The increased prevalence of pathobionts in the gut correlates not only with lipopolysaccharide diffusion but also with the expression of various virulence factors, ultimately contributing to carcinoma development. Contemporary research approaches cancer development from novel perspectives, though bacterial and viral infections remain associated with approximately 15% of cancer cases. Viral pathogens initiate tumorigenesis through inflammatory processes, tumor growth stimulation, and host genome integration of active oncogenes that promote immunosuppression (Xiao et al., 2025). GM alterations mediated by virulence factors, particularly through β-catenin signaling, can stimulate excessive growth of both normal and adenoma cells. The specific virulence factor Fusobacterium adhesin A facilitates this process while simultaneously promoting the proliferation of Fusobacterium nucleatum, a microorganism associated with increased epithelial permeability and microbial invasion. Such compositional shifts in intestinal bacteria also introduce the carcinogenic and genotoxic potential of Fusobacteria phylum members (Jin et al., 2024).

The scientific understanding of CRC has evolved from focusing on specific bacterial associations to recognizing broader GM dysbiosis patterns. Current evidence strongly suggests the adenoma-cancer cascade correlates with elevated Fusobacterium prevalence. Experimental manipulation of these microbial populations using metronidazole demonstrated reduced colon tumor growth in murine models, indicating potential biomarker applications for CRC (Wang et al., 2023). Beyond Fusobacterium, multiple bacterial species including Lactobacillus spp., Streptococcus bovis, Porphyromonas spp., and Roseburia spp. show associations with polyp size progression. Additionally, CRC patients exhibit decreased Firmicutes levels in both tumor biopsies and stool samples, though the magnitude of this decrease varies across studies and populations. While these observations require further validation, the diminished production of SCFAs, resulting from reduced Faecalibacterium and Roseburia populations during CRC development, leads to butyrate deficiency. Consequently, the gastrointestinal environment loses crucial anti-carcinogenic properties, including the induction of tumoral cell apoptosis, T-cell mediation capacity, and proliferation inhibition mechanisms (Ma et al., 2022).

Patients with CDI consistently demonstrate elevated Proteobacteria levels alongside reduced Bacteroidetes and Firmicutes phyla populations (Spigaglia, 2024). While the mere presence of toxigenic Clostridium difficile in the host proves insufficient as an intestinal inflammation biomarker, the TcdA and TcdB enzymes that are secreted during the vegetative growth phase substantially compromise cytoskeleton integrity (Paparella et al., 2021). These glycosyltransferase enzymes modify cytoplasmic Rho GTPases, with the secreted toxins serving as primary pathogenic agents that initiate intestinal tract infections (Paparella et al., 2022). Moreover, antibiotics targeting Clostridium difficile paradoxically promote Enterobacteriaceae proliferation while diminishing Lachnospiraceae abundance, as evidenced by animal model studies. Although prematurely declaring Clostridium difficile gut expansion as a biomarker for Enterobacteriaceae-dominated microbiota would be speculative, this phenomenon has been documented in elderly human subjects. CDI patients admitted to intensive care units exhibit characteristic microbial shifts: reduced diversity in Cryptomycota, Deferribacteres, and Acetothermia taxa, along with decreased Saccharomycetes and Clostridia genera, contrasted by overgrowth of Cryptomycota, Acetothermia, and Deferribacteres (Wang et al., 2020). Mouse model studies utilizing Clostridium difficile strain VPI 10463 spores revealed microbial diversity improvements, particularly demonstrating positive correlation between Akkermansia muciniphila and Bacteroides fragilis treatment outcomes (Wu et al., 2022). Established CDI biomarkers include depleted populations of Lachnospiraceae, Bacteroides, and Ruminococcaceae (Berkell et al., 2021).

