A review published in Frontiers in Microbiology (Sun et al., 2024) examines the relationship between gut microbiota, oxidative stress, and the pathogenesis of major intestinal diseases, including colorectal cancer (CRC), inflammatory bowel disease (IBD), and ulcerative colitis (UC). Drawing on a broad body of preclinical and clinical evidence, the authors provide a comprehensive synthesis of how microbial dysregulation drives disease progression and identify current prevention and therapeutic strategies aimed at restoring microbial balance.
Methodology
Rather than presenting original experimental data, this work is structured as a narrative review, systematically surveying peer-reviewed literature to map the mechanistic links between microbial composition and reactive oxygen species (ROS) generation. The authors integrate findings from animal models, in vitro studies, and clinical trials, organising the evidence thematically around inflammation, immune response modulation, DNA damage, and gut microbiota-modulating therapies. Schematic figures developed via BioRender visually summarise the bidirectional relationships identified across the reviewed literature.
The bidirectional relationship between microbiota and oxidative stress
A central argument of the review is that the relationship between gut dysbiosis and oxidative stress is not unidirectional but mutually reinforcing. On one side, a healthy microbiota contributes to redox homeostasis through the production of short-chain fatty acids (SCFAs) — particularly butyrate, propionate, and acetate — which exert antioxidant effects both locally and systemically. Specific bacterial strains, including Bifidobacterium longum CCFM752 and Lactobacillus plantarum CCFM1149, have been shown to upregulate key antioxidant enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase (Sun et al., 2024).
Conversely, excessive ROS production can itself induce dysbiosis by damaging bacterial DNA and membrane integrity, compromising epithelial barrier function, and selectively favouring the proliferation of pathogenic or pro-inflammatory organisms such as Salmonella enterica and Proteobacteria over beneficial commensals (Sun et al., 2024). This bidirectional dynamic creates a self-reinforcing cycle in which oxidative imbalance and microbial disruption each amplify the other.
Microbiota-mediated oxidative stress in disease pathways
The review details three principal pathways through which microbiota-mediated oxidative stress contributes to intestinal pathology.
In the context of intestinal inflammation, the authors highlight the role of lipopolysaccharide (LPS), an endotoxin released by Gram-negative bacteria, which activates the TLR4 signalling pathway and triggers vascular oxidative stress and endothelial dysfunction. Segmented filamentous bacteria are noted for their capacity to activate T helper 17 cells, fostering a pro-inflammatory milieu linked to IBD and CRC progression (Sun et al., 2024). Mutations in the NOD2 receptor further illustrate how defective microbial sensing exacerbates intestinal carcinogenesis.
With respect to immune modulation, the review documents how dysbiosis-induced barrier disruption allows microbial components to enter systemic circulation, stimulating immune cell activation and perpetuating ROS production. Notably, gut microbiota metabolites have been shown to influence antitumour immune responses and to modulate the efficacy of immune checkpoint inhibitors (ICIs), opening avenues for microbiome-informed cancer immunotherapy (Gopalakrishnan et al., 2018; Sun et al., 2024).
Regarding DNA damage, the dysbiotic microbiome generates genotoxic substances — including secondary bile acids and colibactin produced by certain Escherichia coli strains — capable of inducing single- and double-strand DNA breaks, base modifications, and interference with DNA repair mechanisms. The review notes that Enterococcus faecalis, for instance, produces extracellular hydroxyl radicals that directly damage host cell DNA, contributing to colorectal adenocarcinoma progression (Sun et al., 2024).
Probiotics and prebiotics in the management of intestinal disease
Among the therapeutic strategies reviewed by Sun et al. (2024) for restoring gut microbial equilibrium and mitigating oxidative stress, probiotics and prebiotics have attracted the greatest volume of clinical and preclinical research. Both approaches share the overarching objective of rebalancing the intestinal microbiome, yet they act through distinct mechanisms and on different targets within the gut ecosystem.
