Biology subjects

Rahman, R. J.

Publications and source records attributed to Rahman, R. J..

3 recordsLinked to original sources

bioRxiv2023

Interactions between the gut microbiome, dietary restriction, and aging in genetically diverse mice

The intestinal microbiome changes with age, but the causes and consequences of microbiome aging remain unclear. Furthermore, the gut microbiome has been proposed to mediate the benefit of lifespan- extending interventions such as dietary restriction, but this hypothesis warrants further exploration. Here, by analyzing 2997 metagenomes collected longitudinally from 913 deeply phenotyped, genetically diverse mice, we provide new insights into the interplay between the microbiome, aging, dietary restriction, host genetics, and a wide range of health parameters. First, we find that microbiome uniqueness increases with age across datasets and species. Moreover, age-associated changes are better explained by cumulative exposure to stochastic events (neutral theory) than by the influence of an aging host (selection theory). Second, we unexpectedly find that the majority of microbiome features are significantly heritable and that the amount of variation explained by host genetics is as large as that of aging and dietary restriction. Third, we find that the intensity of dietary restriction parallels the extent of microbiome changes and that dietary restriction does not rejuvenate the microbiome. Lastly, we find that the microbiome is significantly associated with multiple health parameters -- including body composition, immune parameters, and frailty -- but not with lifespan. In summary, this large and multifaceted study sheds light on the factors influencing the microbiome and aspects of host physiology modulated by the microbiome.

microbiology↗

bioRxiv2023

Polyphosphate uses mTOR, pyrophosphate, and Rho GTPase components to potentiate bacterial survival in Dictyostelium

Human macrophages and the eukaryotic microbe Dictyostelium discoideum ingest bacteria by phagocytosis, and then kill the ingested bacteria. Some pathogenic bacteria secrete linear chains of phosphate residues (polyphosphate; polyP), and the polyP causes the phagocytes to not kill the ingested bacteria. In D. discoideum, the effect of polyP requires the G protein-coupled receptor GrlD, suggesting that polyP uses a signal transduction pathway to inhibit killing of ingested bacteria. Here we show that in addition to GrlD, the D. discoideum polyP signaling pathway requires the GPCR interacting arrestin-like protein AdcB, inositol hexakisphosphate kinase A (I6kA), the Rho GTPase RacE, and the TOR component Lst8. D. discoideum also secretes polyP, and at high concentrations polyP inhibits D. discoideum cytokinesis. The polyP inhibition of bacterial killing pathway does not appear to involve many of the polyP inhibition of cytokinesis pathway components. These data suggest the intriguing possibility that if there is a similar polyP inhibition of bacterial killing pathway in macrophages, pharmacologically blocking this pathway could potentiate macrophage killing of pathogenic bacteria. ImportanceAlthough most bacteria are quickly killed after phagocytosis by a eukaryotic cell, some pathogenic bacteria prevent their killing after phagocytosis. Pathogenic Mycobacterium species secrete polyP, and the polyP is necessary for the bacteria to prevent their killing after phagocytosis. Conversely, exogenous polyP prevents the killing of ingested bacteria that are normally killed after phagocytosis by human macrophages and the eukaryotic microbe Dictyostelium discoideum. This suggests the possibility that in these cells, a signal transduction pathway is used to sense polyP and prevent killing of ingested bacteria. In this report, we identify key components of the polyP signal transduction pathway in D. discoideum. In cells lacking these components, polyP is unable to inhibit killing of ingested bacteria. The pathway components have orthologues in human cells, and an exciting possibility is that pharmacologically blocking this pathway in human macrophages would cause them to kill ingested pathogens such as M. tuberculosis.

microbiology↗

bioRxiv2022

Dictyostelium discoideum cells sense their local density and retain nutrients when the cells are about to overgrow their food source

Dictyostelium discoideum is a unicellular eukaryote that eats bacteria, and eventually overgrows the bacteria. D. discoideum cells accumulate extracellular polyphosphate (polyP), and the polyP concentration increases as the local cell density increases. At high cell densities, the correspondingly high extracellular polyP concentrations allow cells to sense that they are about to overgrow their food supply and starve, causing the D. discoideum cells to inhibt their proliferation. In this report, we show that high extracellular polyP inhibits exocytosis of undigested or partially digested nutrients. PolyP decreases cell membrane fluidity and plasma membrane recycling, and this requires the G protein-coupled polyP receptor GrlD, the polyphosphate kinase Ppk1, and the inositol hexakisphosphate kinase I6kA. PolyP did not affect random cell motility, cell speed, or F-actin levels. PolyP decreased membrane saturated fatty acids and altered lipid and protein contents in detergent-insoluble lipid microdomains. Together, these data suggest that D. discoideum cells use polyP as a signal to sense their local cell density and reduce cell membrane fluidity and membrane recycling, perhaps as a mechanism to retain ingested food when the cells are about to starve.

cell biology↗