Glucose-fed microbiota alters C. elegans intestinal epithelium and increases susceptibility to multiple bacterial pathogens.

Overconsumption of dietary sugar can lead to many negative health effects including the development of Type 2 diabetes, metabolic syndrome, cardiovascular disease, and neurodegenerative disorders. Recently, the human intestinal microbiota, strongly associated with our overall health, has also been known to be affected by diet. However, mechanistic insight into the importance of the human intestinal microbiota and the effects of chronic sugar ingestion has not been possible largely due to the complexity of the human microbiome which contains hundreds of types of organisms. Here, we use an interspecies C. elegans/E. coli system, where E. coli are subjected to high sugar, then consumed by the bacterivore host C. elegans to become the microbiota. This glucose-fed microbiota results in a significant lifespan reduction accompanied by reduced healthspan (locomotion), reduced stress resistance, and changes in behavior and feeding. Lifespan reduction is also accompanied by two potential major contributors: increased intestinal bacterial density and increased concentration of reactive oxygen species. The glucose-fed microbiota accelerated the age-related development of intestinal cell permeability, intestinal distention, and dysregulation of immune effectors. Ultimately, the changes in the intestinal epithelium due to aging with the glucose-fed microbiota results in increased susceptibility to multiple bacterial pathogens. Taken together, our data reveal that chronic ingestion of sugar, such as a Western diet, has profound health effects on the host due to changes in the microbiota and may contribute to the current increased incidence of ailments including inflammatory bowel diseases as well as multiple age-related diseases.

Bacterial processing of glucose modulates C. elegans lifespan and healthspan.

Intestinal microbiota play an essential role in the health of a host organism. Here, we define how commensal Escherichia coli (E. coli) alters its host after long term exposure to glucose using a Caenorhabditis elegans-E. coli system where only the bacteria have direct contact with glucose. Our data reveal that bacterial processing of glucose results in reduced lifespan and healthspan including reduced locomotion, oxidative stress resistance, and heat stress resistance in C. elegans. With chronic exposure to glucose, E. coli exhibits growth defects and increased advanced glycation end products. These negative effects are abrogated when the E. coli is not able to process the additional glucose and by the addition of the anti-glycation compound carnosine. Physiological changes of the host C. elegans are accompanied by dysregulation of detoxifying genes including glyoxalase, glutathione-S-transferase, and superoxide dismutase. Loss of the glutathione-S-transferase, gst-4 shortens C. elegans lifespan and blunts the animal's response to a glucose fed bacterial diet. Taken together, we reveal that added dietary sugar may alter intestinal microbial E. coli to decrease lifespan and healthspan of the host and define a critical role of detoxification genes in maintaining health during a chronic high-sugar diet.

Global Cysteine-Reactivity Profiling during Impaired Insulin/IGF-1 Signaling in C. elegans Identifies Uncharacterized Mediators of Longevity.

In the nematode Caenorhabditis elegans, inactivating mutations in the insulin/IGF-1 receptor, DAF-2, result in a 2-fold increase in lifespan mediated by DAF-16, a FOXO-family transcription factor. Downstream protein activities that directly regulate longevity during impaired insulin/IGF-1 signaling (IIS) are poorly characterized. Here, we use global cysteine-reactivity profiling to identify protein activity changes during impaired IIS. Upon confirming that cysteine reactivity is a good predictor of functionality in C. elegans, we profiled cysteine-reactivity changes between daf-2 and daf-16;daf-2 mutants, and identified 40 proteins that display a >2-fold change. Subsequent RNAi-mediated knockdown studies revealed that lbp-3 and K02D7.1 knockdown caused significant increases in lifespan and dauer formation. The proteins encoded by these two genes, LBP-3 and K02D7.1, are implicated in intracellular fatty acid transport and purine metabolism, respectively. These studies demonstrate that cysteine-reactivity profiling can be complementary to abundance-based transcriptomic and proteomic studies, serving to identify uncharacterized mediators of C. elegans longevity.