2020; Zhang et al., 2025). This process triggers chronic systemic inflammation and is strongly linked to the pathogenesis of non-communicable diseases, including inflammatory bowel disease (IBD), obesity, T2D, and CVD.

The human gut microbiome system is highly personalized and established early in life. While the core functional capacity is relatively consistent across healthy adults, taxonomic composition varies significantly between individuals and is shaped by genetics, mode of delivery at birth, infant feeding, and aging (Fan and Pedersen, 2021). Furthermore, environmental factors—most notably dietary habits (e.g., the high-fat, low-fiber Western diet vs. Mediterranean diet) and the use of xenobiotics such as antibiotics—can rapidly and profoundly alter the composition and functional output of this complex system (Lavelle and Sokol, 2020).

Tools to study the role of gut microbiome in human health

The study of the human gut microbiome and its relationship to host health has expanded dramatically in the last two decades, evolving from traditional culture-based methods of aerobic single strains to advanced culture-independent, functional, and multi-omic approaches aimed at establishing molecular causality. Contemporary research now adopts a multi-level strategy that progresses from broad taxonomic associations to the identification of specific molecular mechanisms explaining causal effects on host physiology and disease (; Elkrief et al., 2025; Woo et al., 2023). This framework integrates population-level data with controlled animal models and high-resolution genomic, transcriptomic, proteomic, and chemical analyses to determine how microbial communities influence host health at a molecular level, all integrated through computational and Artificial Intelligence (AI) modeling. Together, these approaches define the current methodological landscape for studying the complex human gut microbiome–host system and provide a foundation for the rational development of microbiome-targeted therapeutics. Below, we survey the main approaches, organized by the type of output information they provide. Figure 1 summarizes these tools.

Health/disease-strain associations and microbial profiling

An initial set of tools and analytical approaches focuses on identifying associations between individual microorganisms or microbial community profiles and health or disease states, without the ability to establish causal relationships

16S rRNA sequencing and metagenomics

16S rRNA gene sequencing is an amplicon technique that provides microbial taxonomic composition, typically at the genus level, at relatively low cost, making it the workhorse of large epidemiological and clinical cohort studies (Regueira-Iglesias et al., 2023). This is complemented with shotgun metagenomic sequencing, which captures the entire gene content of a sample (Quince et al., 2017). This allows for species- and strain-level resolution and the reconstruction of uncultured bacterial genomes, providing a blueprint of the community’s functional potential. These techniques have been systematically used in landmark population-scale studies such as the Human Microbiome Project (Proctor et al., 2019; Turnbaugh et al., 2007) and the MetaHIT consortium (; Ehrlich, 2011), which established reference catalogues of gut microbial genes and their variation across healthy and diseased individuals, thus providing a foundational framework for comparative, functional, and mechanistic studies of host–microbiome interactions.

Biomarker discovery

Population-scale observational studies—both cross-sectional and longitudinal—have been essential for mapping the landscape of microbiome variation in health and disease. These studies combine stool microbiome profiling (typically through 16S or shotgun metagenomics, see above) with detailed phenotyping of the host: diet, lifestyle, medication use, anthropometrics, blood composition, and disease outcomes. This can be combined with metabolomics (see below) if associations with specific metabolites are sought. From here, both biomarkers and microbiota-phenotype associations have been identified by the application of statistical and machine learning approaches in so-called “microbiome-wide association studies” (MWAS), that have allowed to identify microbial strains and profiles associated with different disease states (Ha, 2014; Koeth et al., 2013; Qin et al., 2012; Turnbaugh et al., 2009; Wu et al., 2015).

Strain cultivation and culturomics

Isolation and cultivation of strains allow the full characterization of their functionality and metabolome, besides validating bioinformatic predictions (biomarkers and bacterial genomes) made during the profiling phase. For instance, while software can identify strain-level signatures in metagenomic datasets, these findings must be validated by obtaining a pure culture of the target bacterial isolate (Fan and Pedersen, 2021). However, culturing many rare strains in the human gut microbiome remains a formidable challenge, to the point that 70% of the species in the Unified Human Gastrointestinal Genome database have not been cultured to date (). In this regard, Culturomics—the high-throughput cultivation of microbes under hundreds of different conditions followed by MALDI-TOF identification—has dramatically expanded the repertoire of cultured gut species (Lagier et al., 2018). Once isolated, these strains can be used in “chemistry forward” approaches (see below), such as screening against reporter platforms to identify the bioactive metabolites they produce and their host targets ().

Microbiome depletion and phenotype transfer

Associations between microbiome strains and disease are not necessarily a landmark of causality, as they may arise from reverse causation, where the disease produces the observed microbiome profile rather than being a consequence of it. To move beyond association and establish causality, researchers use models with depleted or engineered microbiomes. However, these models do not reveal directly the molecular mechanism underlying the biological effect.

Germ-free (GF) and gnotobiotic mouse models

GF mice are raised under sterile conditions, while gnotobiotic mice are GF animals colonized with defined microbial strains, yielding a microbiome of known composition (Jans and Vereecke, 2025). Transferring samples of whole microbiota from donors with a given phenotype into GF mice tests causality at the microbiome level: reproduction of the phenotype in recipients indicates a causal role for the microbiome. Colonization with individual strains or defined consortia, typically through oral gavage, further refines this approach, enabling causal attribution at the strain level if the phenotype appears upon inoculation.

Antibiotic treatment

By administering antibiotics to animal models or human volunteers, it is possible to ablate part or almost the whole microbiome and compare phenotypes with the antibiotic-free models. This is a much cheaper approach although less specific, highly dependent on the analyzed strain, and more subject to error (Kennedy et al., 2018)

Fecal microbiota transplantation (FMT)

Transferring fecal matter from a donor (e.g., an obese human twin) into a GF or antibiotic-treated mouse (see above) can establish if a specific phenotype—such as obesity, insulin resistance, or atherosclerosis susceptibility—is transferable and thus microbiome-mediated

Metabolomics and functional multi-omics

These tools provide information that goes beyond the microbiological profile (the identity and distribution of the microbiota components) to provide their functions and chemical products. This information is very useful for pinpointing the molecular mechanisms of microbiota action in different diseases and, therefore, provides definitive support for demonstrating causality. The advent of multi-omics technologies has transformed microbiome research by integrating genomics, transcriptomics, proteomics, and metabolomics, offering a comprehensive, systems-level understanding of it.

