Parabacteroides goldsteinii emerges as a central regulator of metabolic homeostasis across diverse pathological conditions, including obesity, MASLD, AFLD, and immune-mediated metabolic disorders (Figure 3). P. goldsteinii can upregulate the concentration of 7-Keto-LCA in the gut, which has been proven to be an FXR antagonist that promotes Wnt signaling, thereby facilitating the self-renewal of intestinal stem cells (Li et al., 2024b). Its therapeutic effects are mediated through remodeling of gut microbiota, regulation of bioactive metabolites (e.g., SCFAs, BAs), reinforcement of intestinal barrier function, and suppression of inflammatory cascades, positioning it as a promising probiotic candidate for microbiome-targeted interventions.

Parabacteroides goldsteinii functions as a putative beneficial bacterium, exerting therapeutic effects through gut microbiota modulation, intestinal barrier reinforcement, and subsequent attenuation of inflammatory responses and neurotransmitter balance restoration. Its bioactive components (e.g., LPS and zwitterionic polysaccharides) maintain anti-inflammatory activity post-inactivation (Lin et al., 2024). The link between neuropathology and chronic low-grade inflammation suggests P. goldsteinii could ameliorate symptoms through dual mechanisms: microbiota regulation and systemic inflammation reduction (Lin et al., 2022; Morel et al., 2023; Wei et al., 2024; Zeng et al., 2024).

Accumulating evidence in recent years has unveiled intricate connections between gut microbiota and various inflammation-associated disorders. Notably, P. goldsteinii has been identified as a putative probiotic agent, with documented ameliorative effects across multiple inflammatory conditions including but not limited to IBD, organ injury-related inflammation, cutaneous inflammation, infections, and COPD.

Recent studies establish P. goldsteinii as a central regulator in CRC continuum care through multistage modulation of the gut-liver immunity and microbial metabolism. Key mechanisms include:

(i) Synergistic restoration of gut microbiota homeostasis with Ophiocordyceps colitis-associated tumorigenesis (surpassing Cordyceps militaris efficacy), highlighting potential against CRC precursor lesions like IBD (Ji et al., 2021);

(ii) Enhanced anastomosis healing post-CRC surgery via anti-inflammatory activity, countering Alistipes onderdonkii- mediated impairment (Hajjar et al., 2023);

(iii) Inhibition of hepatic metastasis by driving KCs expansion, elucidating microbiota-immune cross-organ antitumor mechanisms (Yuan et al., 2022b);

(iv) Sex-biased abundance inversely correlating with pathogenic A. muciniphila in male CRC models, identifying gender-specific therapeutic targets (Wang et al., 2023); and

(v) Facilitation of 17 β-estradiol (E2) and anti-PD-L1 synergy by reversing immune checkpoint inhibitor resistance through microbiota remodeling (Song et al., 2023).

Notably, Schizophyllum commune polysaccharides indicate dual anti-tumor activity in glioblastoma models by enriching P. goldsteinii and upregulating ARHI expression, expanding host-microbe coevolution applications in cancer therapy (Zheng et al., 2024). Collectively, these findings confirm P. goldsteinii as a master microbial regulator in CRC management, proposing a microbiota-centric paradigm for precision oncology across prevention, metastasis suppression, and therapeutic optimization.

Parabacteroides goldsteinii bidirectionally modulates allergic disease progression through a metabolite-immune interplay. In allergy prevention, perinatal goat milk feeding enriches intestinal P. goldsteinii in neonatal mice, driving immune maturation of gut-associated lymphoid tissue and suppressing house dust mite-induced Th2 inflammation and reducing airway eosinophilic infiltration (highlighting microbiota-targeted dietary interventions’ potential) (Kao et al., 2020). However, its immunomodulatory effects exhibit context-dependent complexity: penicillin-induced P. goldsteinii expansion increases peripheral CD19 + B cell counts but disrupts CD4+/CD8+ T cell ratios, suggesting that microbiota-specific alterations may perturb immune homeostasis (Daniluk et al., 2017). Clinical studies further reveal ancestry-dependent functional divergence–elevated P. goldsteinii abundance in Black children with food allergies positively correlates with asthma risk, implicating host-microbe coevolution in allergic susceptibility (Mahdavinia et al., 2023). Supplementation with short-chain fructans (kestose) and inulin selectively enhances P. goldsteinii proliferation, potentiating SCFA production to alleviate ovalbumin -induced hypersensitivity via IL-4 inhibition and IL-10 induction (Takahashi et al., 2023). We hypothesize that these effects may be modulated by host genetics (e.g., FXR or GPR43 polymorphisms), habitual diet (fiber intake), and environmental factors (antibiotic exposure), which could account for observed inter-individual variability and warrant future stratified clinical trials. These findings collectively position P. goldsteinii as a metabolic orchestrating of allergic regulation, though mechanisms underlying ancestry-specific microbiota-immune crosstalk require systematic dissection through multi-omics approaches to enable clinical translation.

