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Type 2 diabetes mellitus (T2DM) is one of the most common worldwide metabolic disorders, characterized by insulin resistance (IR) and defective insulin secretion by pancreatic β-cells which leads to multiple complications such as bone fragility. This complication might be influenced by other factors such as gender and cardiovascular disease (CVD). However, it is unclear why a certain T2DM group develops bone fragility, and what the molecular mechanism is. Metabolomics is a powerful approach to the study of human metabolism, especially in complex diseases such as T2DM. Thus, this study aimed to identify significant metabolites associated with bone fragility in T2DM patients. To achieve this, 81 individuals were enrolled and classified as T2DM patients (D, n=28), T2DM with bone fragility (D-Frag, n=25), or age-matched non-diabetic subjects (ND, n=28) as the control group. Serum samples were collected and analyzed using liquid chromatography and gas chromatography, both coupled to mass spectrometry (LC-MS and GC-MS, respectively). Samples were compared within four different scenarios: 1) the classical comparison of D vs ND to corroborate previous studies; 2) D-Frag vs D to explore the metabolites mainly associated with bone fragility; 3) the same comparison using male data (MD-Frag vs MD) to study as a more homogeneous model of bone fragility as in women, bone fragility could be mainly associated with hormonal stage and pregnancy; and 4) MD-Frag-CVD vs MD-CVD to explore the influence of bone fragility in the male-based model with CVD considering that most of the T2DM patients suffer from CVD. After analysis of these scenarios, our results suggest that acylcarnitines and glycerophospholipids, among other metabolites, are involved in the development of bone fragility in T2DM.

Abstract The human gut microbiome establishes and matures during infancy, and dysregulation at this stage may lead to pathologies later in life. We conducted a multi-omics study comprising three generations of family members to investigate the early development of the gut microbiota. Fecal samples from 200 individuals, including infants (0-12 months old; 55% females, 45% males) and their respective mothers and grandmothers, were analyzed using two independent metabolomics platforms and metagenomics. For metabolomics, gas chromatography and capillary electrophoresis coupled to mass spectrometry were applied. For metagenomics, both 16S rRNA gene and shotgun sequencing were performed. Here we show that infants greatly vary from their elders in fecal microbiota populations, function, and metabolome. Infants have a less diverse microbiota than adults and present differences in several metabolite classes, such as short- and branched-chain fatty acids, which are associated with shifts in bacterial populations. These findings provide innovative biochemical insights into the shaping of the gut microbiome within the same generational line that could be beneficial in improving childhood health outcomes.

Abstract The B cell response in the germinal centre (GC) reaction requires a unique bioenergetic supply. Although mitochondria are remodelled upon antigen-mediated B cell receptor stimulation, mitochondrial function in B cells is still poorly understood. To gain a better understanding of the role of mitochondria in B cell function, here we generate mice with B cell-specific deficiency in Tfam, a transcription factor necessary for mitochondrial biogenesis. Tfam conditional knock-out (KO) mice display a blockage of the GC reaction and a bias of B cell differentiation towards memory B cells and aged-related B cells, hallmarks of an aged immune response. Unexpectedly, blocked GC reaction in Tfam KO mice is not caused by defects in the bioenergetic supply but is associated with a defect in the remodelling of the lysosomal compartment in B cells. Our results may thus describe a mitochondrial function for lysosome regulation and the downstream antigen presentation in B cells during the GC reaction, the dysruption of which is manifested as an aged immune response.