Metabolomics

This is the study of metabolites in biological tissues to identify the bioactive messengers (like SCFAs or secondary bile acids) that mediate host-microbe communication. These platforms are usually based on mass spectrometry (MS) or nuclear magnetic resonance (NMR). MS methods are commonly coupled with an earlier separation technique, such as gas chromatography or the variants of liquid chromatography—high-performance liquid chromatography and ultra-high performance liquid chromatography. Untargeted metabolomics provides a global snapshot of the “dark chemical matter” in the gut and is open to the identification of new metabolites, while targeted metabolomics allows for precise quantification of known compound classes and specific molecules (; Zhang et al., 2011).

Metatranscriptomics and metaproteomics

These “omics” layers track which genes are actively being transcribed (RNA) and which proteins are being produced, providing deeper insight into real-time microbial activity and function that metagenomics cannot reveal (Ojala et al., 2023)

Human clinical and epidemiological approaches

Once causality is demonstrated in animal model systems, it should be tested in humans through this type of studies. Establishing causality in humans requires rigorous longitudinal and interventional study designs

Longitudinal cohort studies

Here prospective analyses track individuals over time and measure the microbiome before disease onset. If the microbial profile precedes the appearance of the disease, direct causality can be inferred

Randomized controlled trials (RCT)

These are the “gold standard” for determining if a microbiome-targeted intervention (e.g., FTM) can induce a disease or phenotype in the receptor (Prosty et al., 2024). The treatment is randomized and the statistical analysis adjusts the results by confounding factors so that if a significant appearance of the phenotype in the treated samples vs. the controls is observed, this provides a definitive proof of causality. However, RCTs are expensive and complex, so they are used only as final proof for well-supported hypotheses of microbial causality.

Mendelian randomization

This approach leverages host genetic variation in large cohorts to infer causal relationships between the gut microbiome and host phenotypes, thereby mitigating confounding and reverse causation in the absence of treatment randomization (Sanna et al., 2019; Yang et al., 2018). Specifically, host genetic variants—typically single-nucleotide polymorphisms (SNPs)—that are robustly associated with microbial taxa or microbiome-derived metabolites are used as instrumental variables. If such variants are also associated with a clinical phenotype, a causal contribution of the corresponding microbial feature can be inferred. Although less definitive than randomized controlled trials, Mendelian randomization provides an alternative, affordable but valuable surrogate to achieve causal evidence. It is applicable when genetic determinants of microbiome variation are known.

Discovery of molecular mechanisms

Besides the discovery of biomarkers and causality of microbial strains on disease, additional advanced techniques allow pinpointing the specific genes and molecules (molecular mechanism) that drive host health outcomes

Bioactivity-guided fractionation

This traditional “chemistry forward” approach involves screening microbial extracts for specific biological effects (e.g., anti-inflammatory activity) and then isolating the responsible molecule through fractionation and repeated testing, followed by structure elucidation through NMR and/or MS

Functional metagenomics

In this culture-free approach, the total bacterial DNA is fragmented and expressed heterologously as a metagenomic or fosmid DNA library. The resulting clones can be screened to produce clone-specific metabolites in a bioactivity panel. The positive clones are isolated and sequenced to identify the gen or set of genes responsible for the metabolite, and the metabolite structure determined (; ; Milshteyn et al., 2018). The gene or genes can then be used as input of targeted metagenomic analyses to find similar metabolites from other strains.

Genome mining

Here, bioinformatic tools search and analyze biosynthetic gene clusters (BGCs) to predict and discover novel microbial metabolites, such as antibiotics or immunomodulators, directly from genomic sequences (Donia et al., 2014; Scherlach and Hertweck, 2021). These can later be confirmed experimentally

Synthetic biology

Researchers can use CRISPR-Cas9 and other genetic tools to construct “clean deletions” of specific bacterial genes to confirm their role in producing a metabolite or eliciting a host response (Guo et al., 2019)

Computational and AI-based data integration and modelling

Bioinformatics, Cheminformatics, and AI integrate metagenomics, metaproteomics, metabolomics, and host-omics to infer mechanistic microbiome–host interactions, including metabolite-mediated effects on host health and disease. These methods are rapidly advancing the study of microbiome–host interactions and are beginning to reshape drug discovery targeting the human gut microbiome-host system

Recent bioinformatic tools integrate multi-omics data to connect microbial composition, gene expression, and metabolite profiles with host physiology, enabling biomarker discovery and personalized therapeutic strategies (; Sudhakar et al., 2021). Neural-network frameworks such as MiMeNet, MMETHANE, LOCATE, and mmvec learn high-dimensional associations between microbes and metabolites, improving prediction of metabolite abundances and host status, and revealing metabolite-mediated mechanisms of disease (; Morton et al., 2019; Reiman et al., 2021; Shtossel et al., 2024). Parallel advances in host–microbiome protein–protein interaction prediction use machine learning and deep learning, from domain–domain and network-based methods to structure-aware graph models and large protein language models, to infer large-scale human–bacterial interactomes and prioritize key regulatory proteins (Kiouri et al., 2025; Lian et al., 2019; Lim et al., 2022; Pan et al., 2024).

