Impact of serum ferritin and metformin on cognitive function in middle-aged subjects: modulation by the gut microbiome

ENG- The global obesity epidemic represents a major threat to public health worldwide. Obesity is associated with many complications that reduce quality of life and longevity. Complications associated with obesity include an increased risk of type 2 diabetes (T2D), cognitive impairment, and changes in the gut microbiota. Cognitive decline has emerged as a pressing public health concern with the increasing prevalence of obesity, T2D, and aging populations worldwide. Although the gut microbiome's influence on both physiological and pathological metabolic states is increasingly recognized, the available evidence on its impact on cognitive impairment in middle-aged individuals remains scarce. Therefore, the main objective of this thesis was to elucidate the role of the gut microbiome in the complex interplay between serum ferritin, metformin consumption, and cognition. The results showed that serum ferritin was significantly associated with better cognition in people aged 65 years or older. On the other hand, a specific microbial community was associated with cognitive scores and serum ferritin levels. Several bacterial species from the Proteobacteria phylum (Klebsiella pneumoniae, Klebsiella michiganensis, Unclassified Escherichia) were negatively associated with both serum ferritin and cognition. At the functional level, an enrichment of microbial pathways involved in phenylalanine, arginine, and proline metabolism was identified. Consistently, phenylacetylglutamine, a metabolite derived from microbial catabolism of phenylalanine, was negatively associated with serum ferritin, executive function, and language. Concerning metformin, bacterial species from the Firmicutes phylum (Romboutsia timonensis, Romboutsia ilealis) were negatively associated with metformin treatment in T2D patients. In contrast, several bacterial species from the Proteobacteria (Escherichia coli) and Verrucomicrobia (Akkermansia muciniphila) phyla were positively associated. At the functional level, microbial pathways involved in the TCA cycle and butanoate, arginine and proline metabolism were enriched with metformin treatment. The microbial functions (astA, astB, astC, astD, astE, putA) involved in arginine metabolism were related to glutamate production. Consistent with this, in the metabolomics analysis, metformin treatment was strongly associated with the amino acid proline, a metabolite involved in glutamate metabolism