Leucovorin ameliorated methotrexate induced intestinal toxicity via modulation of the gut microbiota

Huang, Xinyi; Fang, Qingwei; Rao, Tai; Zhou, Luping; Zeng, Xiangchang; Tan, Zhi‐Rong; Chen, Lulu; Ouyang, Dongsheng

doi:10.1016/j.taap.2020.114900

Cited by 30 publications

(20 citation statements)

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“…Drugs with MTX have been used to treat autoimmune diseases and cancer, and their intestinal toxicity has been described in humans and mice (Huang et al, 2020). Firstly, we determined that MTX-exposed nematodes significantly enhanced fluorescence intensity of Nile Red compared to control nematodes (NGM plates without MTX) (Figure 6a) (increase of 35.1%) showing an alteration in intestinal permeability in C. elegans, as previously reported for other toxins [53] and also shown for MTX in mice and rats [54,55]. [54,55].…”

Section: Gut Barrier Protection and Inhibition Of Bacterial Colonization Capacitysupporting

confidence: 72%

Heat-Treated Bifidobacterium longum CECT-7347: A Whole-Cell Postbiotic with Antioxidant, Anti-Inflammatory, and Gut-Barrier Protection Properties

et al. 2021

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Non-viable preparations of probiotics, as whole-cell postbiotics, attract increasing interest because of their intrinsic technological stability, and their functional properties, such as immune system modulation, gut barrier maintenance, and protection against pathogens. However, reports on Bifidobacteria-derived postbiotics remain scarce. This study aims to demonstrate the functional properties of a heat-treated (HT), non-viable, Bifidobacterium longum strain, CECT-7347, a strain previously selected for its anti-inflammatory phenotype and ability to improve biomarkers of intestinal integrity in clinical trials. The study used the nematode Caenorhabditis elegans and HT-29 cell cultures as eukaryotic model systems. Our results show that HT-CECT-7347 preserves the capacity to protect against oxidative stress damage, while it also reduces acute inflammatory response and gut-barrier disruption, and inhibits bacterial colonization, by activating pathways related to innate immune function. These findings highlight the interest of the ingredient as a novel postbiotic and pave the way to broaden the range of HT-CECT-7347 applications in gut health.

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Section: Gut Barrier Protection and Inhibition Of Bacterial Colonization Capacitysupporting

confidence: 72%

Heat-Treated Bifidobacterium longum CECT-7347: A Whole-Cell Postbiotic with Antioxidant, Anti-Inflammatory, and Gut-Barrier Protection Properties

et al. 2021

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“…A similar study confirmed the microbial dysbiosis caused by MTX in mice with a significantly decreased abundance of Bacteroides fragilis , and supplemental Bacteroides fragilis respited MTX-induced inflammatory reactions and macrophage polarization (Zhou et al, 2018a). Moreover, Bifidobacterium longum was also found to be a probiotic in attenuating MTX-induced intestine damage, which was discovered in the co-treatment of leucovorin with MTX for the sake of reducing its side effects (Huang et al, 2020b). Supplementation with probiotics perturbed by drugs is the most direct and explicit way in alleviating microbiota related adverse effects, but safety remains a question for long-term adhibition.…”

Section: Methotrexatesupporting

confidence: 56%

Connecting the dots: targeting gut microbiota in drug toxicity

Luo¹,

Zhou²

2020

Preprint

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Gut microbiota has been demonstrated to have a vast influence on human health in recent decades and its role in initiating, aggravating, or ameliorating diseases is emerging. Therapeutic strategies have therefore increasingly developed by targeting gut microbial modulation. Recently, its contribution to heterogeneous toxicological responses is also gaining attention, especially in drug-induced toxicity. Oral drugs interact directly with gut microbiota within the gastrointestinal tract and a number of them elicit toxicity mediated by intestinal microbiota. Present studies focus more on the unidirectional influence of how xenobiotics disturb intestinal microbial composition and function and consequently induce altered homeostasis. However, interactions between gut microbiota and xenobiotics are bidirectional and the impact of gut microbiota on xenobiotics especially on drugs should not be neglected. Thus, in this review, we intend to focus on how gut microbiota modulates drug toxicity by highlighting gut microbiota, microbial enzyme, and metabolites to proffer references for seeking common countermeasures in coping with drug toxicity by targeting gut microbiota. Moreover, we give a hypothesis that drugs capable of inducing gut dysbiosis tend to more or less impact the gut-connected organs as evidenced by the drug-induced hepatic encephalopathy, indicating an underlying link among the gut, liver, brain, and other possible organs in drug-induced toxicity.

