# Emerging Therapeutic Approaches for Modulating the Intestinal Microbiota

**Authors:** Ilaria Cosimato, Annalisa Brescia, Gianluigi Franci, Vincenzo Casolaro, Veronica Folliero

PMC · DOI: 10.3390/pharmaceutics18020197 · 2026-02-03

## TL;DR

This paper reviews new ways to change gut microbes to improve health, focusing on therapies like fecal transplants and bacteriophages.

## Contribution

The paper provides an updated overview of novel microbiota-targeted therapies, including FMT, BCT, phage therapy, and OMVs.

## Key findings

- FMT is effective for treating recurrent C. difficile infections and is being explored for IBD and IBS.
- BCT offers a standardized alternative to FMT with early clinical success.
- Phage therapy and OMVs show promise for targeted microbial modulation but require more clinical validation.

## Abstract

Background/Objectives: The gut microbiota is increasingly recognized as a key determinant of human health, playing a vital role in metabolism, immunity, and disease susceptibility. Dysbiosis, or microbial imbalance, is associated with gastrointestinal disorders such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), and Clostridioides difficile infection (CDI), as well as extraintestinal conditions, including obesity, cardiovascular disease, and neuropsychiatric disorders. This review aims to provide an updated overview of emerging therapeutic strategies to modulate the gut microbiota to restore eubiosis and improve health outcomes. Methods: A narrative review of recent literature was conducted, focusing on preclinical and clinical studies investigating microbiota-targeted therapies. The review primarily covers innovative interventional approaches, including fecal microbiota transplantation (FMT), bacterial consortium transplantation (BCT), bacteriophage therapy and outer membrane vesicles (OMVs). Results: Evidence supports the role of probiotics, prebiotics, and synbiotics in remodeling microbial communities and improving host health, although their effects may be strain- and context-dependent. FMT has demonstrated high efficacy in the treatment of recurrent Clostridium difficile infections and is being studied for IBD, IBS and extraintestinal diseases, following the recent Food and Drug Administration approval of the first commercial FMT products. BCT offers a standardized alternative to donor-derived material, with early clinical successes such as FDA-approved SER-109. Phage therapy and OMVs represent promising frontiers, offering targeted microbial modulation and interactions with the immune system, although clinical data remain limited. Conclusions: Emerging gut microbiota modulation strategies offer new perspectives for precision medicine and could transform the prevention and treatment of many diseases, but further studies are needed to ensure their safety, standardization, and clinical application.

## Linked entities

- **Diseases:** irritable bowel syndrome (MONDO:0005052), inflammatory bowel disease (MONDO:0005265), obesity (MONDO:0011122), cardiovascular disease (MONDO:0004995)
- **Species:** Clostridioides difficile (taxon 1496)