Parabacteroides goldsteinii mediates pivotal pathophysiological mechanisms role in the IBS (Yu et al., 2021). Red ginseng (RG) intervention significantly ameliorates intestinal hypersensitivity and anxiety-like behaviors in IBS murine models, demonstrating efficacy comparable to first-line clinical therapeutics. Mechanistic studies establish that these benefits require RG-induced enrichment of intestinal P. goldsteinii. Specifically, RG promotes P. goldsteinii proliferation to suppress pro-inflammatory cytokine (e.g., IL-1β) release while bidirectionally modulating key microbiota-gut-brain axis mediators–as demonstrated by corticosterone downregulation and c-Fos activation–thereby synergistically alleviating visceral pain and central nervous comorbidities (Yu et al., 2021). These findings position P. goldsteinii as a potential therapeutic target for IBS while offering a translational framework for neurogastroenterological interventions leveraging microbiota-host crosstalk.

The regulatory role of P. goldsteinii in systemic autoimmune diseases has garnered increasing attention. Studies have indicated that this bacterium and its secreted OMVs suppress NET formation by activating the Cav-1-Nrf2 signaling axis, thereby mitigating inflammatory progression in RA and revealing novel microbiota-immune regulatory mechanisms in autoimmunity (Ye et al., 2025). Further investigations indicate that both P. goldsteinii and the medicinal fungal polysaccharides (Hirsutella sinensis) can re-establish immune homeostasis, markedly reduce anti-dsDNA autoantibody levels, and alleviate renal and splenic pathological damage in systemic lupus erythematosus (SLE) mouse models (Chang et al., 2024). Collectively, these findings establish P. goldsteinii as a cross-disease regulatory hub in autoimmunity, pathogenesis, advancing targeted intervention strategies leveraging microbiota-derived signaling molecules (e.g., OMVs) or microbe-drug.

Pharmacological agents dynamically regulate P. goldsteinii abundance and functional activity through direct antimicrobial effects or indirect modulation of host-microbiota crosstalk. Metformin–a first-line type 2 diabetes (T2D) therapy–reprograms BA metabolism by suppressing primary BA (PBA)-producing Weissella spp. and reducing secondary BA-converting Parabacteroides spp. (Zhang et al., 2023). This dysbiosis downregulates anti-inflammatory genes (e.g., JUND) and inhibits P. goldsteinii colonization via FXR signaling suppression, ultimately exacerbating intestinal barrier dysfunction in intolerant patients (Zhang et al., 2023). Similarly, gender-affirming hormone therapy induces sex steroid-driven gut microbiota restructuring, with P. goldsteinii abundance fluctuations suggesting sex hormones modulate its ecological niche competition through immune-metabolic axis rewiring (Liwinski et al., 2024). Non-steroidal anti-inflammatory drugs (NSAIDs, e.g., aspirin) exhibit a bidirectional relationship with P. goldsteinii: NSAID-induced gut injury reduces P. goldsteinii abundance and its protective metabolites (7-keto-LCA), while exogenous supplementation of P. goldsteinii or its metabolites reverses epithelial damage by reactivating FXR-mediated repair pathways (Li et al., 2024b). Collectively, pharmacological agents constitute critical modulators of P. goldsteinii ecology, offering rationale to optimize therapeutic regimens or develop microbiota-targeted adjuvants.