Probiotics: mechanisms and evidence
Probiotics are defined as living microorganisms that, when administered in adequate quantities, confer measurable health benefits on the host (Hill et al., 2014). The principal organisms employed in clinical and research contexts include strains of Lactobacillus, Bifidobacterium, Saccharomyces cerevisiae var. boulardii, and the Gram-negative Escherichia coli Nissle 1917. Their therapeutic relevance in intestinal disease derives from a convergence of complementary biological activities: restoration of microbial balance, reinforcement of the epithelial barrier, immunomodulation, and direct attenuation of oxidative stress (Sun et al., 2024).
At the level of redox homeostasis, specific probiotic strains have demonstrated measurable capacity to reduce ROS accumulation within the intestinal environment. Lactobacillus rhamnosus GG (LGG) has been particularly well studied in this regard. Animal models simulating alcohol-induced intestinal permeability have shown that regular LGG administration restores barrier function, reduces oxidative stress markers in intestinal tissue, and significantly attenuates the severity of hepatic injury secondary to gut leakage (Wang et al., 2011). These effects are mediated at least in part through activation of the Keap1/Nrf2 antioxidant signalling pathway, as demonstrated in vitro by studies examining the response of intestinal epithelial cells to LGG-derived exopolysaccharides under hydrogen peroxide challenge (Li et al., 2021; Sun et al., 2024).
Beyond whole-cell probiotic activity, the review highlights evidence that probiotic-derived compounds — including surface-layer proteins, bacteriocins, and secreted bioactive factors — may exert protective effects independently of live organism administration. The probiotic combination VSL#3, for instance, has demonstrated capacity to reduce colonic inflammation and overall disease activity in interleukin-10-deficient animal models of colitis (Sun et al., 2024). The utility of such preparations reinforces the concept that the therapeutic potential of probiotics extends beyond colonisation per se, encompassing paracrine and immunomodulatory activities mediated by microbial metabolites and structural components.
The clinical evidence reviewed by Sun et al. (2024) supports a role for Lactobacillus and Bifidobacterium strains in reducing disease activity indices and improving quality of life in patients with IBD and IBS, though the authors acknowledge heterogeneity in trial outcomes and the importance of strain-specific effects. Probiotics are understood to act not only by direct colonisation but also by modifying the indigenous microbial community, shifting the gut lumen towards a more anti-inflammatory composition and thereby reducing the bacterial products that perpetuate oxidative and inflammatory cascades (Sanders et al., 2019; Suez et al., 2018).
Prebiotics: selective microbial stimulation and anti-inflammatory consequences
Prebiotics operate through a fundamentally different mechanism: rather than introducing exogenous organisms, they function as selectively fermentable substrates that stimulate the growth and metabolic activity of beneficial resident bacteria, thereby indirectly modulating host physiology (Sanders et al., 2019). The predominant classes examined in the literature — inulin-type fructans, fructo-oligosaccharides (FOS), and galacto-oligosaccharides (GOS) — share the capacity to reach the distal gut largely intact, where they are fermented by saccharolytic bacteria into SCFAs and other bioactive compounds.
Inulin has been among the most extensively studied prebiotics in the context of intestinal disease. Clinical trials in patients with IBD and IBS have demonstrated that inulin supplementation promotes the selective proliferation of Bifidobacterium and Lactobacillus species, producing a compositional shift in the gut microbiota that favours reduced pathogenic bacterial load and diminished mucosal inflammation (Vandeputte et al., 2017; Sun et al., 2024). This microbial remodelling is accompanied by increased SCFA output, which in turn supports colonocyte energy metabolism, reduces luminal pH, and suppresses the growth of acid-sensitive pathogens.
Fructo-oligosaccharides (FOS) have demonstrated analogous effects, with supplementation studies reporting increased abundance of Bifidobacterium and Faecalibacterium prausnitzii — a butyrate-producing commensal consistently associated with intestinal health and reduced inflammatory activity (Chi et al., 2020; Sun et al., 2024). The anti-inflammatory properties of FOS-driven microbial shifts are attributed both to enhanced SCFA production and to modulation of immune signalling pathways within the intestinal mucosa.
