Targeting the gut microbiome in inflammatory bowel disease: from concept to clinical reality
Article information
Abstract
The gut microbiota, a complex community of trillions of microorganisms inhabiting the human gastrointestinal tract, has emerged as a critical regulator of immune homeostasis and gastrointestinal health. In the context of inflammatory bowel disease (IBD), comprising primarily Crohn’s disease and ulcerative colitis, disruptions to this microbial ecosystem—collectively termed dysbiosis—have been increasingly recognized as central to disease pathogenesis. Recent research has established that alterations in gut microbiota not only reflect disease states but may actively drive immune dysregulation, barrier dysfunction, and mucosal inflammation. This review synthesizes current knowledge on the role of the gut microbiota in IBD and evaluates the therapeutic landscape of microbiota-modulating strategies using selected examples. Fecal microbiota transplantation, while offering proof-of-concept validation, is hindered by standardization challenges and variable clinical outcomes. As a response, microbiome-based therapeutics have evolved toward defined live biotherapeutic products including bacterial consortia and single-strain products, postbiotics, and metabolite-centered approaches targeting specific pathways. Groundbreaking research into rationally designed synthetic microbiomes and next-generation probiotics is driving a paradigm shift in microbiota-based treatment for IBD from empirical to precision-guided interventions.
INTRODUCTION
Inflammatory bowel disease (IBD), which encompasses Crohn’s disease (CD) and ulcerative colitis (UC), represents chronic, relapsing inflammatory disorders of the gastrointestinal tract with multifactorial etiology. Although the interplay of host genetics, immune responses, environmental factors, and diet is well established, the gut microbiota has emerged as a pivotal contributor to both disease onset and progression. The gut microbiome comprises diverse bacteria, viruses, fungi, and archaea that engage in complex interactions with host epithelial and immune cells, as well as with one another. In healthy individuals, these microbial consortia maintain immune equilibrium, synthesize beneficial metabolites such as short-chain fatty acids (SCFAs), and prevent colonization by pathogens.
Recent metagenomic studies, including those utilizing longitudinal cohorts, have demonstrated that perturbations in microbial composition, referred to as dysbiosis, are detectable years before clinical IBD diagnosis [1]. These perturbations are characterized by a reduction in beneficial taxa such as Faecalibacterium prausnitzii and other members of the Ruminococcaceae family, along with a corresponding expansion of potentially harmful species like adherent-invasive Escherichia coli, Klebsiella pneumoniae, and Ruminococcus gnavus [2]. Such shifts not only reflect disease state but may potentiate inflammatory pathways via increased epithelial permeability, aberrant antigen presentation, and activation of pro-inflammatory cytokine networks.
The evolution of IBD research has transitioned from descriptive taxonomic profiling to functional and mechanistic exploration. Metabolomics, transcriptomics, and gnotobiotic mouse models have illuminated key pathways through which microbial communities modulate host immunity. These insights have propelled the development of therapeutic strategies aimed at restoring microbial homeostasis or at using microbiome-derived compounds as therapeutic agents. The current review evaluates the scientific rationale, clinical efficacy, and translational potential of various microbiota-targeted therapies in IBD by using selected examples (Table 1) [3-8].
Summary of the Various Microbiota-Targeted Therapies in Inflammatory Bowel Disease
MICROBIAL DYSBIOSIS AND PATHOGENESIS IN IBD
A growing body of translational research has solidified the role of gut dysbiosis in the pathogenesis of IBD. Dysbiosis in IBD is marked by a reduced diversity of commensal microbes and a simultaneous enrichment of pro-inflammatory taxa. Longitudinal studies, such as those from the Crohn’s and Colitis Canada Genetic Environmental Microbial project, have demonstrated that shifts in microbial communities, including an increased abundance of Ruminoccus torques and Blautia and decreased abundance of F. prausnitzii, may precede clinical symptoms by several years [1]. Similarly, alterations of the gut microbiome have been associated with disease recurrence [9].
Experimental models support these observations. Germfree mice colonized with fecal samples from IBD patients exhibit exaggerated colitis symptoms compared to those receiving feces from healthy donors [10]. These results are corroborated by data demonstrating that microbiota from individuals with CD or UC are capable of triggering mucosal inflammation and disrupting epithelial barrier function.
Pathobionts such as adherent-invasive E. coli and Fusobacterium nucleatum are frequently overrepresented in IBD patients. These bacteria are able to adhere to and invade intestinal epithelial cells, evade host immunity, and stimulate pro-inflammatory cytokines like interleukin (IL)-1β and tumor necrosis factor α. On the other hand, beneficial bacteria such as F. prausnitzii produce butyrate and other SCFAs that reinforce epithelial integrity and promote regulatory T cell development [11].