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“…Intestinal toxicity is a common adverse event of MTX and may influence the entire intestinal tract, contributing to symptoms like nausea, bloating, and diarrhea. The gut microbiome has been reported to be able to modulate the host response to chemotherapeutic drugs and be associated with the intestinal toxicity of MTX (34,35). We speculated that there might be an undiscovered positive role of C alleles at MTHFR A1298C on the MTX-gut microbiome interaction, relieving the symptomatic vomiting.…”

Section: Mthfr A1298cmentioning

confidence: 97%

Influence of Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphism on High-Dose Methotrexate-Related Toxicities in Pediatric Non-Hodgkin Lymphoma Patients

Lü

Zhu

et al. 2021

Front. Oncol.

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PurposeThis retrospective study aimed to investigate the relationships between the methylenetetrahydrofolate reductase (MTHFR) C677T/A1298C and high-dose methotrexate (HD-MTX)-related toxicities in pediatric non-Hodgkin lymphoma (NHL) patients.Patients and MethodsWe reviewed the medical records of 93 NHL patients aged under 18 years who received HD-MTX therapy at the dose of 5 g/m2 with 24-h infusion at Sun Yat-sen University Cancer Center between 2014 and 2019.ResultsThere were 61 males and 32 females, with a median age of 8.8 years (0.9–15.8 years). The tumor types included lymphoblastic lymphoma (n = 38), Burkitt’s lymphoma (n = 31), anaplastic large cell lymphoma (n = 18), diffuse large B-cell lymphoma (n = 6). Overall, 355 courses of HD-MTX therapy were prescribed. All patients were rescued with calcium folinate 12 h after the end of MTX infusion. We found that plasma MTX levels > 0.2 μmol/L at 48 h post-infusion increased the risk of developing oral mucositis (2.4% VS. 9.5%, P = 0.018). Also, patients carrying the C677T and T677T genotypes had tendencies to be more susceptible to oral mucositis (P = 0.034). Patients harboring mutant 677T allele were more likely to develop leucopenia (38.5 vs. 50.3%, P = 0.025) and thrombocytopenia (22.0 vs. 32.4%, P = 0.028). For polymorphism A1298C, the mutant genotype played a protective role in vomiting (11.1 vs. 4.3%, P = 0.018) but increased the risk of anemia (23.8 vs. 41.7%, P < 0.001) and leucopenia (38.1 vs. 50.3%, P = 0.021).ConclusionChildhood NHL patients harboring C677T genotype were more vulnerable to oral mucositis, leucopenia, and thrombocytopenia, while those with A1298C genotype were at a decreased risk of vomiting and more likely to develop anemia and leucopenia.

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Leucovorin ameliorated methotrexate induced intestinal toxicity via modulation of the gut microbiota

Cited by 30 publications

References 54 publications

Heat-Treated Bifidobacterium longum CECT-7347: A Whole-Cell Postbiotic with Antioxidant, Anti-Inflammatory, and Gut-Barrier Protection Properties

Heat-Treated Bifidobacterium longum CECT-7347: A Whole-Cell Postbiotic with Antioxidant, Anti-Inflammatory, and Gut-Barrier Protection Properties

Connecting the dots: targeting gut microbiota in drug toxicity

Influence of Methylenetetrahydrofolate Reductase C677T and A1298C Polymorphism on High-Dose Methotrexate-Related Toxicities in Pediatric Non-Hodgkin Lymphoma Patients

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