Galacto-oligosaccharides (GOS), derived from lactose, have similarly been shown in clinical settings to increase populations of Bifidobacterium and Lactobacillus following supplementation, contributing to a more favourable gut microbial ecology (Monteagudo-Mera et al., 2016; Sun et al., 2024).
Of particular mechanistic interest is the antioxidant dimension of prebiotic activity. Silver fir (Abies alba) bark extract has been documented to exhibit direct antioxidant properties while simultaneously acting as a prebiotic substrate for multiple Lactobacillus species, including L. paracasei, L. acidophilus, L. rhamnosus, and L. bulgaricus (Stojanov et al., 2021; Sun et al., 2024). This dual activity — direct ROS scavenging combined with indirect modulation of the antioxidant microbiome — illustrates the potential for selected prebiotic compounds to operate on multiple therapeutic levels simultaneously.
The authors nonetheless underscore a critical limitation of current prebiotic research: the considerable inter-individual variability in microbial response. Because the compositional baseline of the gut microbiome differs substantially between individuals as a function of age, diet, genetics, and prior antibiotic exposure, the same prebiotic intervention may yield markedly different microbial and clinical outcomes across patient populations (Bedu-Ferrari et al., 2022; Sun et al., 2024). This variability reinforces the argument for personalised nutritional strategies in the clinical deployment of prebiotics, and highlights the need for more granular mechanistic studies capable of identifying which microbial and host variables predict therapeutic response.
Synergistic potential and outlook
Taken together, the evidence surveyed by Sun et al. (2024) positions both probiotics and prebiotics as legitimate components of a multi-modal therapeutic framework for intestinal disease, particularly in the context of oxidative stress modulation:
- probiotics contribute through direct antioxidant enzyme induction, barrier reinforcement, and immunomodulation;
- prebiotics act upstream, reshaping the resident microbial ecosystem to favour organisms whose metabolic outputs — above all SCFAs — reduce the oxidative burden on intestinal epithelial cells.
The combination of both approaches in synbiotic formulations represents a logical extension of this rationale, though the clinical evidence base for synbiotics in oxidative stress-related intestinal pathology remains in an early phase of development.
Additional therapeutic approaches
The review additionally evaluates two further therapeutic modalities:
- fecal microbiota transplantation (FMT) has emerged as an important approach in mechanistically elucidating the causal role of the microbiome in chronic intestinal disease, with documented efficacy in recurrent Clostridioides difficile infection and exploratory results in UC (Costello et al., 2019). The authors caution, however, that methodological heterogeneity across clinical trials limits the generalisability of findings, and that standardisation of FMT protocols remains an urgent research priority (Sun et al., 2024);
- antibiotics such as metronidazole, ciprofloxacin, and rifaximin have been used to target pathogenic populations in IBD and Crohn’s disease, with evidence of compositional microbiota remodelling. Nevertheless, the review stresses that prolonged or indiscriminate antibiotic use risks further disrupting microbial equilibrium, selecting for drug-resistant strains, and precipitating antibiotic-associated diarrhoea — outcomes that may paradoxically worsen the oxidative burden (Sun et al., 2024).
Conclusions
Sun et al. (2024) conclude that the gut microbiome occupies a pivotal regulatory position in intestinal redox balance, with a state of dysbiosis sufficient to initiate or amplify the oxidative cascades underpinning CRC, IBD, and UC. The authors anticipate that future research will clarify the molecular pathways governing this interaction and yield bacteria-derived metabolites or enzymatic targets with therapeutic relevance. They further propose that antioxidant supplementation, used in conjunction with microbiota-modulating interventions, represents a promising integrative strategy for the prevention and management of intestinal diseases.
Dario Dongo
Credit cover julien Tromeur su Unsplash
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Dario Dongo, lawyer and journalist, PhD in international food law, founder of WIISE (FARE - GIFT - Food Times) and Égalité.