Microbial-derived metabolites such as tryptophan catabolites also play an important immunoregulatory role. Indoles, produced by some members of the gut microbiota and from the metabolisms of tryptophan, activate the aryl hydrocarbon receptor (AhR), which induces IL-22 production by lymphoid cells, enhance the production of antimicrobial peptides, con-tributing to maintaining epithelial cell integrity [12,13]. Disruptions in this axis—either due to microbial loss or metabolic dysfunction—can predispose the gut to inflammatory insults.
Overall, the convergence of human cohort studies, microbial profiling, and animal models provides compelling evidence that microbial dysbiosis is not merely an epiphenomenon but a central player in IBD pathogenesis. It can thus be targeted from a therapeutic perspective using different strategies that aim to reduce pathobiont colonization (using antibiotics or phagotherapy) or to favor beneficial microbes (Fig. 1). The use of antibiotics has shown moderate efficacy in specific contexts, and it is associated with several drawbacks, including the emergence of antibiotic resistance and toxicity. Researchers are investigating approaches using phages that would specifically target pathobionts within the human gut without impacting the commensal microbiota adversely [14,15].
Different types of strategies to target the gut microbiota in inflammatory bowel disease (IBD). FMT, fecal microbiota transplantation; LBP, live biotherapeutic product; AIEC, adherent-invasive Escherichia coli.
FECAL MICROBIOTA TRANSPLANTATION
Fecal microbiota transplantation (FMT) represents the earliest clinical application of microbiota-based therapies in IBD. It involves transferring stool from a healthy donor to an IBD patient to restore microbial diversity and function. Initial enthusiasm for FMT stemmed from its success in treating recurrent Clostridioides difficile infections, where cure rates exceeded 80% [16]. This prompted investigations into its potential for chronic inflammatory diseases such as UC and CD.
Multiple randomized controlled trials have examined FMT efficacy in UC. Rossen et al. [3], Moayyedi et al. [4], and Paramsothy et al. [5] showed superiority compared to placebo in inducing clinical remission, and this was confirmed in more recent trials such as Costello et al. [6] and Haifer et al. [7] However, there is high variability across these studies (including donor variability, number and route of administration, i.e. colonoscopy, nasoduodenal tube, oral capsule), their size is globally limited, and no maintenance data are available. In CD the data are scarce and only 1 randomized controlled trial that evaluated the effect of FMT to maintain corticosteroid-induced clinical remission has been published so far [8]. Despite a limited number of subjects, higher engraftment by donor microbiota within the recipient’s gut was associated with more extended remission maintenance. A result that needs to be confirmed in larger studies.
Mechanistically, the effectiveness of FMT is believed to de-pend on microbial engraftment and restoration of metabolic output [17-19]. However, only a fraction of transplanted microbes successfully colonize the host gut, and long-term stability remains uncertain.
Moreover, to be able to use FMT in the treatment of chronic diseases such as IBD, a kind of standardization is mandatory, while it is indeed impossible to standardize FMT. Metagenomic studies revealed that up to 50% of shotgun metagenomics reads cannot be mapped to any known microorganism, and even when reads can be mapped to known bacteria, up to 50% of identified genes are of unknown function. And this is even worse for metabolites present in human stools that cannot be identified in 80% to 90 % of the cases [20,21]. And this is not even mentioning other components of human stools such as viruses, Archaea, Fungi, Protists, and human cell material.
Given these challenges, the field is now shifting away from crude stool-based approaches toward more refined and reproducible therapeutic formulations such as defined bacterial consortia and single-strain therapeutics. Nonetheless, FMT remains an essential proof-of-concept that therapeutic modulation of the microbiota can yield clinical benefit in IBD.
LIVE BIOTHERAPEUTIC PRODUCTS
The limitations associated with FMT—including poor reproducibility, regulatory uncertainty, and the presence of unknown or potentially harmful microorganisms—have spurred interest in more defined microbiome-based therapeutics. Live biotherapeutic products (LBPs) represent a rational evolution of this approach, offering better safety profiles and mechanistic clarity.
LBPs are formulations consisting of one or more live microorganisms derived from human gut microbiome that are supposed to confer health benefits. These organisms are carefully and rationally selected based on human data (such as comparison between patients and healthy subjects) and/or functional criteria such as immunomodulatory capacity, ability to enhance mucosal barrier integrity, or restore dysbiotic microbial networks.