On the other hand, cheminformatic approaches have further expanded the translational potential of microbiome research. Systematic curation and analysis of experimentally reported metabolite–target interactions, combined with large-scale virtual screening, have expanded known interaction spaces by more than four-fold, addressing longstanding chemobiological gaps (Orgaz et al., 2024). AI-driven modeling of the physicochemical properties, structural features, and biodistribution of microbial metabolites (Gil-Pichardo et al., 2023), together with analyses of functional group usage and interaction patterns derived from microbial metabolite–protein complexes in the Protein Data Bank (), provide actionable design principles for small-molecule therapeutics targeting microbiome-associated pathways.

Collectively, these computational advances are underpinned by data and analytical infrastructures generated through large-scale microbiome initiatives, including the Human Microbiome Project and the MetaHIT (; Ehrlich, 2011; Proctor et al., 2019; Turnbaugh et al., 2007), as well as comprehensive reference metagenomes (), BGC repositories (Palaniappan et al., 2020), and curated metabolomic databases (Guijas et al., 2018; Wishart et al., 2023; 2022; Xue et al., 2020). Together, these databases and AI-driven methodologies are laying the foundation for mechanism-informed, microbiome-based drug discovery and precision therapeutic development. Table 1 collects some of the most outstanding computational tools and resources in this area.

Main computational rehis work

Modulating the human gut microbiome for therapeutic purposes

Therapeutic strategies targeting the gut microbiome–host system span a broad continuum, ranging from complex, ecosystem-wide interventions aimed at restoring homeostasis, to highly targeted molecular-level modulations, with intermediate approaches acting at the strain level. In the following sections, we outline the most relevant strategies, progressing from holistic interventions toward increasing specificity, and highlighting their applications, strengths and limitations, as well as their degree of clinical maturity and regulatory status. Figure 2 summarizes the main types of therapeutic interventions.

Ecosystem-level interventions

Ecosystem-level interventions target the entire microbial community structure to restore diversity and function, instead of attempting to rebalance a particular microbial species or signaling pathway. They include FMT and dietary interventions

FMT

FMT as a therapy involves the transfer of processed stool from a healthy donor to a receiving patient to restore a “healthy” microbial-host ecosystem with appropriate metabolite production and associated functionality, including pathogen defense. It is a pragmatic or “black box” approach that in principle does not require a detailed understanding of the strain or molecular basis of the disease, only assuming that the donor microbiome and its associated healthy phenotype is going to be replicated in the receptor gut upon transplantation. FMT has reached a significant degree of maturity in some cases, like Rebyota and Vowst, recently approved by the Food And Drug Administration (FDA) of the United States of America (USA) for the prevention of recurrent Clostridium difficile infection (rCDI), significantly outperforming standard vancomycin treatments (Kao et al., 2017; Kassam et al., 2013; Nood et al., 2013; Wang et al., 2024a). However, for other conditions, FMT remains in an emerging or experimental phase. For example, it is being explored in early-stage trials for Crohn’s disease, metabolic syndrome, obesity, and as a tool to overcome resistance to immune checkpoint inhibitors in cancer patients (Elkrief et al., 2025; Hou K. et al., 2022; Sun et al., 2025). FMT carries a safety advantage over traditional organ transplants as it lacks the risk of biological rejection by the body (). Despite these benefits, FMT is associated with significant disadvantages and risks, primarily due to the transfer of an ill-defined and non-standardized microbial community. There is a documented risk of transmitting pathogenic organisms, including norovirus and drug-resistant Escherichia coli, with rare cases of fatal sepsis leading to temporary suspensions of clinical trials by the FDA (). Moreover, engraftment of the sample is not guaranteed, and the disease phenotype can revert. Furthermore, studies suggest the potential for inadvertently transferring undesired donor phenotypes, such as obesity or susceptibility to atherosclerosis (Gregory et al., 2015; Ridaura et al., 2013). Finally, logistical challenges also persist, as maintaining the viability of anaerobic bacteria requires a strict cold-chain (often −80 °C) for transportation.

All these factors make this approach difficult to easily comply with current government safety regulations when promoted as drug. In this case, they would fall under the FDA’s regulatory rubric of Live Biotherapeutic Products (LBPs), defined as “biological products that contain live organisms and are used for the prevention, treatment, or cure of a disease or condition in humans, and is not a vaccine”. An LBP requires for a therapeutic indication an Investigational New Drug (IND) application, involving rigorous taxonomic identification, proof of safety (including the exclusion of virulence factors), phased clinical trials to prove efficacy, and standardized manufacturing following Good Manufacturing Practices (GMP). The two drugs mentioned above, Rebyota and Vowst, are successful examples of this FDA approval path.

Outside the USA, comparable regulatory expectations apply but are implemented differently. In both Canada and Europe, clinical use or investigation of FMT beyond C. difficile infection similarly requires authorization under investigational frameworks overseen by the Health Canada and the European Medicines Agency (EMA). However, regulatory details vary: the FDA and EMA generally permit approaches such as homogenization or pooling of donor stool to improve scalability and reduce inter-donor variability, whereas Health Canada currently restricts such practices. In addition, the European Union does not define a dedicated LBP regulatory category, instead regulating therapeutic microorganisms within broader medicinal product classifications. Notably, despite their approval by the FDA, neither Rebyota nor Vowst are currently approved across all other major international regulatory agencies.

Dietary interventions

Dietary interventions represent the most accessible strategy for modulating the gut microbiome to treat chronic diseases. They involve modifying nutritional intake through specific patterns like the Mediterranean diet or foods containing components like fiber and resistant starch. The primary advantages of this approach are its inherent safety, non-invasive nature, and cost-effectiveness, offering holistic benefits across multiple disease pathways: they regulate systemic inflammation, enhance gut barrier integrity, and improve metabolic parameters without the infection risks associated with invasive microbial transfers. The disadvantages lie in its low specificity, the highly individualized nature of host responses, and their requirement for long-term compliance. In addition, it has a more prophylactic nature, so for more serious disease conditions (colon cancer, IBD, microbial infections) it is only expected to be used as adjuvant for more specific therapies.

