This Monday 07/10/2024 at 9:30am Ms. Marisel Rosell has read her doctoral thesis entitled: "Impact of serum ferritin and metformin on cognitive function in middle-aged subjects: modulation by the gut microbiome" directed by Prof. José Manuel Fernández-Real Lemos, Dr. Jordi Mayneris Perxachs and Prof. Ina Bergheim.

ABSTRACT

The global obesity epidemic is a serious threat to public health worldwide. Obesity is associated with multiple complications that reduce quality of life and life expectancy. Complications associated with obesity include an increased risk of type 2 diabetes mellitus (DM2), cognitive impairment or alterations in the intestinal microbiota. Cognitive impairment has become an urgent public health problem due to the increasing prevalence of obesity, T2DM and population aging worldwide. Preclinical studies have demonstrated the fundamental role of the intestinal microbiota in brain development, in the modulation of cognitive function and in the proper functioning of the central nervous system. However, although the influence of the gut microbiota on physiological and pathological metabolic states is increasingly recognized, the available evidence on its impact on cognitive impairment in middle-aged people remains scarce. Therefore, the main aim of this thesis was to elucidate the role of gut microbiota in the complex interaction between serum ferritin, metformin treatment and cognition. The results showed that, in people aged 65 and older, higher levels of serum ferritin were associated with better cognition. On the other hand, a specific microbial community was associated with cognitive scores and serum ferritin levels. Several bacterial species of the phylum Proteobacteria (Klebsiella pneumoniae, Klebsiella michiganensis, unclassified Escherichia) were negatively associated with both serum ferritin and cognition. At the functional level, an enrichment of the microbial pathways involved in the metabolism of phenylalanine, arginine and proline was identified. Consistently, phenylacetylglutamine, a metabolite derived from the microbial catabolism of phenylalanine was negatively associated with serum ferritin and cognition. In relation to metformin, in patients with DM2, bacterial species of the phylum Firmicutes (Romboutsia timonensis, Romboutsia ilealis) were negatively associated with metformin treatment, while several bacterial species of the phylum Proteobacteria (Escherichia coli) and Verrucomicrobia (Akkermansia muciniphila ) were positively associated. At the functional level, the microbial pathways involved in the tricarboxylic acid cycle and the metabolism of butanoate, arginine and proline showed an enrichment after metformin treatment. Microbial functions (astA, astB, astC, astD, astE, putA) involved in arginine metabolism were related to glutamate production. Consistently, in the metabolomic analysis, metformin treatment was strongly associated with the amino acid proline, a metabolite involved in glutamate metabolism. These results suggest that the beneficial effects of metformin and serum ferritin on cognition might be mediated by changes in gut microbiota composition and functionality. However, further studies are needed to confirm these results and evaluate their clinical implications.