1. Defined Microbial Consortia
One of the most prominent examples in IBD is VE202. It is a defined 16-strain bacterial consortium derived from healthy human donors selected for its ability to induce FoxP3+ regulatory T cells. These strains have been selected following a complex process based on successive experiments of germ-free mice colonization and their administration to adult mice had therapeutic effect in colitis models [22].
Further development in this area includes large-scale synthetic microbiomes that aim to replicate the full metabolic and immunologic functionality of a healthy gut. Cheng et al. [23] constructed a 119-strain “artificial microbiome.” These strains were selected based on their prevalence in human gut, metabolic capabilities, and ability to fill ecological niches within the gut. When introduced into germ-free mice, the artificial microbiome was capable of metabolizing bile acids, and producing SCFAs and indoles at levels similar to native microbiota, indicating functional equivalence.
Compared to FMT, defined consortia offer the advantages of manufacturing consistency, enhanced safety, and greater flexibility for mechanistic dissection. As regulatory frameworks for LBPs become more robust, these products are positioned to become central to microbiome-modulating strategies for IBD and potentially other chronic inflammatory conditions.
Recent clinical trials, such as the VE202 phase 2 study, are now testing these consortia in larger, multicenter settings. These studies aim to evaluate not just clinical remission, but also microbial engraftment, mucosal healing, and immune markers such as regulatory T cell counts and cytokine profiles.
Importantly, synergy among microbial members is not merely additive. Studies have shown that consortia designed with metabolic cross-feeding and spatial organization in mind are more effective in modulating host responses [24]. For instance, one bacterium may degrade complex polysaccharides into simpler substrates, which are then fermented by another to produce SCFAs. These cascade effects underscore the importance of rational design based on ecological principles.
2. Single-Strain Approaches: F. prausnitzii
While multi-strain consortia offer broad functional coverage, single-strain approaches offer targeted immunological effects with potentially simpler manufacturing and regulatory pathways. F. prausnitzii, a key butyrate-producing commensal from the Firmicutes phylum, has emerged as a particularly promising candidate. It is one of the most prevalent and abundant species in the healthy human gut and a core member of the intestinal microbiome [25].
In patients with IBD, F. prausnitzii abundance is consistently reduced, and its loss correlates with increased disease severity and mucosal inflammation. Our landmark work in 2008 [26] demonstrated its anti-inflammatory properties, including inhibition of nuclear factor-kappa B signaling in intestinal epithelial cells and promotion of IL-10 production by immune cells. Subsequent studies confirmed its ability to induce CD4+CD8α++ regulatory T cells, enhance epithelial barrier integrity, and promote resolution of inflammation [27].
Mechanistically, F. prausnitzii produces key metabolites such as butyrate and the microbial anti-inflammatory molecule (MAM), which reinforce gut barrier functions and reduce cytokine-driven epithelial damage [28,29]. However, in the last few years, it has become clearer that a large part of the immunomodulatory effects of F. prausnitzii rely on molecules present on the bacterial wall that interact with antigen-presenting cells such as monocytes, macrophages, and dendritic cells to induce an anti-inflammatory phenotype notably characterized by an increased production of IL-10 and a decreased production of pro-inflammatory cytokines (Fig. 2) [27,30,31].
Mechanisms underlying the anti-inflammatory effects of Faecalibacterium prausnitzii. MAM, microbial anti-inflammatory molecule; NF-kB, nuclear factor-kappa B; IL-10, interleukin 10.
Animal studies have shown that oral administration of this bacterium can significantly attenuate colitis severity, making it a leading candidate for monotherapy or adjunctive use with other agents in IBD [27,30].
Clinical translation has begun with EXL01, a novel lyophilized oral capsule formulation designed for targeted release of F. prausnitzii in the small intestine. A completed phase 1/2a trial in patients with CD who achieved corticosteroid-induced clinical response showed no major safety and some signal of target engagement (NCT05542355, ongoing analysis). A follow-up phase 2 trial (MAINTAIN-POP) is currently enrolling patients to evaluate further its role in preventing postoperative recurrence (NCT06925061). These trials underscore the feasibility and promise of targeted single-strain therapy in IBD management.
POSTBIOTICS AND MICROBIAL METABOLITE THERAPIES
Postbiotics represent a novel class of microbiome-targeted interventions that bypass the need for live organisms. They are composed of microbial-derived metabolites, inactivated cells, or structural components that can elicit beneficial effects on the host [32]. In the context of IBD, postbiotics offer the potential to retain the therapeutic benefits of live microbes while eliminating risks related to colonization, transfer of antibiotic resistance genes, or unintended systemic infections.