Strain-level interventions

In this case, the result of the intervention is the promotion/demotion of one or few microbial strains, instead of a wholesale remodeling of the host microbiome like in the ecosystem-level interventions. It is therefore an intervention of intermediate specificity. In this area, we have probiotics, bacteriophages, and prebiotics

Probiotics

Probiotics are defined as live, non-pathogenic microorganisms that, when directly administered in adequate amounts, confer a health benefit on the host (Hill et al., 2014). This therapeutic category is broadly divided into traditional probiotics—such as Lactobacillus, Bifidobacterium, and certain yeasts—which are easily cultivable and have a long history of use, and next-generation probiotics (NGPs), comprising rationally designed consortia of typically anaerobic strains of the adult human gut microbiota (O’Toole et al., 2017). NGPs are often derived from significantly beneficial human gut commensals like Akkermansia muciniphila, Faecalibacterium prausnitzii, and Roseburia, which were identified through advanced genomic sequencing for their specific functional roles in maintaining metabolic and immune homeostasis (O’Toole et al., 2017). Unlike broad interventions like FMT, probiotics offer a more practical and targeted method for modulating the gut environment, acting through more specific mechanisms such as competing with pathogens for niches, enhancing the intestinal epithelial barrier, and producing beneficial metabolites like SCFAs, amino acids, and vitamins (Howarth and Wang, 2013). In this case, it is expected that the beneficial effect has been pinpointed to one or few specific microbial strains, even though the molecular mechanism of action may not be known.

The degree of maturity for probiotic interventions varies significantly by strain and clinical indication. Traditional probiotics are highly mature as dietary supplements and are widely used over the counter (OCT) for managing conditions such as antibiotic-associated diarrhea and acute gastroenteritis (Howarth and Wang, 2013; O’Toole et al., 2017; Sanders et al., 2019). However, the use of NGPs as primary clinical treatments for complex conditions like metabolic syndrome, cancer, and neurodegenerative diseases remain in an emerging and experimental phase, and large-scale, randomized controlled trials are still needed to establish definitive clinical efficacy across diverse human populations (Kristensen et al., 2016).

Significant disadvantages and risks hinder the widespread clinical adoption of probiotics. A major challenge is stable colonization; many probiotic strains struggle to survive the harsh acidity of the stomach and often fail to engraft permanently in the host’s intestine, leading to only transient effects (Kristensen et al., 2016; Wu et al., 2021). Furthermore, the efficacy of probiotics is highly individualized, as the host’s baseline microbiome composition determines whether a strain can successfully integrate. There are also notable safety concerns, particularly for immunocompromised patients or those with a “leaky gut” (see above), where probiotic bacteria can translocate into the bloodstream, potentially causing bacteremia, fungemia, or sepsis (Doron and Snydman, 2015). Additionally, quality control issues persist in the supplement market, with audits revealing that many OTC products contain dead organisms, different species than those listed on the label, or even antimicrobial resistance genes (Elkrief et al., 2025).

The regulatory status of probiotics is increasingly evolving toward stricter oversight, particularly when products are intended for disease treatment rather than general wellness. In the USA, most traditional probiotics are marketed as dietary supplements and are considered generally recognized as safe (GRAS) by the FDA, but they are not permitted to claim prevention or treatment of specific diseases. By contrast, NGPs intended for therapeutic use are typically regulated as LBPs and must follow drug-like development pathways. Regulatory approaches outside USA are multiple: in the European Union, additional classifications such as “foods for special medical purposes” may apply in certain countries; in Australia, the Therapeutic Goods Administration (TGA) regulates probiotics as foods or complementary medicines depending on the claims made; and in Canada, Health Canada generally classifies probiotics as Natural Health Products subject to pre-market authorization. Despite these regional differences, regulatory agencies are converging on a common expectation for NGPs, requiring rigorous strain characterization, clear provenance, and pharmaceutical-grade safety and efficacy data comparable to those demanded for conventional drugs.

Bacteriophages

Bacteriophages, or phages, are naturally occurring viruses that specifically target and replicate within bacterial cells, offering a highly precise method for modulating the gut microbiome-host system (Karn et al., 2023). Unlike broad-spectrum antibiotics, phage therapy can utilize the viral lifecycle—particularly the lytic cycle, which results in the lysis of the bacterial cell—to selectively eliminate pathobionts or specific pathogen strains without disrupting beneficial commensal microbes (Lin et al., 2017). Therefore, they comprise a powerful potential tool to control the levels of specific strains in the human microbiome. Advances in synthetic biology now allow for the development of engineered phages that can deliver recombinant DNA payloads to particular gut organisms or neutralize specific virulence factors without inducing cell lysis, leaning in this last case the approach towards a molecular-level intervention (Hsu et al., 2020). Bacteriophages are integral to the regulation of the microbial population, and when directed as therapy, they could reshape gut metabolome as well.

The degree of maturity for phage-based microbiome modulation remains in the emerging and experimental phase (Mahmud et al., 2024; Voorhees et al., 2020). While preclinical evidence in mouse models—such as the use of phages to treat alcoholic liver disease or colorectal cancer—is robust, research into the mechanisms by which the gut microbiota prevents phage infection is currently categorized as being in an immature stage (Lin et al., 2017; Liu H. et al., 2025). Small-scale human safety trials have confirmed that specific phage cocktails are well-tolerated and can accumulate in the lower gut, but large-scale clinical validation of their efficacy across diverse human populations is still lacking (Mahmud et al., 2024).

The primary advantage of microbiota-directed bacteriophages is their potential exceptional specificity, which enables the targeting of individual bacterial strains associated with disease—such as Klebsiella pneumoniae in IBD—while sparing the rest of the ecosystem (Federici et al., 2022). However, significant disadvantages exist, most notably the potential for bacteria to rapidly develop resistance through mechanisms like surface receptor blockage or abortive infection (Furuyama and Sircili, 2021). Furthermore, individual phage-bacteria interactions can have unpredictable downstream effects on other community members, and some studies have linked the expansion of certain phages to aggravated intestinal inflammation and colitis (Gogokhia et al., 2019; Voorhees et al., 2020).

