Metformin's Impact On Immune Response Genes And Gut Microbiota In COVID-19 Patients With Type 2 Diabetes

COVID-19 News: The COVID-19 pandemic, having impacted over 700 million people globally, has been a major global concern for the past four years. Even though the World Health Organization declared the pandemic officially ended in 2023, the emergence of new variants such as JN.1 continues to pose significant threats. Among the various risk factors associated with severe outcomes, type 2 diabetes (T2D) has stood out, leading to heightened concerns about hospitalization and mortality. In this context, metformin, a primary treatment for T2D, has shown promising pleiotropic properties that extend beyond glycemic control. This COVID-19 News report delves into the intricate relationships between metformin, gut microbiota, and the mRNA expression of pro-inflammatory and anti-inflammatory T-lymphocyte subpopulations in COVID-19 patients with T2D. The study was conducted by researchers from Uzhhorod National University-Ukraine, I. Horbachevsky Ternopil National Medical University-Ukraine and University of Bergen-Norway.


Metformin's Impact On Immune Response Genes And Gut
Microbiota In COVID-19 Patients With Type 2 Diabetes

Thailand Medical News had also previously covered on the merits of Metformin in treating various aspects of the COVID-19 disease and even in preventing Long COVID!
 
https://www.thailandmedical.news/news/breaking-news-metformin-shows-remarkable-results-in-reducing-sars-cov-2-viral-loads-in-phase-3-randomized-clinical-trial-conducted-in-america
 
https://www.thailandmedical.news/news/yet-another-study,-this-time-led-by-scientists-from-the-university-of-minnesota-shows-that-metformin-decreases-risk-of-covid-19-severity
 
https://www.thailandmedical.news/news/spanish-study-shows-that-metformin-glucophage-lowers-risk-of-disease-severity-and-fatal-outcomes-in-diabetic-patients-infected-with-covid-19
 
https://www.thailandmedical.news/news/university-of-minnesota-led-phase-three-randomized-clinical-trial-shows-that-metformin-reduces-risk-of-covid-19-disease-severity-and-mortality-
 
in-type-2-diabetes-patients-contracting-covid-19">https://www.thailandmedical.news/news/covid-19-drugs-university-of-alabama-study-shows-that-metformin-decreases-mortality-rate-in-type-2-diabetes-patients-contracting-covid-19
 
https://www.thailandmedical.news/news/latest-medical-news-reports-that-metformin-can-drastically-reduce-covid-19-mortality-risks-in-women
 
https://www.thailandmedical.news/news/breaking-metformin-might-emerge-as-another-covid-19-drug-candidate-with-university-of-minnesota-now-receiving-funding-for-further-research
 
https://www.thailandmedical.news/news/metformin-university-of-minnesota-researchers-discover-that-metformin-may-lower-risk-of-covid-19-deaths-in-obese-and-or-diabetic-women
 
https://www.thailandmedical.news/news/covid-19-news-weill-cornell-study-finds-that-sars-cov-2-infects-and-triggers-senescence-of-dopamine-neurons-metformin-helps
 
https://www.thailandmedical.news/news/long-covid-news-university-of-minnesota-study-shows-that-early-use-of-metformin-during-sars-cov-2-infection-can-prevent-long-covid
 
https://www.thailandmedical.news/news/breaking-u-s-randomized-clinical-trial-findings-published-in-lancet-shows-that-metformin-reduces-risk-of-developing-long-covid-by-40-percent
 
https://www.thailandmedical.news/news/cleveland-clinic-and-northwestern-university-study-shows-that-metformin-could-be-repurposed-to-treat-atrial-fibrillation-findings-relevant-in-covid-se
 
Metformin and Its Pleiotropic Effects
As a widely used oral antidiabetic medication, metformin's influence on glycemic control is well-established. However, recent research has revealed its pleiotropic effects, suggesting potential benefits in mitigating disease severity and expediting recovery in COVID-19 patients with T2D. One of the key mechanisms behind these benefits is metformin's anti-inflammatory properties. By impacting the immunometabolism of lymphocytes, metformin can influence the differentiation and balance between pro-inflammatory T helper 1 (Th1) and T helper 17 (Th17) cells, as well as anti-inflammatory regulatory T cells (Treg). This modulation has the potential to reduce inflammation and the risk of cytokine storms, which are often associated with severe cases of COVID-19.
 