The incidence of NEC in pediatric populations is promoted by immature immunity, enteral feeding practices, bottle-feeding, and resulting dysbiosis. This pathological condition primarily triggers gut inflammation in premature newborns, with particularly high susceptibility observed in infants weighing less than 1500g at birth, demonstrating a mortality rate approaching 30%. While various interventions have been explored to alleviate or eliminate NEC, several proposed mechanisms including breast milk lactoferrin and immunoglobulins, oral supplementation with prebiotics (galacto-oligosaccharide, lactose, and fructose-oligosaccharide), and probiotic Bifidobacterium breve BBG-001 - have proven ineffective. The precise etiology of NEC remains at preliminary stages of investigation. Enterobacteriaceae associated with NEC produce hexacylated lipopolysaccharides that function as potent pyrogens, inducing inflammatory responses mediated through TLR4 signaling pathways (Gomart et al., 2021). While most research has focused on extrauterine factors, emerging evidence suggests intrauterine factors such as antenatal antibiotic exposure may also confer NEC risk (Klerk et al., 2022).

The GM of low-birth-weight preterm infants appears linked to neurodevelopmental impairment through dysbiosis-mediated mechanisms involving the gut-brain axis. This connection is increasingly recognized as a potential diagnostic marker for NEC alongside late-onset sepsis (Duan et al., 2020). The gut-brain axis facilitates bidirectional communication, and in NEC, systemic inflammation and microbial metabolites may impact the developing brain, though the precise molecular pathways require further elucidation. The primary microbial determinant of NEC in preterm infants appears to be intestinal Gammaproteobacteria, which suppress Bifidobacterium populations that would normally dominate in breastfed term infants. Prolonged antibiotic use, known to increase NEC risk, likely exacerbates this reduction in bifidobacterial counts. Furthermore, activation of TLR4 pathways appears to contribute to the suppression of Bifidobacterium colonization in preterm neonates (Huang et al., 2025).

Among chronic gastrointestinal disorders, IBD, encompassing Crohn’s disease (CD) and ulcerative colitis (UC), remains poorly understood etiologically. Recent investigations have associated IBD pathogenesis with GM alterations and modifications in tumor necrosis factor and interleukin signaling pathways (Xie et al., 2025). IBD patients typically exhibit reduced Firmicutes alongside elevated Proteobacteria and Actinobacteria populations. Notably, studies in genetically susceptible mice indicate dysbiosis may precede overt inflammation. Firmicutes prausnitzii, a bacterial species with important anti-inflammatory properties and significant SCFA production capacity, demonstrates particularly low abundance in IBD patients. This reduction is especially pronounced in CD cases. In contrast, Enterococcus, Lactobacillus, and Bifidobacterium species may be dominant in certain IBD patient cohorts (Tamburini et al., 2024).

Current evidence regarding microbiota dysbiosis patterns in IBD subtypes remains inconsistent, necessitating further research before clinical applications can be considered (Santana et al., 2022). For instance, while CD correlates with generally low Bacteroides levels, UC dysbiosis specifically associates with increased Bacteroides fragilis and Bacteroides vulgatus populations (Nomura et al., 2021; Tharu et al., 2024). Other studies report Bifidobacterium and Lactobacillus dominance in UC groups, contrasted by Fusobacterium and Escherichia-Shigella predominance in CD cohorts (Zhang et al., 2020; Scanu et al., 2024). E. coli Nissle 1917, an alternative probiotic to mesalazine for UC treatment, exemplifies this by outcompeting other E. coli strains for iron during inflammation (Zhao et al., 2022; Wang Y. et al., 2025).

Research has established the oncogenic properties of Helicobacter pylori (H. pylori), demonstrating its association with malignant transformation in gastric tissues. Both normal and pathogenic H. pylori strains increase adenocarcinoma risk by inducing chronic inflammation and disrupting β-catenin signaling in epithelial cells (Wang et al., 2024b). Herbal formulations demonstrate significant effects on GM by enhancing postoperative gastrointestinal function recovery, improving tumor response, and conferring better performance status while reducing adverse effects (Xu et al., 2022). The established pathogenesis of gastric cancer involves disordered innate and adaptive immunity, imbalanced GM colonization, mucosal barrier dysfunction, genetic variations, and environmental and personalized risk factors. Chinese herbal products such as Xiaoyaosan modulate GM composition by increasing Lactobacillus, Proteus, and Bacteroides abundance while reducing Rickerella and Desulfovibrio, serving as biomarkers for gastric environment modulation (Zhao et al., 2021). The adenoma-carcinoma sequence in gastric carcinogenesis typically shows reduced anti-inflammatory bacteria and SCFA-producing bacteria alongside increased pro-inflammatory species. Bacterial-induced cytotoxic effects causing DNA damage have been well documented. However, non-invasive screening methods based on specific microbiota markers remain necessary for clinical applications (Wu et al., 2024).