Regulatory agencies remain cautious regarding the use of bacteriophages to treat, cure, or prevent diseases of the gut, primarily due to concerns about ecological stability, the potential for horizontal gene transfer, and the durability of phage-induced perturbations within the complex gut microbiome. In the USA, the FDA classifies therapeutic bacteriophages under the LBP framework, requiring submission of an IND application. In contrast, as above described the EMA currently lacks a regulatory category equivalent to the LBP designation and instead evaluates bacteriophages under existing frameworks for biological medicinal products. Similarly, both Health Canada and TGA regulate bacteriophages as biological drugs.

Prebiotics

Microbiota-directed prebiotics are defined as substrates that are selectively utilized by host microorganisms to confer a health benefit (Gibson et al., 2017; Gibson and Roberfroid, 1995; Sanders et al., 2019). Traditionally, these molecules consist of complex carbohydrates such as inulin, fructo-oligosaccharides, and resistant starch, which remain undigested in the upper gastrointestinal tract and reach the colon intact. There, they serve as key carbon sources for specific bacterial taxa, promoting their selective expansion (Gibson and Roberfroid, 1995; Monteagudo-Mera et al., 2016). Fermentation of these substrates by microbes, including Lactobacillus and Bifidobacterium, generates health-associated metabolites such as SCFAs. Beyond SCFA production, the resulting microbial outgrowth can yield additional bioactive metabolites and suppress pathogen colonization through competitive exclusion. Although prebiotics are molecular entities, their biological effects manifest primarily at the strain and community level through modulation of microbial composition, motivating their inclusion in this section.

While prebiotics are well established for general health promotion and wellness, their use as primary therapeutic interventions for diseases such as IBD, cancer, or metabolic syndrome remains largely exploratory (Dewulf et al., 2013; Everard et al., 2011; Nicolucci et al., 2017; Sanders et al., 2019). Their major advantages include a strong safety profile, non-invasive administration, and cost-effectiveness compared with microbial transplants or conventional pharmacological agents. Moreover, prebiotics offer a practical means of reshaping microbial ecosystems at scale, potentially delivering pleiotropic benefits across multiple host pathways. However, these advantages are counterbalanced by important limitations, most notably limited specificity and pronounced inter-individual variability. Host responses to a given prebiotic are highly dependent on baseline microbiome composition, particularly the presence of taxa capable of metabolizing the substrate (; Salonen et al., 2014; Zeevi et al., 2015; Zmora et al., 2018). In some contexts, prebiotic supplementation may even produce paradoxical effects, exacerbating inflammation in individuals lacking appropriate fermenting microbes (). In addition, microbiome resilience often leads to rapid reversion toward baseline, dysbiotic states once supplementation is discontinued (Wang et al., 2024b).

Several strategies are being explored to improve the specificity and durability of prebiotic interventions. Co-administration of prebiotics with the probiotic strains that utilize them—an approach termed synbiotics—has been proposed to enhance engraftment and functional targeting (Swanson et al., 2020), although clinical evidence for a consistent advantage remains mixed (Hou K. et al., 2022). An alternative and potentially more precise strategy is the development of synthetic prebiotics, including engineered glycans and polysaccharides designed to selectively engage defined microbial functions. Preclinical studies suggest that such compounds can attenuate intestinal inflammation and restore epithelial barrier integrity in models of colitis (Tolonen et al., 2022).

From a regulatory perspective, most prebiotics are currently marketed as dietary supplements or food additives and are therefore subject to relatively limited oversight. When prebiotics are developed explicitly for the treatment, prevention, or management of disease, however, they may fall under more stringent regulatory frameworks, including classification as “foods for special medical purposes” or, in some cases, the requirement to pursue formal clinical trial authorization, such as an IND application in the USA or equivalent Clinical Trial Application (CTA) pathways under the EMA, Health Canada, or the TGA. Looking ahead, the field is increasingly shifting toward precision microbiome modulation, leveraging metagenomic profiling and machine-learning approaches to predict individual responses and to support the development of standardized, clinical-grade prebiotic formulations (Zeevi et al., 2015).

Molecular-level interventions

The third group of interventions include basically compounds of different origins and chemotypes that exert their effect at a molecular level. They can be both molecules from the microbiome itself (postbiotics) and synthetic molecules (small-molecule drugs). In addition, while not compounds, in this class of intervention could be included emerging single-strain therapeutic probiotics such as ADS024 (Bacillus velezensis), which produces proteases that cleave C. difficile toxins for rCDI therapy (O’Donnell et al., 2022), Saccharomyces strains engineered to produce recombinant proteins in the intestine (Kim et al., 2023), or synthetic bacteriophages designed to act through a specific molecular mechanism (see above).

Postbiotics

Postbiotics are broadly defined as bioactive compounds produced during a microbial process—including microbial metabolites like SCFAs, bacterial cell components, or inactivated (pasteurized) microbial cells—that confer a health benefit on the host (Malagón-Rojas et al., 2020; Salminen et al., 2021). Thus, they represent microbiome-derived molecules or molecular assemblies that act at the molecular level through direct interactions with host proteins and signaling pathways. This therapeutic approach is currently in an emerging and experimental phase for clinical disease treatment, and while preclinical evidence in animal models is robust, human data is still primarily derived from early-stage pilot studies (Duan et al., 2024; Guggeis et al., 2025). A major milestone in this field was a pilot human trial demonstrating that a 3-month regimen of pasteurized A. muciniphila safely improved insulin sensitivity and other metabolic markers in overweight individuals, providing proof of concept for postbiotic-based therapies in humans (Depommier et al., 2019).