## Full-text entities

- **Genes:** IGHE (immunoglobulin heavy constant epsilon) [NCBI Gene 3497] {aka IgE}, TNF (tumor necrosis factor) [NCBI Gene 7124] {aka DIF, IMD127, TNF-alpha, TNFA, TNFSF2, TNLG1F}, OCLN (occludin) [NCBI Gene 100506658] {aka BLCPMG, PPP1R115, PTORCH1}, IL10 (interleukin 10) [NCBI Gene 3586] {aka CSIF, GVHDS, IL-10, IL10A, TGIF}, AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 207] {aka AKT, PKB, PKB-ALPHA, PRKBA, RAC, RAC-ALPHA}, IL1A (interleukin 1 alpha) [NCBI Gene 3552] {aka IL-1 alpha, IL-1A, IL1, IL1-ALPHA, IL1F1}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, INS (insulin) [NCBI Gene 3630] {aka IDDM, IDDM1, IDDM2, ILPR, IRDN, MODY10}, CLEC7A (C-type lectin domain containing 7A) [NCBI Gene 64581] {aka BGR, CANDF4, CD369, CLECSF12, DECTIN1, SCARE2}, PDCD1 (programmed cell death 1) [NCBI Gene 5133] {aka ADMIO4, AIMTBS, CD279, PD-1, PD1, SLEB2}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 4513] {aka COII, MTCO2}, IL15 (interleukin 15) [NCBI Gene 3600] {aka IL-15}, MMP2 (matrix metallopeptidase 2) [NCBI Gene 4313] {aka CLG4, CLG4A, MMP-2, MMP-II, MONA, TBE-1}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, FOXP3 (forkhead box P3) [NCBI Gene 50943] {aka AIID, DIETER, IPEX, JM2, PIDX, XPID}, NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, mucin [NCBI Gene 100508689], CARD9 (caspase recruitment domain family member 9) [NCBI Gene 64170] {aka CANDF2, IMD103, hCARD9}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, MMP9 (matrix metallopeptidase 9) [NCBI Gene 4318] {aka CLG4B, GELB, MANDP2, MMP-9}, GADD45A (growth arrest and DNA damage inducible alpha) [NCBI Gene 1647] {aka DDIT1, GADD45}, IL6 (interleukin 6) [NCBI Gene 3569] {aka BSF-2, BSF2, CDF, HGF, HSF, IFN-beta-2}, CLDN1 (claudin 1) [NCBI Gene 9076] {aka CLD1, ILVASC, SEMP1}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, IL2 (interleukin 2) [NCBI Gene 3558] {aka IL-2, TCGF, lymphokine}, HCRT (hypocretin neuropeptide precursor) [NCBI Gene 3060] {aka NRCLP1, OX, PPOX}, CD274 (CD274 molecule) [NCBI Gene 29126] {aka ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1}, IL5 (interleukin 5) [NCBI Gene 3567] {aka EDF, IL-5, TRF}, IL13 (interleukin 13) [NCBI Gene 3596] {aka IL-13, P600}, RELA (RELA proto-oncogene, NF-kB subunit) [NCBI Gene 5970] {aka AIF3BL3, CMCU, NFKB3, p65}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, IL9 (interleukin 9) [NCBI Gene 3578] {aka HP40, IL-9, P40}, CXCL2 (C-X-C motif chemokine ligand 2) [NCBI Gene 2920] {aka CINC-2a, GRO2, GROb, MGSA-b, MIP-2a, MIP2}, NFKBIA (NFKB inhibitor alpha) [NCBI Gene 4792] {aka EDAID2, IKBA, MAD-3, NFKBI}, TJP1 (tight junction protein 1) [NCBI Gene 7082] {aka ZO-1}, IL4 (interleukin 4) [NCBI Gene 3565] {aka BCGF-1, BCGF1, BSF-1, BSF1, IL-4}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}
- **Diseases:** skin diseases (MESH:D012871), injury to (MESH:D014947), neurodegenerative disorders (MESH:D019636), extraintestinal diseases (MESH:D004194), autoimmune and inflammatory conditions (MESH:D007249), cirrhosis (MESH:D005355), metabolic syndrome (MESH:D024821), liver cirrhosis (MESH:D008103), abdominal pain (MESH:D015746), edema (MESH:D004487), asthma (MESH:D001249), neuropsychiatric conditions (MESH:D001523), diabetes (MESH:D003920), Dysbiosis (MESH:D064806), cancer (MESH:D009369), fatigue (MESH:D005221), dermatitis (MESH:D003872), overweight (MESH:D050177), diarrhea (MESH:D003967), autoimmune diseases (MESH:D001327), obese (MESH:D009765), non-small cell lung cancer (MESH:D002289), autoinflammation (MESH:D056660), metabolic diseases (MESH:D008659), connective tissue diseases (MESH:D003240), bacterial colonization (MESH:D015179), Gut-Associated Diseases (MESH:C536735), CDI (MESH:D003015), rheumatoid arthritis (MESH:D001172), toxicity (MESH:D064420), weight loss (MESH:D015431), food allergy (MESH:D005512), insulin resistance (MESH:D007333), CD (MESH:D003424), infection (MESH:D007239), cardiovascular disease (MESH:D002318), gastrointestinal diseases (MESH:D005767), metabolic and immune dysfunction (MESH:D007154), Colitis (MESH:D003092), gastrointestinal tract (MESH:D005770), allergies (MESH:D004342), constipation (MESH:D003248), IBS (MESH:D043183), OMVs (MESH:D015433), type 2 diabetes (MESH:D003924), bacterial (MESH:D001424), adiposity (MESH:D018205), depressed (MESH:D003866), mucosal damage (MESH:D052016), IBD (MESH:D015212), UC (MESH:D003093), allergic and other chronic diseases (MESH:D002908), infectious diarrhea (MESH:D003141), bloating (MESH:C535647), immune and metabolic dysregulation (OMIM:614878), neurodevelopmental disorders (MESH:D002658), Intestinal Diseases (MESH:D007410)