One of the most promising avenues in postbiotic research involves tryptophan-derived metabolites that function as AhR agonists [12]. AhR is a ligand-activated transcription factor that plays a central role in maintaining mucosal immunity. Activation of AhR leads to the induction of IL-22, which is involved in epithelial regeneration, antimicrobial peptide production, and restoration of mucosal homeostasis. Several studies have shown that the gut microbiota of patients with IBD exhibits a reduced ability to produce AhR agonists, playing a role in intestinal inflammation [13,33]. In addition, among the tryptophan-derived metabolites, we recently demonstrated that xanthurenic (XANA) and kynurenic (KYNA) acids have anti-inflammatory properties and that the exogenous administration of a recombinant version of aminoadipate aminotransferase the enzyme involved in the production of XANA and KYNA, successfully protected mice from colitis. This study paves the way for new therapeutic strategies that aim to correct alterations in tryptophan metabolites by manipulating the endogenous metabolic pathway using aminoadipate aminotransferase, rather than by administering these metabolites [33].
Another key family of postbiotics is SCFAs, including acetate, propionate, and butyrate [34]. These metabolites are produced by the fermentation of dietary fibers by gut bacteria and are known to serve as energy sources for colonocytes, enhance tight junction integrity, and suppress inflammation through different mechanisms, including G-protein coupled receptors (e.g., GPR43) [35]. Exogenous administration of SCFAs has shown therapeutic potential in murine models of colitis [36], though challenges with delivery and dosing have prevented its application in humans to date.
Other microbial products under investigation include microbial cell wall components like peptidoglycan fragments, bacterial-derived extracellular vesicles, and specialized proteins such as the MAM from F. prausnitzii [29]. These components may act via Toll-like receptors or other pattern recognition pathways to modulate innate and adaptive immunity.
The development of postbiotic therapies is appealing not only for safety and scalability but also for their ability to deliver specific immunomodulatory signals without the complexity of live microorganisms. As technologies for metabolomic profiling and synthetic biology advance, postbiotics may play a leading role in the next generation of IBD therapies.
Several clinical-stage programs are now developing postbiotic therapies as standalone or adjunctive treatments. For instance, synthetic tryptophan metabolites with enhanced AhR affinity are being evaluated in early-phase trials for colitis [37]. Similarly, encapsulated butyrate derivatives and novel delivery mechanisms—such as colon-targeted release coatings— are in development to overcome challenges of degradation in the upper gastrointestinal tract [38]. Other postbiotic strategies include leveraging microbial peptides with antimicrobial and anti-inflammatory properties. One such compound, MAM from F. prausnitzii, has been shown to reduce epithelial permeability and suppress pro-inflammatory gene expression in preclinical models [29]. Recombinant production and stabilization of such peptides could yield new classes of microbiomeinspired biologics.
These innovations are positioning postbiotics as a promising frontier in microbiome therapeutics.
CLINICAL CHALLENGES AND THERAPEUTIC POSITIONING
Despite significant advances in microbiome science, the translation of microbiota-targeted therapies into routine clinical practice remains fraught with challenges. One of the most pressing issues is the lack of standardization across studies, particularly in terms of donor selection for FMT, microbial strain identification, and manufacturing processes for LBPs. Furthermore, the regulatory framework governing microbiome-based products is still evolving, often lagging behind scientific discovery.
Microbiome-based therapies are mechanistically distinct from the immunosuppressants used in IBD. They often lack the rapid anti-inflammatory effects seen with corticosteroids or biologics, making them less suited for managing acute flares. However, their capacity to restore immune tolerance, promote mucosal healing, and induce long-term homeostasis positions them as ideal agents for maintenance therapy and relapse prevention. This conceptual shift necessitates new trial designs and endpoints. For example, clinical trials must account for the time lag between administration and clinical effect, as well as interindividual variability in microbial composition. Stratifying patients based on microbiota profiles or inflammatory biomarkers may improve the likelihood of identifying responders.
The IMPACT trial we conducted more than 10 years ago provides a useful case study [8]. The concept of the study involved using a dual approach targeting both the immune system and the microbiota using a combination of FMT and host-directed therapies. After achieving clinical remission with corticosteroid, a single FMT was performed through colonoscopy with the aim of maintaining the remission. The number of patients enrolled in this pilot study was low, but the results suggested a superiority of FMT compared to placebo with a trend regarding the rate of clinical recurrence and statistically significant differences regarding other readouts such as endoscopic severity and C-reactive protein level. Building on these promising results, we are now conducting the MIRACLE trial, that investigates in a much larger number of patients, the effect of FMT as a maintenance strategy following anti-tumor necrosis factor withdrawal in CD (NCT04997733). While these studies are still exploratory, they underscore the importance of timing and therapeutic context in determining the efficacy of microbiome-based treatments in IBD.