Beyond H. pylori, the most prevalent bacterial pathogen associated with GC reduced gastric acidity caused by H. pylori enable colonization by other potentially carcinogenic microbiota. Certain bacteria thriving in hypoacidic conditions, including Lactobacillus, Neisseria, E. coli, and Staphylococcus, produce carcinogenic N-nitroso compounds through nitrogen compound conversion. Notably, Lactobacillus-mediated increases in gastric lactic acid concentration promote inflammation while providing energy for tumor angiogenesis (McDermott et al., 2000). H. pylori induces damage through dysregulation of DNA transcription factors and reactive nitrogen intermediate generation, triggering inflammatory cascades in gastric mucosa (Nadeem et al., 2020). Studies in Chinese populations identified Dialister pneumosintes, Peptostreptococcus stomatis, Parvimonas micra, Streptococcus anginosus, and Slackia exigua as significantly enriched bacterial taxa in GC cases (Yang et al., 2020). Korean population studies identified H. pylori, Propionibacterium acnes, and P. copri as the strongest GC risk factors, while Lactococcus lactis appeared protective (Leonard et al., 2020). Animal models of GC showing Proteobacteria and Actinobacteria abundance corroborate findings in human gastric carcinogenesis (Coker et al., 2018).

The well-established association between gastroenteritis events and IBS confirms that gut dysbiosis leading to abnormal intestinal immune activation and subsequent inflammation represents a significant risk factor. Fermentable oligo-, di-, and monosaccharides and polyols reduce luminal bacteria populations (Bifidobacterium and Faecalibacterium prausnitzii) while controlling dysbiosis at lower concentrations, though their long-term microbiome effects require further investigation. Despite conflicting study results, IBS patients consistently demonstrate increased Firmicutes and decreased Bacteroidetes (Pittayanon et al., 2019; Napolitano et al., 2023).

Bacteriocins, which are toxic proteins and peptides secreted by gut bacteria, represent a competitive survival mechanism targeting rival taxa for nutrient and biomolecule utilization. These secretions include short antimicrobial peptides called microcins. Bacteriocin-expressed immunity proteins provide protection against toxic effects within the producing bacterial populations (Milajerdi et al., 2021).

Bacteriocin production is well-documented in Enterobacteriaceae, such as colicins in E. coli and pesticins in Yersinia pestis, often expressed under nutrient stress (Darbandi et al., 2022). Their activity can exacerbate microbial population shifts during inflammation by inducing genotoxic and oxidative stress in susceptible bacteria. Beyond these, other forms like Pseudomonas pyocins and mechanisms in Gram-positive bacteria, such as Enterococcus faecalis, utilize diverse strategies like nucleic acid cleavage or plasmid-borne competition (Virolle et al., 2020) (Table 1).

A comparative analysis of the gastrointestinal disorders discussed reveals a recurring pattern of gut microbiota dysbiosis, commonly characterized by a depletion of beneficial, SCFA-producing bacteria, often within the Firmicutes phylum, and a concomitant expansion of pro-inflammatory taxa, frequently Proteobacteria. This shared ecological disturbance underscores a fundamental breakdown in microbial homeostasis that predisposes the gastrointestinal tract to disease. However, this common backdrop gives rise to distinct, disorder-specific pathological mechanisms through unique “microbiota-molecule-host” interactions. For instance, carcinogenesis in CRC is significantly driven by Fusobacterium nucleatum-mediated activation of the β-catenin pathway, while the pathology of CDI is uniquely defined by direct toxin-induced damage. Similarly, NEC hinges on hyperactive TLR4 signaling in response to lipopolysaccharides, and IBD involves NF-κB pathway activation and a loss of immune tolerance.

