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Gut microbiota can regulate host physiological and pathological status through gut-brain communications or pathways. However, the impact of the gut microbiome on neuropeptides and proteins involved in regulating brain functions and behaviors is still not clearly understood. To address the problem, integrated label-free and 10-plex DiLeu isobaric tag-based quantitative methods were implemented to compare the profiling of neuropeptides and proteins in the hypothalamus of germ-free (GF) vs. conventionally-raised (ConvR) mice. A total of 2,943 endogenous peptides from 63 neuropeptide precursors and 3,971 proteins in the mouse hypothalamus were identified. Among these 368 significantly changed peptides (fold changes over 1.5, and p-value < 0.05), 73.6% of the peptides showed higher levels in GF-mice than in ConvR-mice, and 26.4% of the peptides had higher levels in ConvR-mice than in GF-mice. These peptides were mainly from Secretogranin-2, Phosphatidylethanolamine-binding protein-1, ProSAAS, and Proenkephalin-A. Quantitative proteomic analysis employing DiLeu isobaric tags revealed that 282 proteins were significantly up- or down-regulated (fold changes over 1.2, and p-value < 0.05) among the 3,277 quantified proteins. These neuropeptides and proteins were mainly involved in regulating behaviors, transmitter release, signaling pathways, and synapses. Interestingly, pathways including long-term potentiation, long-term depression, and circadian entrainment were involved. In the present study, a combined label-free and 10-plex DiLeu-based quantitative method enable a comprehensive profiling of gut microbiome induced dynamic changes of neuropeptides and proteins in the hypothalamus, suggesting that the gut microbiome might mediate a range of behavioral changes, brain development, learning, and memory through these neuropeptides and proteins.
Rui Liu,Pingli Wei,Caitlin Keller,Nicola Salvatore Orefice,Yatao Shi,Zihui Li,Junfeng Huang,Yusi Cui,Dustin C Frost,Shuying Han,Tzu-Wen L Cross,Federico E Rey,Lingjun Li