Technologies systems biology, multiomics This review outlines the current state and recent progress in the use of engineered probiotics

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2025 and 2026, spanning 4 journals. Those papers have been cited 46 times in total.

Supporting evidence — 4 representative gaps

• Duloxetine as a gut-brain axis modulator in irritable bowel syndrome: neuroimmune, microbiota, and pharmacogenomic perspectives (2026) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi

  Although accumulating evidence supports the therapeutic role of duloxetine in IBS, several critical gaps remain to be addressed. Future studies should aim to: Mechanistic Insights: Conduct preclinical investigations into duloxetine’s modulation of GBA, particularly its effects on CRH-5HT-NA signaling, microglial activation, and cytokine regulation. Mapping these pathways will clarify whether its benefits extend beyond neurotransmit- ter reuptake inhibition to neuroimmune and microbiota- mediated mechanisms. Microbiota Interactions: Explore how duloxetine influ- ences gut microbial composition and short-chain fatty acid (SCFA) production. Given the role of dysbiosis in IBS, research integrating microbiota profiling with clini- cal response would provide valuable precision-based insights. Microbiome-responsive delivery strategies: Beyond using the microbiome as a biomarker of response, future stud- ies may also explore whether it can be actively lever- aged as a therapeutic tool for duloxetine delivery in IBS. Emerging microbiome-active drug delivery systems (MADDS) are designed to use microbial stimuli, such as bacterial enzymes, metabolites, biofilms, local pH or chemical gradients, and receptor-mediated interactions, to trigger site-specific drug release or activation. In IBS, such microbiota-responsive platforms could theoreti- cally improve duloxetine targeting to intestinal regions characterized by dysbiosis, low-grade inflammation, or altered microbial metabolism, while potentially reduc- ing systemic exposure and adverse effects. However, this concept remains experimental, and microbiota-triggered duloxetine delivery has not yet been validated in IBS. Future work should therefore investigate whether dulox- etine can be incorporated into microbiome-responsive formulations and whether such approaches improve GBA modulation, tolerability, and clinical outcomes compared with conventional systemic administration. Biomarker-Guided Trials: Large-scale, longitudinal clini- cal trials should stratify patients by IBS subtype, comorbid depression, and genetic polymorphisms (e.g., CYP2D6, CYP1A2). Incorporating biomarkers such as serum cytokines, cortisol rhythms, and fecal microbiota signatures could refine patient selection and optimize dosing strategies. Comparative and Combination Studies: Head-to-head clini- cal trials comparing duloxetine with SSRIs, TCAs, and gut- directed therapies (e.g., rifaximin, probiotics, dietary inter- ventions) are needed. Evaluating combination regimens, particularly duloxetine with low-FODMAP diets or micro- biota-targeted interventions, may reveal synergistic effects. Neuroimaging Approaches: Functional MRI and PET studies could provide translational evidence on how duloxetine alters central circuits involved in pain percep- tion, stress regulation, and visceral hypersensitivity. Naunyn-Schmiedeberg's Archives of Pharmacology pain-predominant symptoms. Its dual action on serotonergic and noradrenergic signaling, together with emerging evi- dence for anti-inflammatory and neuroimmune modulation, positions it as a potential GBA regulator. Compared with other antidepressants, duloxetine demonstrates favorable tol- erability and efficacy in improving both gastrointestinal and psychological symptoms. Nonetheless, the precise molecular and microbiota-mediated mechanisms remain incompletely defined, and robust, biomarker-driven clinical trials are war- ranted. Ultimately, integrating pharmacogenomics, micro- biota profiling, and neuroimaging approaches may pave the way for precision medicine strategies, allowing duloxetine to be positioned more effectively in the management of IBS. Author contributions A.M.M.: Visualization, Writing original draft, Writing-review and editing, Software, Supervision. M.R.: Writing and revision of the manuscript.H.M.A., N.R.H., T.J.A., A.K.A., A.I.A.: Collected the related research literature and papers and drafted the manuscript. G.E.B.: Conceptualization. All authors have approved and read the final manuscript. The authors confirm that no paper mill and artificial intelligence was used.  Data availability All source data for this work (or generated in this study) are available upon reasonable request.