The primary advantages of postbiotics include their well-defined chemical structure (particularly for metabolites and purified cellular components), stable dosing, and ease of storage and transport compared to live microbial therapies (Duan et al., 2024). They offer a superior safety profile by eliminating the risk of transmitting live pathogens and of horizontal transfer of antibiotic resistance genes. Furthermore, postbiotics do not require stable intestinal colonization to exert their effects, bypassing a major ecological hurdle faced by traditional probiotics. However, significant disadvantages include their restricted chemical space (by definition, they are of microbial origin), the restricted biological space (in most cases they tap from biological interactions already existing in nature), putative pharmacokinetic and pharmacodynamic issues, and the potential for “paradoxical effects” depending on the dosage and host context (Duan et al., 2024).

As described before for other interventions, the use of postbiotics can require a weak regulation if marketed as dietary supplements for general health, but if developed specifically to treat, prevent, or cure a human disease, it must follow the strict IND/CTA pathway, like a small-molecule drug

Small-molecule drugs

Small-molecule interventions derived from synthetic medicinal chemistry aim to modulate the gut microbiome–host system by targeting specific microbial enzymatic activities or host receptors (indeed, potentially the whole human and microbial proteomes). Under this definition, antibiotics—whether narrow- or broad-spectrum—are formally included; however, their primary mode of action is the elimination or growth suppression of pathogenic strains. However, microbiome research has expanded this paradigm toward the non-lethal and selective modulation of commensal and mutualistic microbial signaling pathways and host–microbe interactions, an approach that reduces selective pressure for resistance while broadening therapeutic applications and including host targets. Examples of these are inhibitors of bacterial metabolic pathways, such as β-glucuronidase (GUS) inhibitors to alleviate chemotherapy-induced toxicity by preventing the GUS to reactivate glucuronized anticancer compounds (; Ervin et al., 2019; Wallace et al., 2010), or choline–TMA lyase inhibitors to limit production of the cardiovascular risk factor metabolite TMAO (; ; ; ; Roberts et al., 2018; Wang et al., 2015). In addition, this category encompasses molecular mimics of beneficial microbial metabolites targeting host receptors, including synthetic bile acid derivatives (e.g., obeticholic acid) that agonize host receptors such as FXR and TGR5 for the treatment of metabolic and liver diseases (; Pellicciari et al., 2009; 2002), as well as synthetic indole-based agonists of PXR for the management of intestinal inflammation (Dvorak et al., 2020; Dvořák et al., 2024; 2020; Li et al., 2021). The degree of maturity for this approach is variable, such that the compounds targeting microbial enzymes remain in preclinical phases, while molecules modulating host receptors have reached Phases I-II and there are even cases like obeticholic acid, that has been approved for primary biliary cholangitis in the USA, although recently restricted in patients with advanced cirrhosis (FDA post, 2026).

The primary advantages of small molecules include their high specificity and precision, which allows for the modulation of individual microbial functions while preserving the overall diversity of the ecosystem. Unlike FMT or engineered strains, small molecules provide precise, dose-dependent, and reversible control, enabling modulation of even uncultured or genetically intractable microorganisms. They also allow for unique pharmacokinetic optimization, such as designing compounds with limited systemic absorption to minimize off-target effects in the host. Additional advantages come from its flexibility, since this approach permits to tap from an unrestricted chemical space, only limited by synthetic feasibility, as well as unrestricted biological space, open to the potential use of the whole human and microbial proteomes. The most significant disadvantage is the previous requirement for pinpointing a host or microbial target with causal association with a disease at a molecular level.

The current regulatory status for small molecules is a major strength too, as they follow a well-established drug development pathway. Unlike the LBPs, which require a specialized framework for living organisms which has been recently defined, small-molecule inhibitors and metabolite mimics utilize the standard IND process. Because approximately 90% of current drugs are small molecules, the regulatory and manufacturing infrastructure is significantly more mature than for other microbiome-based modalities.

Perspective

Achievements to date

Targeting the human gut microbiome–host system constitutes a compelling and fundamentally new paradigm in drug discovery, with the potential to overcome several of the structural limitations currently confronting the pharmaceutical industry. By extending therapeutic exploration beyond human-derived biology, this approach unlocks access to previously unexplored chemobiological spaces, helping to address the increasing challenge of identifying patentable and clearly differentiated drug candidates and targets. In this context, our group has recently provided a systematic mapping of the existing chemobiological landscape in this field, together with a more than four-fold expansion achieved through validated predictions of novel metabolite–target interaction (Orgaz et al., 2024). By making this extensive set of predictions openly available, we aim to catalyze experimental validation efforts and accelerate the discovery of new chemobiological spaces within the microbiome–host interface.

The gut microbiome offers a vast and largely untapped repertoire of small molecule chemotypes originating (totally or partially) from microbial metabolism. These microbial metabolites play central roles in host–microbiome communication and represent a rich source of novel scaffolds and pharmacophores for drug discovery. In this respect, they echo the historical success of therapeutics inspired by endogenous human metabolites—such as catecholamines, steroids, and folates—which have long served as templates for systemic drugs (). Harnessing the chemical diversity of microbial metabolites may likewise enable the development of innovative small-molecule therapeutics with novel mechanisms of action, distinct intellectual property profiles, and alternative physicochemical and structural constraints (Gil-Pichardo et al., 2023). Moreover, our recent statistical analysis of microbial metabolite–target interactions at atomic resolution indicates that these molecules stabilize their binding to proteins through functional groups and interaction patterns that differ from those typically exploited by orally administered systemic drugs, thereby revealing new design principles for drug discovery based on microbiome-derived compounds ().