Transcriptional Regulation of T-lymphocytes
The balance between different T-lymphocyte subpopulations, including Th1, Th2, Th17, and Treg cells, is critical for maintaining immune homeostasis.
 
Dysregulation of these cells has been implicated in various autoimmune diseases and chronic inflammatory conditions. In the context of COVID-19, an imbalance in the activation of these immune cell subsets can contribute to the severity of the disease. The current study focused on three key genes involved in the transcriptional regulation of Treg, Th1, and Th17 cells: FOXP3, TBX21, and RORC. The results showed that individuals not taking metformin exhibited altered expression levels of these genes, while metformin-treated individuals displayed a more balanced expression pattern, suggesting a potential regulatory effect of the medication on immune responses.
 
Gut Microbiota and Metformin
The composition of gut microbiota undergoes significant alterations in individuals with both T2D and COVID-19. The bidirectional communication pathway known as the gut–lung axis highlights the interconnectedness of these systems, with gut microbiota influencing inflammation in the lungs. Metformin, being a common oral hypoglycemic agent, has been shown to have beneficial effects on gut microbiota in patients with both conditions. The medication promotes the growth of beneficial bacteria, such as Akkermansia muciniphila, and reduces pro-inflammatory cytokine levels in the gut. This dual effect could contribute to improved outcomes in COVID-19 patients with T2D, as it may reduce both lung and systemic inflammation.
 
Results and Correlations
The study revealed that metformin-treated individuals exhibited a more favorable T-lymphocyte gene expression profile, with an upregulation of FOXP3 and downregulation of RORC and TBX21. Additionally, a positive correlation was observed between the Th17/Treg ratio and the F/B ratio, suggesting an association between gut microbiota imbalance and T-cell subset dysregulation. Metformin-treated individuals showed lower inflammatory markers and higher gut microbiota diversity, aligning with previous studies demonstrating the medication's anti-inflammatory and microbiota-modulating effects.
 
Discussion
The positive correlations between T-lymphocyte ratios, gut microbiota composition, and inflammatory markers suggest an intricate interplay between immune responses and the gut microbiota in metformin-treated individuals. The study adds valuable insights into the molecular changes induced by metformin, such as upregulation of PRKAA1 and downregulation of SLC2A1 and MTOR, contributing to decreased inflammatory markers. These findings complement existing research, highlighting metformin's potential to mitigate excessive immune responses and cytokine storms in severe COVID-19 cases.
 
Clinical Implications
While the study provides compelling evidence of metformin's potential benefits in COVID-19 patients with T2D, it acknowledges limitations, such as a small sample size and reliance on culture-based microbiota analysis. Future research using advanced sequencing techniques and larger cohorts is crucial for a comprehensive understanding. Nevertheless, the study suggests that metformin's modulation of immune responses and gut microbiota diversity opens avenues for therapeutic interventions, emphasizing the need for further well-controlled clinical trials to validate and refine these observations.
 
Conclusion
In conclusion, this study underscores the potential of metformin to influence key immune response genes and modulate gut microbiota in COVID-19 patients with T2D. The observed upregulation of anti-inflammatory markers and downregulation of pro-inflammatory markers in metformin-treated individuals point towards a beneficial impact. However, cautious interpretation is warranted due to study limitations, urging the need for extensive, well-controlled research to solidify metformin's role in immune modulation during COVID-19. These findings offer a promising foundation for future clinical applications and therapeutic strategies, highlighting metformin as a potential ally in the fight against severe outcomes in COVID-19 patients with T2D.
 
The study findings were published in the peer reviewed journal: Viruses.
https://www.mdpi.com/1999-4915/16/2/281
 
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