These distinct mechanistic pathways, in turn, dictate the application of targeted therapeutic strategies. While FMT serves as a broad-spectrum intervention to reset the microbial community in CDI, other disorders require more nuanced approaches. These include phage therapy or prebiotics to target specific pathobionts like F. nucleatumin CRC, H. pylori and herbal formulations to modulate the carcinogenic microenvironment in gastric cancer, and biologic therapies or engineered microbes to counter specific immune dysregulation in IBD. Even in IBS, where dysbiosis is subtler, interventions like the low FODMAP diet aim to correct metabolically driven symptoms. Thus, the clinical management of gastrointestinal diseases is increasingly informed by an understanding of both the common themes of dysbiosis and the specific microbial drivers and mechanisms underlying each condition.

Beyond conventional probiotics and prebiotics, several novel therapeutic strategies are under active investigation. Phage therapy offers a highly targeted approach to eliminate specific pathobionts. For instance, a 2025 clinical trial demonstrated the efficacy of a phage cocktail in selectively reducing Fusobacterium nucleatum loads in CRC patients, thereby remodeling the tumor microenvironment and enhancing response to chemotherapy (Ding et al., 2025; Wu et al., 2025).

Engineered microbes, or synthetic probiotics, represent a frontier in precision microbiome medicine. These are genetically modified bacterial chassis (E. coli Nissle 1917) designed to secrete therapeutic molecules, such as antimicrobial peptides (microcins) or immunomodulatory proteins, directly within the gut niche. While promising, their clinical translation requires rigorous safety assessments to address concerns regarding horizontal gene transfer and long-term ecological impact (Zhang et al., 2025).

Furthermore, the distinction between live probiotics and their inactivated counterparts, or postbiotics, is of growing clinical interest. Postbiotics, which include heat-killed microbes, cell-free supernatants, and purified microbial components (SCFAs, surface proteins), offer potential advantages in safety (no risk of translocation or antibiotic resistance gene transfer) and stability over live biotherapeutics. In IBD, certain postbiotic formulations have demonstrated efficacy comparable to live probiotics in inducing anti-inflammatory responses and enhancing barrier function, suggesting their utility in vulnerable patient populations (Calvanese et al., 2025).

To overcome the “one-size-fits-all” limitation, future therapies must move toward personalized GM modulation. This involves a multi-step pathway: First, baseline microbiota detection using 16S rRNA or shotgun metagenomic sequencing to establish key indicators like α/β-diversity and specific taxon abundances. Second, stratified intervention plans based on this profile; for example, IBD patients with a Firmicutes abundance below 30% might be prioritized for FMT, while those with high Ruminococcaceae could respond better to specific prebiotics. Finally, dynamic monitoring through repeated fecal metabolomics (tracking SCFA levels) or microbial sequencing is crucial for assessing response and adjusting therapy.

The gut ecosystem extends beyond bacteria to include fungi and viruses, which play critical roles in health and disease. Recent research underscores the significant role of fungal dysbiosis (mycobiota) in IBD pathogenesis, highlighting mechanisms such as immune activation via Dectin-1/CARD9/IL-17 pathways, fungal-bacterial interactions, and the potential of antifungal strategies and fungal-focused therapies (Chen et al., 2025). Fungi-bacteria interactions are increasingly implicated in GI disorders; for example, Candida overgrowth can exacerbate IBD by competing for nutrients with beneficial bacteria and directly stimulating pro-inflammatory responses (Ding et al., 2025). Conversely, phages (bacterial viruses) are key regulators of bacterial populations through targeted lysis of pathogens. An altered “virome” is noted in IBD and CRC, suggesting phages could be harnessed to precisely reshape the microbial community (Zhang et al., 2025). Beyond established strategies, emerging areas show considerable promise, including the role of GM in modulating immunotherapy outcomes for gastrointestinal cancers (Zuo et al., 2024), and the development of engineered microbial therapeutics and postbiotics, as discussed in Section 3.2.