Poor cognition is associated with increased abundance of Alistipes and decreased abundance of Clostridium genera in the gut

Background: Brain and gut health are intricately connected via the gut-microbiota-brain axis. Studies have shown that gut dysbiosis is associated with neurodegenerative diseases, including Alzheimer’s disease. However, how cognitive changes affects the gut microbiome structure is currently understudied. We aimed to assess the association between the gut microbiome and global cognitive scores in the Framingham Heart Study (FHS). Method: Our sample included 1,014 participants (mean age 52, 55% female) of the third generation FHS cohort with available stool samples, cognitive assessments, and no history of dementia or stroke (Table 1).We quantified the gut microbiome composition using 16S rRNA sequencing and performed multivariable association and differential abundance analyses, adjusting for age, sex, education, BMI, and other confounders. The global cognitive score (GCS) was built using neuropsychological assessments of four cognitive domains: Executive function (trails-making B); Processing speed (visual reproduction immediate and delayed); Language (similarity test); and Memory (logical memory immediate and delayed). Participants were additionally stratified by GCS with lower and higher scores indicating poor and normal cognition, respectively. Result: Our results (Figure 1) showed that individuals with poor cognition have a decreased abundance of genera Clostridium (OR = 0.69, 95% CI [0.55, 0.86]) and Ruminococcus (0.93, [0.93, 0.94]). Meanwhile, the genus Alistipes, previously connected to anxiety, chronic fatigue syndrome, depression, and hypertension, was more abundant (1.06, [1.05, 1.06]) in the poor cognition group. Moreover, the genus Pseudobutyrivibrio, a butyrate-producing bacteria from the rumen, was also found to be highly abundant (1.12, [1.11, 1.14]) in the poor cognition compared to normal. Finally, there was no difference in alpha and beta diversity between cognitive groups (Figure 2). Conclusion: Our study suggests that the abundance of several genera, including Pseudobutyrivibrio, Alistipes, Ruminococcus, and Clostridium is associated with cognition in middle-age. Clostridium was previously proposed as novel probiotics for human health, and increasing its abundance was viewed as an effective strategy to regulate and maintain the homeostasis of the gut microbiota. As all these bacteria have neuroprotective effects, manipulating their abundance through diet and pre/pro-biotics could be a research path for preserving global cognitive function in the future

Evolutionary Couplings and Molecular Dynamic Simulations Highlight Details of GPCRs Heterodimers’ Interfaces

A growing body of evidence suggests that only a few amino acids (“hot-spots”) at the interface contribute most of the binding energy in transient protein-protein interactions. However, experimental protocols to identify these hot-spots are highly labor-intensive and expensive. Computational methods, including evolutionary couplings, have been proposed to predict the hot-spots, but they generally fail to provide details of the interacting amino acids. Here we showed that unbiased evolutionary methods followed by biased molecular dynamic simulations could achieve this goal and reveal critical elements of protein complexes. We applied the methodology to selected G-protein coupled receptors (GPCRs), known for their therapeutic properties. We used the structure-prior-assisted direct coupling analysis (SP-DCA) to predict the binding interfaces of A2aR/D2R, CB1R/D2R, A2aR/CB1R, 5HT2AR/D2R, and 5-HT2AR/mGluR2 receptor heterodimers, which all agreed with published data. In order to highlight details of the interactions, we performed molecular dynamic (MD) simulations using the newly developed AWSEM energy model. We found that these receptors interact primarily through critical residues at the C and N terminal domains and the third intracellular loop (ICL3). The MD simulations showed that these residues are energetically necessary for dimerization and revealed their native conformational state. We subsequently applied the methodology to the 5-HT2AR/5-HTR4R heterodimer, given its implication in drug addiction and neurodegenerative pathologies such as Alzheimer’s disease (AD). Further, the SP-DCA analysis showed that 5-HT2AR and 5-HTR4R heterodimerize through the C-terminal domain of 5-HT2AR and ICL3 of 5-HT4R. However, elucidating the details of GPCR interactions would accelerate the discovery of druggable sites and improve our knowledge of the etiology of common diseases, including AD