  generalfuture work
  Keywords: duloxetine microbiota whether microbiome delivery trials future modulation effects mediated microbial clini responsive strategies biomarker
• Importance of the inflammasome in gut-brain axis: from pathological driver to therapeutic target (2026) · Inflammopharmacology · doi

  Despite the robust preclinical data linking the inflamma- some, the gut microbiome, and neurological outcomes, trans- lating these findings into viable human therapeutics faces several substantial hurdles that must direct future research paradigms. The reliance on murine models presents a fun- damental challenge. The baseline immunological profile, specifically the genetic regulation and activation thresholds of the inflammasome, differs significantly between mice and humans. Human macrophages can sometimes bypass the strict dual signal requirement necessary in murine cells, complicating the direct translation of inhibitor efficacy. Standard experimental models often utilize acute, highly toxic compounds (for example, DSS for colitis, MPTP for Parkinson’s disease) to trigger inflammasome activation. These models fail to accurately recapitulate the low-grade, decades-long progression of chronic neuroinflammation and dysbiosis characteristic of human neurodegenerative and metabolic diseases. Unlike SPF mice housed in con- trolled environments, the human microbiome is vastly heterogeneous. Variables such as geography, long-term dietary habits, stress, and circadian disruptions drastically alter microbial composition. A major limitation in clinical cohort studies is the failure to account for routine polyphar- macy. Common medications, notably metformin, proton pump inhibitors, and frequent antibiotic use, profoundly shift the microbiome and alter systemic immune baselines, masking or mimicking specific microbiota-inflammasome interactions. Moreover, there are inconsistencies in method- ologies. The frequent use of 16S rRNA sequencing provides only taxonomic data, whereas functional mapping requires shotgun metagenomics and metabolomics. Standardizing multi-omics approaches is a critical necessity for future studies. Currently, diagnosing central inflammasome activation in living patients is exceedingly difficult. While peripheral markers, such as serum IL-1β, IL-18, or circulating cas- pase-1 indicate systemic inflammation, they do not reliably reflect microglial inflammasome status due to the restric- tive nature of the BBB. There is an urgent clinical need for the development and validation of advanced neuroimaging tools, specifically Positron Emission Tomography (PET) radiotracers that can selectively bind to activated inflam- masome complexes or specific reactive microglial states in vivo. To bridge the translational gap, we believe, the field must embrace models utilizing germ-free mice colonized with the microbiota of specific human cohorts with clini- cally important phenotype to study patient-specific disease trajectories. Moreover, the integration of multi-omics will pave the way for personalized medicine, where a patient’s microbial metabolome and systemic inflammatory mark- ers are profiled to determine if they are ideal candidates for specific inflammasome inhibitors, postbiotics, or precision microbial consortia.

  generalfuture work
  Keywords: inflammasome human specific models microbiome activation mice microbial systemic must direct future murine specifically disease
• Gut Microbiota-Derived Metabolites in Atherosclerosis: Pathways, Biomarkers, and Targets (2025) · International Journal of Molecular Sciences · cited 27× · doi