- **Chemicals:** sugars (MESH:D000073893), docosapentaenoic acid (MESH:C026219), sucralose (MESH:C026285), acesulfame potassium (MESH:C006362), triglycerides (MESH:D014280), carbon (MESH:D002244), metronidazole (MESH:D008795), bilirubin (MESH:D001663), L-histidine (MESH:D006639), amoxicillin-clavulanate (MESH:D019980), vancomycin (MESH:D014640), Fe (MESH:D007501), piroxicam (MESH:D010894), aspartame (MESH:D001218), vitamin A (MESH:D014801), meropenem (MESH:D000077731), Metformin (MESH:D008687), gluconate (MESH:C030691), malate (MESH:C030298), ceramide (MESH:D002518), gentamicin (MESH:D005839), xanthosine (MESH:C005893), retinoic acid (MESH:D014212), rifaximin (MESH:D000078262), D-glycerate-2-phosphate (-), T4 (MESH:D013974), polydextrose (MESH:C033375), melatonin (MESH:D008550), bile acid (MESH:D001647), NO (MESH:D009614), putrescine (MESH:D011700), TCA (MESH:D014238), propionate (MESH:D011422), FAD (MESH:D005182), creatine (MESH:D003401), fatty acids (MESH:D005227), Butyrate (MESH:D002087), nicotinic acid (MESH:D009525), GMP (MESH:C066524), LPS (MESH:D008070), lipids (MESH:D008055), sucrose (MESH:D013395), purine (MESH:C030985), DSS (MESH:D016264), prebiotics (MESH:D056692), mannitol (MESH:D008353), glucose (MESH:D005947), creatinine (MESH:D003404), Mg (MESH:D008274), trehalose (MESH:D014199), stearoyl ethanolamide (MESH:C466089), SCFA (MESH:D005232), heavy metals (MESH:D019216), Ca (MESH:D002118), MP (MESH:D000080545), reactive oxygen species (MESH:D017382), cytidine (MESH:D003562), alcohol (MESH:D000438), fumarate (MESH:D005650)
- **Species:** Escherichia coli (E. coli, species) [taxon 562], Acidaminococcus intestini (species) [taxon 187327], Bifidobacterium longum (species) [taxon 216816], Candida albicans (species) [taxon 5476], Klebsiella pneumoniae (species) [taxon 573], Lacticaseibacillus rhamnosus (species) [taxon 47715], Anaerotruncus (genus) [taxon 244127], Helicobacter (genus) [taxon 209], Peptococcus (genus) [taxon 2740], Cricetus cricetus (black-bellied hamster, species) [taxon 10034], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932], Malassezia restricta (species) [taxon 76775], Pseudocoprococcus catus (species) [taxon 116085], Mediterraneibacter gnavus (species) [taxon 33038], Mus musculus (house mouse, species) [taxon 10090], Pseudomonas aeruginosa (species) [taxon 287], Eshraghiella crossota (species) [taxon 45851], Parabacteroides distasonis (species) [taxon 823], Pseudomonadota (proteobacteria, phylum) [taxon 1224], Barnesiella intestinihominis (species) [taxon 487174], Veillonella (genus) [taxon 29465], Eubacterium ramulus (species) [taxon 39490], [Clostridium] scindens (species) [taxon 29347], Enterobacterales (order) [taxon 91347], Penicillium (genus) [taxon 5073], Clostridia (class) [taxon 186801], Roseburia (genus) [taxon 841], Allobaculum (genus) [taxon 174708], Bacteroides uniformis (species) [taxon 820], Clostridium butyricum (species) [taxon 1492], Enterococcus (genus) [taxon 1350], Lacticaseibacillus paracasei (species) [taxon 1597], Bacteroides ovatus (species) [taxon 28116], Sutterella (genus) [taxon 40544], Fusicatenibacter saccharivorans (species) [taxon 1150298], Danio rerio (leopard danio, species) [taxon 7955], Lacticaseibacillus casei (species) [taxon 1582], Lactobacillus gasseri (species) [taxon 1596], Bilophila (genus) [taxon 35832], Akkermansia muciniphila (species) [taxon 239935], Lentilactobacillus parabuchneri (species) [taxon 152331], Alloprevotella (genus) [taxon 1283313], Clostridioides difficile (species) [taxon 1496], Faecalibacterium prausnitzii (species) [taxon 853], Homo sapiens (human, species) [taxon 9606], Lactobacillus kefiranofaciens subsp. kefirgranum (subspecies) [taxon 190906], Alistipes (genus) [taxon 239759], Bacteroides fragilis (species) [taxon 817], Enterorhabdus (genus) [taxon 580024], [Clostridium] leptum (species) [taxon 1535], Lactobacillus acidophilus NCFM (strain) [taxon 272621], Rhodococcus (genus) [taxon 1661425], Escherichia coli Nissle 1917 (strain) [taxon 316435], Segatella copri (species) [taxon 165179], Streptococcus gallolyticus (species) [taxon 315405], Blastocystis (genus) [taxon 12967], Methanobrevibacter smithii (species) [taxon 2173], Enterobacteriaceae (enterobacteria, family) [taxon 543], Shigella (genus) [taxon 620], Entamoeba (genus) [taxon 5758]
- **Cell lines:** Caco-2 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0025), C57BL/6 — Mus musculus (Mouse), Transformed cell line (CVCL_C0MU), HT29 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0320)

## Figures

3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12944148/full.md

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Source: https://tomesphere.com/paper/PMC12944148