Highlights d Microbiome functional analysis reveals changes in carbohydrate-active enzymes in PD d Higher number of bacterial mucin and host degradation enzymes link to PD d Metabolic modeling reveals the contribution of bacterialspecific metabolism in PD d Gut-community modeling reveals the role of bacterial folate

Dysbiosis in the gut microbiome composition may be promoted by therapeutic drugs such as metformin, the world’s most prescribed antidiabetic drug. Under metformin treatment, disturbances of the intestinal microbes lead to increased abundance of Escherichia spp., Akkermansia muciniphila, Subdoligranulum variabile and decreased abundance of Intestinibacter bartlettii. This alteration may potentially lead to adverse effects on the host metabolism, with the depletion of butyrate producer genus. However, an increased production of butyrate and propionate was verified in metformin-treated Type 2 diabetes (T2D) patients. The mechanisms underlying these nutritional alterations and their relation with gut microbiota dysbiosis remain unclear. Here, we used Genome-scale Metabolic Models of the representative gut bacteria Escherichia spp., I. bartlettii, A. muciniphila, and S. variabile to elucidate their bacterial metabolism and its effect on intestinal nutrient pool, including macronutrients (e.g., amino acids and short chain fatty acids), minerals and chemical elements (e.g., iron and oxygen). We applied flux balance analysis (FBA) coupled with synthetic lethality analysis interactions to identify combinations of reactions and extracellular nutrients whose absence prevents growth. Our analyses suggest that Escherichia sp. is the bacteria least vulnerable to nutrient availability. We have also examined bacterial contribution to extracellular nutrients including short chain fatty acids, amino acids, and gasses. For instance, Escherichia sp. and S. variabile may contribute to the production of important short chain fatty acids (e.g., acetate and butyrate, respectively) involved in the host physiology under aerobic and anaerobic conditions. We have also identified pathway susceptibility to nutrient availability and reaction changes among the four bacteria using both FBA and flux variability analysis. For instance, lipopolysaccharide synthesis, nucleotide sugar metabolism, and amino acid metabolism are pathways susceptible to changes in Escherichia sp. and A. muciniphila. Our observations highlight important commensal and competing behavior, and their association with cellular metabolism for prevalent gut microbes. The results of our analysis have potential important implications for development of new therapeutic approaches in T2D patients through the development of prebiotics, probiotics, or postbiotics.

Neurodegenerative diseases (NDDs) comprise a broad range of progressive neurological disorders with multifactorial etiology contributing to disease pathophysiology. Evidence of the microbiome involvement in the gut-brain axis urges the interest in understanding metabolic interactions between the microbiota and host physiology in NDDs. Systems Biology offers a holistic integrative approach to study the interplay between the different biologic systems as part of a whole, and may elucidate the host-microbiome interactions in NDDs. We reviewed direct and indirect pathways through which the microbiota can modulate the bidirectional communication of the gut-brain axis, and explored the evidence of microbial dysbiosis in Alzheimer's and Parkinson's diseases. As the gut microbiota being strongly affected by diet, the potential approaches to targeting the human microbiota through diet for the stimulation of neuroprotective microbialmetabolites secretion were described. We explored the potential of Genome-scale metabolic models (GEMs) to infer microbe-microbe and host-microbe interactions and to identify the microbiome contribution to disease development or prevention. Finally, a systemic approach based on GEMs and 'omics integration, that would allow the design of sustainable personalized anti-inflammatory diets in NDDs prevention, through the modulation of gut microbiota was described.

The role of gut microbiota in humans is of great interest, and metagenomics provided the possibilities for extensively analysing bacterial diversity in health and disease. Here we explored the human gut microbiome samples across 19 countries, performing compositional, functional and integrative analysis. To complement these data and analyse the stability of the microbiome, we followed 86 healthy Swedish individuals over one year, with four sampling times and extensive clinical phenotyping. The integrative analysis of temporal microbiome changes shows the existence of two types of species with a tendency to vary in abundance with time, here called outflow and inflow species. Importantly, the former tends to be enriched in disease, while the latter is enriched in health. We suggest that the decrease of disease-associated outflow and the increase of health-associated inflow species with time may be a fundamental albeit previously unrecognized aspect of the homeostasis maintenance in a healthy microbiome.