  This review consolidates current evidence highlighting the gut microbiota as a central player in atherosclerosis, a multifaceted cardiovascular disease with mechanisms still under exploration. Through the production of metabolites such as trimethylamine N-oxide (TMAO), lipopolysaccharides (LPS), short-chain fatty acids (SCFAs), and bile acids, the gut microbiota contributes to vascular inflammation, endothelial dysfunction, and immune modulation. These microbial products not only provide mechanistic insight but also hold promise as diagnostic biomarkers and therapeutic targets. Future research must move beyond association and address causality and clinical translation. Large-scale longitudinal and interventional studies are needed to validate microbiota-derived metabolites as biomarkers of cardiovascular risk. The integration of multi-omics technologies (metagenomics, metabolomics, transcriptomics) with clini- cal phenotyping may help identify robust microbial signatures. A major frontier lies in the development of personalized microbiota-based therapies, including tailored dietary interventions, targeted pre/probiotics, and fecal microbiota transplantation adapted to patient-specific microbial and genetic profiles. Novel pharmacological strategies targeting microbial metabolism, such as TMAO inhibitors or bile acid receptor agonists, also warrant investigation in early-phase clinical trials. Despite major advances, significant knowledge gaps remain. First, while inhibition of TMAO production reduces atherosclerosis in preclinical models, it is unknown whether such strategies can reduce plaque burden or cardiovascular events in humans. Second, microbiota-derived biomarkers (TMAO, SCFAs, bile acids) show promise, but their clinical utility is limited by variability in assays, diet, and host genetics, requiring standardization and validation in prospective cohorts. Third, the role of emerging metabolites (e.g., indole derivatives, polyamines) is not fully understood, and their mechanistic contribution to vascular disease requires clarification. Fourth, the interplay between microbiota and the immune system is complex; recent findings suggest causal links, but how immune– microbiota crosstalk translates into human atherosclerosis remains uncertain. Finally, personalization is a major challenge, as diet, genetics, comorbidities, and drug use must be considered when designing therapeutic strategies. Ultimately, translating microbiota science into cardiovascular medicine will require personalized, mechanistically informed, and clinically validated approaches that integrate microbiome modulation into the broader framework of precision cardiology. Author Contributions: Conceptualization: M.T. and O.-M.S.; methodology: A.-G.B.; investigation: A.-K.T.-C.; writing—original draft: A.-G.B. and O.-M.S.; writing—review and editing: M.T. and A.-K.T.-C.; A.-K.T.-C. and M.T. contributed equally to this manuscript and share first authorship. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Data Availability Statement: Data are contained within the article. Conflicts of Interest: The authors declare no conflicts of interest.

  generalfuture work
  Keywords: microbiota cardiovascular tmao microbial atherosclerosis metabolites acids bile immune biomarkers clinical major strategies review disease
• Engineered probiotics for inflammatory bowel disease therapy: mechanisms, delivery strategies, and precision medicine (2026) · Frontiers in Microbiology · cited 19× · doi

  technologies systems biology, multiomics This review outlines the current state and recent progress in the use of engineered probiotics for treating IBD. Through genetic modification and synthetic biology, these probiotics produce various therapeutic molecules, regulating the balance of the gut microbiota, strengthening intestinal barrier function, and modulating immune responses (Steidler et al., 2000; Zhou et al., 2021). Notably, their development and clinical translation are increasingly empowered by ongoing advances (genomics, in transcriptomics, metabolomics), and artificial intelligence (AI), which enable more precise identification of patient-specific microbial and immune dysfunctions—an essential prerequisite for targeted IBD management. Engineered probiotics exhibit significant therapeutic potential for UC and CD, with three key advantages: targeted delivery to inflamed areas (lowering side effects in noninflamed regions; Sang et al., 2025), synergistic application with other therapies to potentially enhance efficacy, and the capacity for personalized interventions. Specifically, the integration of multiomics data and AI-driven analysis may decipher individual microbial–immune dysregulation patterns, thereby optimizing treatment outcomes and reducing adverse effects, although this requires further clinical validation (Abeltino et al., 2024; Li M. F. et al., 2024; Li M. M. et al., 2024). Despite their potential, the following critical challenges remain: improving the survival and colonization of engineered probiotics in the complex intestinal microenvironment; ensuring their long-term safety and stability without inducing irreversible perturbations to the host microbiota; and validating the accuracy, reliability, and generalizability of AI-powered predictive models for patient therapy responses. While systems biology and multiomics technologies offer promising approaches to address these issues, their practical implementation remains challenging. Thus, optimizing probiotic formulations to align with individual patient profiles, guided by

  generalfuture work
  Keywords: probiotics biology multiomics engineered immune patient technologies systems therapeutic microbiota intestinal responses clinical microbial targeted

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