Beyond chemical diversity, this paradigm also opens the possibility of therapeutically targeting the gut metagenome, which is estimated to be approximately two orders of magnitude larger than the human genome (Grice and Segre, 2012). Whereas traditional antibiotic strategies primarily focused on eliminating pathogenic microorganisms, microbiome-targeted drug discovery instead emphasizes the modulation of the vastly larger and functionally diverse repertoire of commensal microbial strains and their genome products, often through non-lethal mechanisms. Accordingly, a growing number of small-molecule drug discovery efforts have centered on microbial metabolic enzymes, including bile salt hydrolases (; ; Jones et al., 2026; Wang et al., 2023), glycoside hydrolases (; E. Kowalewski and R. Redinbo, 2025; Ervin et al., 2019; Graboski et al., 2024; Pellock et al., 2018; Wallace et al., 2010), choline TMA-lyases (; Gabr and Świderek, 2020; Orman et al., 2019; Pathak et al., 2020; Roberts et al., 2018; Wang et al., 2015; Woo et al., 2024), ureases (Richards-Corke et al., 2025), and amino acid decarboxylases (Maini Rekdal et al., 2019; Williams et al., 2014). In parallel, several host proteins involved in host–microbiome signaling have been reprioritized as drug targets within this framework, including the nuclear receptors FXR (Ma et al., 2013; Pellicciari et al., 2002), PXR (Dvořák et al., 2020; Illés et al., 2020; Li et al., 2021; Sládeková et al., 2023b) and the AhR (Dvořák et al., 2021; Grycová et al., 2022; Sládeková et al., 2023a); as well as G-protein coupled receptors TGR5 (; Pellicciari et al., 2009), GPR109A (Imbriglio et al., 2011) and GPR41/43 (Milligan et al., 2017). For recent reviews of the field, see (Ma et al., 2022; Woo et al., 2023). From a pharmaceutical development perspective, inhibitors of microbial enzymes remain predominantly in preclinical stages, whereas modulators of host receptors span a range of clinical phases: in most cases, they are in Phase I-II, although as mentioned before obeticholic acid, a synthetic bile acid derivative, has been approved in the USA for the primary biliary cholangitis indication. Other examples of approved drugs targeting host targets in the gut are the anti-diabetic compounds acarbose, voglibose and miglitol, which inhibit intestinal α-glucosidases, although it has been recently demonstrated their inhibition of microbial isoforms of the enzyme too (Tan et al., 2018).

In addition to conventional small-molecule approaches, targeting the gut microbiome has given rise to a diverse set of novel drug modalities that are highly specific to this system, including FMT, probiotics, prebiotics, and postbiotics. Historically, these modalities have not been regulated as medicines per se but rather marketed as OCT dietary supplements under the GRAS designation (probiotics, prebiotics, postbiotics) or administered as medical procedures in hospital settings under enforcement discretion (FMT).

A notable exception is represented by the FMT-derived products Rebyota and Vowst, which have recently obtained FDA approval as biological drugs for the prevention of rCDI. Their approval was enabled by the implementation of standardized manufacturing processes designed to ensure reproducible composition and functional activity, together with successful completion of Phase III clinical trials (FDA: Fecal Microbiota Products for B.E., 2024). These products exemplify the FDA’s category of LBPs. In contrast, the EMA and other agencies currently subsume such products under the broader category of biological medicinal products and have not yet granted marketing authorization to FMT-derived therapies.

Additional examples of standardized, donor-derived FMT products developed as LBPs include CP101 and RBX7455, for rCDI too; however, neither has achieved FDA approval to date: development of CP101 was discontinued following Phase III evaluation, while RBX7455 has not publicly progressed beyond early clinical development (Monday et al., 2024)

But LBPs need not be derived necessarily from donor stool. An alternative and increasingly prominent strategy involves NGPs composed of defined consortia of cultured microbial strains, offering greater compositional control, scalability, and mechanistic interpretability than donor-derived products. A leading example is VE303, a defined consortium of commensal Clostridia strains indicated to prevent rCDI and currently in Phase III clinical development (Louie et al., 2023). Another non-donor LBP modality are bacteriophage cocktails like LBP-EC01, currently in Phase II for recurrent urinary tract infections by E. coli (Kim et al., 2024). In this case, the phages contain a CRISPR-Cas3 payload that degrades the bacterial DNA upon infection.

By contrast, prebiotics and postbiotics remain less advanced as regulatory drug classes. A notable exception among prebiotic-like agents is lactulose, a prescription drug approved for constipation and hepatic encephalopathy (HE) that predates the formal definition of “prebiotic,” yet functions mechanistically as one by selectively promoting the growth of saccharolytic, non-urease producing bacteria, which decreases the high ammonium levels causing HE (; Odenwald et al., 2023). Despite increasing clinical interest in both naturally derived and synthetic prebiotics, as well as in postbiotic preparations such as heat-inactivated bacterial products and microbial lysates, neither category has yet achieved broad regulatory approval as standalone pharmaceutical drug classes, and most candidates remain in early-to mid-stage clinical development rather than Phase III.

Challenges and the future ahead

Looking ahead, the maturation of the microbiome–host drug discovery field hinges on progress in two principal areas. First, there is a pressing need to deepen our understanding of the causal roles played by the microbiome in human disease, particularly at the molecular level (). Advancing from association to causation to mechanism requires systematic progression along the pipeline of microbial profile-disease association → profile confirmation → causality in model systems → molecular characterization → validation in human cohorts → molecular mechanistic elucidation (Figure 1). Achieving this demands the coordinated application of multi-omics, epidemiological and interventional studies, functional metagenomics, gnotobiotic models, synthetic biology, and biochemical and cellular assays, increasingly integrated through computational approaches such as AI, Bioinformatics, and Cheminformatics.

Although often depicted as a linear process for conceptual clarity, in practice these steps are pursued iteratively and in parallel. For example, epidemiological studies combined with multi-omic profiling can narrow disease associations to a small set of candidate metabolites, which can then be linked to putative host targets based on prior knowledge and validated through focused mechanistic studies to establish causality (Mastrangelo et al., 2025). Conversely, functional metagenomic screens of disease-associated microbiomes can directly uncover previously unknown metabolite–host target interactions (), generating hypotheses that can be subsequently tested in gnotobiotic models and human cohorts. Moreover, the combination of multi-omic datasets with AI, Cheminformatics, and Bioinformatics can also directly provide metabolite-target interactions statistically associated with disease for further experimental confirmation (Nuzzo et al., 2021).