Importantly, microbiome-based interventions are expected to be much safer than immunosuppressants, making them attractive candidates for fragile populations as well as for combination regimens. Their safety profile could allow earlier intervention in disease progression or usage in pediatric and elderly populations. However, larger trials with rigorous endpoint validation are necessary to establish their role in standard care algorithms.
The regulatory landscape for LBPs and defined microbial therapies is also evolving. In the United States, the Food and Drug Administration classifies LBPs as biological products, subject to investigational new drug applications and rigorous manufacturing standards under Good Manufacturing Practice. In Europe, the European Medicines Agency has issued guidance for human medicinal products containing live organisms, but challenges remain around strain identity, stability, and consistency.
Finally, patient perception is another important factor to consider. Microbiome-based therapies are often seen as more “natural” or holistic, which may influence adherence and expectations. Effective communication about mechanisms, risks, and timelines will be essential in clinical deployment.
CONCLUSION AND FUTURE PERSPECTIVES
The field of microbiome research has undergone a paradigm shift, moving from observational associations to interventional strategies that leverage the therapeutic potential of gut microbes and their metabolites. In IBD, where long-term remission and mucosal healing remain elusive for many patients, microbiome-based interventions offer a novel mechanism of action that complements existing host-targeted therapies.
FMT has validated the concept that modulating the microbiota can induce clinical benefit. However, this type of treatment raises important ethical concerns related to donor rights, safety, and commercialization. Donors undergo rigorous screening and provide biological material that may ultimately be used to develop therapies with significant commercial value, yet questions about the ownership and control of donated microbiota remain unresolved. Informed consent must address not only immediate health risks but also the possibility of long-term clinical and commercial use of their biological material. Equitable donor selection is also essential, as strict eligibility criteria may systematically exclude certain populations, potentially introducing bias into the microbial profiles used for treatment. These concerns underscore the urgent need for clear, transparent policies on informed consent, benefit-sharing, and donor protection in the context of FMT. Despite its other inherent limitations, including variability, safety, and lack of standardization, FMT has paved the way for more sophisticated therapeutics. Defined microbial consortia and LBPs bring greater reproducibility, safety, and regulatory clarity. Similarly, single-strain products such as F. prausnitzii demonstrate that targeted immunomodulation is both feasible and effective. Postbiotics also represent an attractive strategy, although they have mostly not yet reached the clinical stage.
Future therapeutic strategies will likely integrate microbiome-based products with immunosuppressants or biologics to enhance efficacy and reduce side effects. This combinatorial approach may enable precision medicine in IBD, with treatments tailored to an individual’s microbial and immunological profile. To achieve this vision, substantial challenges must be addressed: scalable manufacturing, validated biomarkers for response prediction, long-term safety data, and streamlined regulatory approval paths.
Furthermore, microbiome research must extend beyond bacteria to include viromes, mycobiomes, and the interplay with host genetics and diet. Advances in computational biology, synthetic ecology, and single-cell multiomics will be critical in unraveling this complexity. Interdisciplinary collaboration between gastroenterologists, microbiologists, immunologists, and data scientists will be essential to translate laboratory findings into durable clinical outcomes.
In conclusion, the gut microbiota represents a promising frontier in the management of IBD. While hurdles remain, continued innovation and clinical validation may transform microbiome therapeutics from experimental adjuncts to mainstream treatment modalities. Besides the aim of restoring ecological balance, strategies taking advantage of microbiome-derived compounds to act on host cells in a more common pharma development framework are attractive. Indeed, from a purely medical perspective, the only objective is to restore the health of the patient. Whether achieving this objective is associated or not with a supposedly improved gut microbiome should be considered secondary.
Notes
Funding Source
Sokol H received funding from the European Research Council (ERC, ENERGISED, ERC-2021-COG-101043802) and MSDAVENIR.
Conflict of Interest
Sokol H reports lecture fees, board membership, or consultancy from Carenity, AbbVie, Astellas, Danone, Ferring, Fresenius, Mayoly Spindler, MSD, Novartis, Roche, Tillots, Enterome, BiomX, Takeda, Lilly, Sanofi, Viatris, Galapagos, LFB, Janssen, Biocodex, has stocks from Enterome and is co-founder of Exeliom Biosciences. Except for that, no potential conflict of interest relevant to this article was reported.
Data Availability Statement
Not applicable.
Author Contributions
Writing and approval of the final manuscript: Rolhion N, Sokol H.