Dietary components and lifestyle patterns govern P. goldsteinii colonization through metabolite-mediated microbial interactions, immune regulation, and host circadian rhythm integration. Notably, fermentable fibers, such as inulin increase P. goldsteinii abundance and upregulate its outer membrane protein A (OmpA), which subsequently activates IL-22 signaling to stimulate antimicrobial peptide (e.g., Regenerating islet-derived protein 3 gamma/beta; REG3γ/β) secretion (Wang et al., 2024). This establishes a self-reinforcing immune-microbial loop critical for gut homeostasis (Wang et al., 2024). Furthermore, P. goldsteinii-derived acetate and butyrate can modulate host circadian gene expression in intestinal epithelial cells by inhibiting histone deacetylases in vitro (Fawad et al., 2022). Whether this mechanism synchronizes host-microbe circadian rhythms in vivo remains to be directly demonstrated for P. goldsteinii. Critically, individuals with balanced metabolic profiles exhibit higher P. goldsteinii abundance than dysbiotjc counterparts, suggesting sustained adherence to fiber-rich diets, prebiotics, and regular exercise maintains microbial diversity (e.g., SCFA levels) and metabolic homeostasis (e.g., glycogen reserves). These practices mitigate anemia risk and comorbid disorders (Liang et al., 2024). Collectively, these mechanistic insights position dietary and lifestyle interventions as precision tools for P. goldsteinii-centric microbiota engineering.

Parabacteroides goldsteinii exhibits therapeutic potential through multiple mechanisms (Figure 1): immunomodulation via SCFA-mediated suppression of NF-κB signaling, reducing pro-inflammatory cytokines (e.g., TNF-α, IL-6) while enhancing regulatory T cell (Treg) differentiation (Su et al., 2025); metabolic regulation through improved glucose/lipid homeostasis and insulin sensitivity (Wu et al., 2019; Cai et al., 2020); and intestinal barrier reinforcement by upregulating tight junction proteins (ZO-1, occludin). However, its obligate anaerobic physiology impedes industrial-scale production, necessitating specialized culturing systems (e.g., anaerobic chambers, reduced media) that incur high costs and instability. Innovative solutions include: (i) Building on research for other obligate anaerobes (e.g., Bacteroides spp. and Clostridium spp.), develop co-culture strategies pairing P. goldsteinii with facultative anaerobes (e.g., engineered E. coli) to deplete oxygen and create anaerobic micro-niches (Kim et al., 2022; Brown et al., 2021, 2023); (ii) Cryoprotectant formulations (trehalose, skim milk) to enhance viability during lyophilization; (iii) Encapsulation technologies (e.g., alginate-chitosan matrices) for gastric acid resistance and targeted intestinal delivery (Han et al., 2020); and (iv) Standardized strain screening for anti-inflammatory activity and colonization efficiency, combined with synbiotic formulations (e.g., arabinoxylan) to enable clinical translation (Zhou et al., 2024).

While FMT restores P. goldsteinii abundance in conditions like IBD and obesity (Wu et al., 2019), its therapeutic contribution remains obscured by donor microbiota complexity. Advanced multi-omics approaches (metagenomics, metabolomics) are required to deconvolute P. goldsteinii-specific effects from polymicrobial interactions. Metagenomics and metabolomics serve as complementary analytical frameworks in FMT research, enabling mechanistic dissection of FMT efficacy through structural and functional dimensions (Yu et al., 2023). Specifically: 16S rRNA gene sequencing or shotgun metagenomics quantitatively profiles taxonomic composition, α-diversity shifts, and donor-strain engraftment in recipients pre- and post-FMT. These methods track, for instance, P. goldsteinii colonization efficiency. Metagenomic functional annotation identifies microbial metabolic pathways, determining whether FMT restores host metabolic homeostasis via specific gene transfers (e.g., buk encoding butyrate kinase). High-coverage sequencing resolves single-nucleotide polymorphisms (SNPs) between donor and recipient strains, thereby identifying competitively dominant taxa–such as antioxidant-enriched A. muciniphila strains–that achieve successful engraftment. Predictive models integrating host factors (baseline microbiota, immunogenetics) may identify FMT-responsive subpopulations. Ex vivo intestinal organoid systems enable dose-dependent analysis of P. goldsteinii-mediated anti-inflammatory effects, thereby guiding personalized FMT protocols.

CRISPR-based engineering of P. goldsteinii may yield smart therapeutic strains: (i) Context-responsive systems: ROS-inducible IL-10 expression for targeted anti-inflammatory therapy in colitis models (Skrypnyk et al., 2024); (ii) Precision delivery platforms: Engineered strains secreting metabolites (e.g., 7-keto-LCA) to repair NSAID-induced epithelial damage.

Current limitations include the lack of genetic tools adapted for strict anaerobes, necessitating development of anaerobic-compatible CRISPR systems and transformation protocols. Key translational barriers: (i) Technical hurdles in large-scale cultivation; (ii) Incomplete understanding of dose-effect relationships; (iii) Paucity of strain-specific genetic toolkits. Overcoming these requires interdisciplinary collaboration to bridge microbial ecology, bioengineering, and clinical pharmacology.