Abstract
LGM2605 is a synthetic version of the naturally occurring flaxseed lignan secoisolariciresinol diglucoside (SDG), with known anti‐inflammatory and antioxidant properties; however, its effects on gut microbial composition have not previously been evaluated. In the present study, we sought to determine how the 10‐day oral administration of LGM2605 alters the gut microbiota of mice. Eight‐week‐old female C57BL/6 mice were treated with either LGM2605 or saline, administered daily via oral gavage over a 10‐day treatment period. Upon termination of treatment, mouse cecums (n = 31) were collected, and cecal DNA was isolated. 16S rRNA genes were sequenced and analyzed in Mothur to identify changes in gut microbial composition induced by LGM2605 treatment (v. saline control). We then assessed community composition, performed indicator taxa analysis, and measured alpha and beta diversity. Overall, LGM2605 significantly altered the gut microbiota of mice; we reported alterations in 3 bacterial phyla and 22 genera as a result of treatment. The study here identifies for the first time significant alterations in the gut microbiota of mice following oral administration of LGM2605, in general shifting toward a more anti‐inflammatory composition. These findings lay the foundation for future investigations utilizing LGM2605 to control gut dysbiosis and, by extension, systemic inflammation.LGM2605 is a synthetic version of the naturally occurring flaxseed lignan secoisolariciresinol diglucoside (SDG), with known anti‐inflammatory and antioxidant properties; however, its effects on gut microbial composition have not previously been evaluated. In the present study, we sought to determine how the 10‐day oral administration of LGM2605 alters the gut microbiota of mice. Eight‐week‐old female C57BL/6 mice were treated with either LGM2605 or saline, administered daily via oral gavage over a 10‐day treatment period. Upon termination of treatment, mouse cecums (n = 31) were collected, and cecal DNA was isolated. 16S rRNA genes were sequenced and analyzed in Mothur to identify changes in gut microbial composition induced by LGM2605 treatment (v. saline control). We then assessed community composition, performed indicator taxa analysis, and measured alpha and beta diversity. Overall, LGM2605 significantly altered the gut microbiota of mice; we reported alterations in 3 bacterial phyla and 22 genera as a result of treatment. The study here identifies for the first time significant alterations in the gut microbiota of mice following oral administration of LGM2605, in general shifting toward a more anti‐inflammatory composition. These findings lay the foundation for future investigations utilizing LGM2605 to control gut dysbiosis and, by extension, systemic inflammation.
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Key Points
The synthetic flaxseed lignan LGM2605 has been evaluated as a therapeutic alternative to naturally occurring SDG, as it has significantly greater bioavailability compared to whole flaxseed and can be readily produced in a laboratory setting. Previous studies have demonstrated the usefulness of LGM2605 in controlling inflammation and oxidative stress responses in models of radiation and asbestos exposure, likely resulting from the ability of LGM2605 to scavenge radical species and reduce inflammatory cytokine production. The protective effects of LGM2605 may be especially important in lung and breast cancer radiation therapies to reduce damage to bystander organs. Much like that of SDG, the biological activity of synthetic LGM2605 depends largely on metabolism by residential gut bacteria. The influence of LGM2605 on gut microbial composition has not yet been evaluated.
In the present study, the authors determined the effects of orally administered LGM2605 on the gut microbiota of mice. The human gut is generally less responsive to dietary intervention but relatively minor compositional changes have been observed within just 10 days of treatment. Changes in gut microbial composition were identified by analysis of 16S rRNA genes of DNA extracted from mouse cecums. It was predicted that oral administration of LGM2605 would lead to beneficial changes in gut microbial composition relative to control, increasing the prevalence of bacteria characterized as anti‐inflammatory while decreasing the prevalence of bacteria characterized as pro‐inflammatory.
LGM2605 treatment led to significant alterations in gut microbial composition compared with saline only. At the phylum level, LGM2605 treatment led to a decreased Firmicutes/Bacteroidetes ratio which is generally associated with lower intestinal and systemic inflammation, lower risk of obesity, and higher overall bacterial diversity. LGM2605 treatment also led to an increased prevalence of Proteobacteria. At the genus level, LGM2605 treatment contributed to an increase in several genera associated with anti‐inflammatory effects, including Alistipes, Anaeroplasma, and Faecalibaculum. Both Alistipes and Anaeroplasma are associated with increased production of the anti‐inflammatory cytokine TGF‐β, which upregulates mucosal IgA expression, thereby strengthening the intestinal barrier and reducing gut permeability. Alistipes is also associated with increased production of the anti‐inflammatory cytokine IL‐10, which may help to suppress overactive immune responses.
LGM2605 treatment also contributed to a decrease in several genera that are associated with pro‐inflammatory effects, including Turicibacter and Streptococcus. Both of these genera are implicated in various forms of autoimmune disease, including inflammatory bowel disease and rheumatoid arthritis. LGM2605 treatment also led to a decreased abundance of Bifidobacterium, which is considered to be both anti‐inflammatory and probiotic. As a probiotic, Bifidobacterium alters gut microbial composition by stimulating the growth of residential bacteria while reducing the growth of bacterial pathogens. Furthermore, Bifidobacterium may help to regulate the balance of T‐helper 1 (Th1)/T‐helper 2 (Th2) cells. Th1‐biased immune responses are often implicated in autoimmune disease and increased production of the pro‐inflammatory cytokines IFN‐γ and TNF‐α.
Overall, this study provides evidence that short‐term dietary treatment with the synthetic flaxseed derivative LGM2605 significantly alters the gut microbiota of mice, in general shifting towards a more anti‐inflammatory composition. Despite the short experimental duration, the findings presented here suggest that LGM2605 treatment positively impacts the gut microbiota of mice, which may contribute to the previously reported anti‐inflammatory, antioxidant, and chemoprotective effects of LGM2605. This study also establishes baseline changes in gut microbiota following oral LGM2605 administration, which will be an important reference point for future studies.