A clear illustration of the need for molecular-level causal resolution is the role of the gut microbiome in neurodegeneration. Multiple, non-exclusive lines of evidence implicate the microbiome as an upstream contributor through at least two mechanistic axes: microbially derived metabolites, and heterologous amyloid cross-aggregation. Microbial metabolites have been shown to modulate microglial maturation, neuroinflammatory tone, and blood–brain barrier integrity, with altered metabolite profiles consistently reported in Parkinson’s and Alzheimer’s disease cohorts and supported by causality in gnotobiotic and metabolite supplementation models (; ; Pascale et al., 2020; Sampson et al., 2016). In parallel, functional bacterial amyloids can promote heterologous nucleation of α-synuclein, amyloid-β, and tau despite limited sequence homology, thereby accelerating pathological protein aggregation (Fernández-Calvet et al., 2024; Friedland and Chapman, 2017; Javed et al., 2020; Sampson, 2025). Disentangling the relative contributions and potential interplay of these mechanisms will be essential for the rational design of therapeutic strategies targeting the gut–brain axis.

Another area requiring further attention is the development of effective strategies for localized delivery of microbiome-targeted therapeutics. Localized delivery is essential because the upper gastrointestinal tract is a hostile environment where extreme acidity and digestive enzymes can inactivate LBPs, absorb small molecules, or denature biologics before they reach their target (; McCoubrey et al., 2023). Furthermore, the resident microbiome itself can act as a delivery barrier by enzymatically inactivating drugs—as seen in the microbial reduction of digoxin—or by transforming compounds into toxic metabolites (Kamath et al., 2025a). Spatially precise delivery is also necessary for small-molecule inhibitors of microbial enzymes and gut-localized host receptors, where restriction to the intestinal lumen maximizes local drug exposure while minimizing off-target interactions mediated by systemic circulation (; Gil-Pichardo et al., 2023; Holmes et al., 2012). Finally, localized release helps overcome inter-individual physiological variability, such as shifts in luminal pH or accelerated transit times caused by disease states like IBD, which often cause conventional single-trigger delivery systems to fail (Kamath et al., 2025b).

In this area, we have recently developed an AI-based cheminformatic model to predict gut permanence from molecular structure that can be applied by medicinal and computational chemists when designing small molecule drugs with distribution restricted to the gut (Gil-Pichardo et al., 2023). From the Drug Delivery field, innovative solutions involve the so-called Microbiome-Active Drug Delivery Systems (MADDS), which leverage site-specific microbial stimuli to trigger therapeutic activation or release (Kamath et al., 2025a). Enzyme-responsive systems use fermentable polysaccharide coatings (like pectin or guar gum) or azo-linked prodrugs that remain intact in the proximal gut but are selectively degraded or cleaved by the dense anaerobic microbiota in the colon (Kamath et al., 2025a). To improve reliability, advanced multi-stimuli platforms such as Phloral and OPTICORE utilize parallel triggers, combining pH-sensitive polymers with microbiota-degradable starch to ensure robust drug release even if individual physiological parameters fluctuate (). Other advanced designs include redox-responsive hydrogels and reactive oxygen species (ROS)-sensitive nanocarriers that target the high levels of oxidative stress found specifically at sites of colonic inflammation (Kamath et al., 2025a).

These specialized delivery technologies are critical for various microbiome-targeted therapeutic modalities. Probiotics, for example, require microencapsulation or “biofilm-mimetic” formulations to protect them from gastric acid and promote successful niche engraftment (Govender et al., 2013). Postbiotics in general and metabolites in particular like butyrate and propionate are often delivered via colonic-targeted tablets or as prebiotic conjugates (e.g., inulin-propionate ester) to overcome their naturally low oral bioavailability and short systemic half-lives (). Similarly, oral FMT products increasingly rely on colon-specific coatings to provide scalable and less invasive alternatives to rectal administration (as used for RBX2660), while other formulations (e.g., Vowst) leverage acid-resistant bacterial spores to ensure distal gut delivery. Beyond microbiome-directed therapies although related to it, localized delivery strategies are also being explored in oncology, where in situ inactivation of systemic antibiotics within the large intestine aims to preserve commensal microbiota integrity and maintain responsiveness to immune checkpoint inhibitors (Elkrief et al., 2025).

Conclusion

Targeting the human gut microbiome-host system has opened multiple exciting avenues for drug discovery that span new chemobiological spaces, drug modalities, biodistribution, and drug delivery methods. The success of these therapies depends on integrated microbiome research across multiple levels to better elucidate the underlying chemistry and biology of this fascinating system. This Perspective shows the high potential of this research field, that is demonstrated by several drugs already in the clinic or very close to it.

Statements

Data availability statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author

Funding

The author(s) declared that financial support was received for this work and/or its publication. This work has been funded by grant PID 2021-127318OB-I00 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest

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The author(s) declared that generative AI was used in the creation of this manuscript. The figures were generated by ChatGPT following instructions of the author

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Summary

Keywords

bacteriophages, drug discovery, fecal microbiota transplantation, human gut microbiome, microbial metabolites, postbiotics, prebiotics, probiotics

Citation

Colmenarejo G (2026) Modulating the human gut microbiome-host system: a new drug discovery paradigm. Front. Drug Discov. 6:1898583. doi: 10.3389/fddsv.2026.1898583

Received

02 June 2026

Revised

16 June 2026

Accepted

17 June 2026

Published

14 July 2026

Volume

6 – 2026

Edited by

José L. Medina-Franco, National Autonomous University of Mexico, Mexico

Reviewed by

Edgar López-López, Uppsala University, Sweden

Updates

Copyright

© 2026 Colmenarejo

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Disclaimer

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