(PTFS11-01-24) Intestinal Sphingolipid Disruption May Precede Age-Related Lipid Malabsorption

Objectives: Aging is associated with heightened inflammation and intestinal epithelial barrier dysfunction—processes linked to nutrient malabsorption in the elderly. Growing evidence indicates that disruptions to host-microbiome communication precede the decline in intestinal nutrient absorption and immune system function associated with aging. Gut microbiota-derived sphingolipids (SL) impact host lipid metabolism and inflammation, but how gut SLs are shaped during old age is not known. We hypothesized that aging inflammation and reduced barrier integrity are related to changes in gut lipid metabolism.

Methods: Here we used young (8-10 m.o.) and old (18-20 m.o.) C57BL/6 mice and analyzed the lipidomic profile of colonic contents using Liquid Chromatography/Mass Spectrometry (LC/MS). In vivo and ex vivo inflammation and immunogenicity were tested in colon tissue and contents.

Results: First, we revealed that gut SL metabolism is robustly altered with age, hallmarked by the accumulation of numerous SL and ceramides (Cer). We also found that aged SLs are strongly associated with signs of intestinal inflammation including higher calprotectin (p < 0.0001) (marker of immune cell infiltration) and ex vivo immune reactivity (measured by toll-like receptor TLR4 reporter assay) of intestinal mucosa (p < 0.05) and feces (p < 0.001). Next, we examined if lipid metabolism of aged mice would differentially recover after a broad-spectrum antibiotic challenge. We administered an antibiotic cocktail (ABX) to drinking water of young and old mice for 1wk, followed by a 1wk washout period. ABX exposure led to a robust accumulation of intestinal triglycerides species (TG) in old mice, indicating heightened lipid malabsorption in aged mice. ABX-induced TG accumulation in the colon of aged mice is associated with delayed recovery of microbiome composition and immunogenic properties of the microbiota.

Conclusions: Our results provide new evidence that gut SL metabolism shifts considerably with advanced age and that antibiotic-induced nutrient malabsorption may be more pronounced in geriatric populations. Future studies are needed to understand how microbiota and host lipid metabolism contribute to inflammatory and intestinal barrier processes that impact health during aging.

Funding Sources: This study was funded in part by the National Institute on Aging.