Methionine Restriction Improves Gut Barrier Function by Reshaping Diurnal Rhythms of Inflammation-Related Microbes in Aged Mice

Abstract

Age-related gut barrier dysfunction and dysbiosis of the gut microbiome play crucial roles in human aging. Dietary methionine restriction (MR) has been reported to extend lifespan and reduce the inflammatory response; however, its protective effects on age-related gut barrier dysfunction remain unclear. Accordingly, we focus on the effects of MR on inflammation and gut function. We found a 3-month methionine-restriction reduced inflammatory factors in the serum of aged mice. Moreover, MR reduced gut permeability in aged mice and increased the levels of the tight junction proteins mRNAs, including those of occludin, claudin-1, and zona occludens-1. MR significantly reduced bacterial endotoxin lipopolysaccharide concentration in aged mice serum. By using 16s rRNA sequencing to analyze microbiome diurnal rhythmicity during 24 h, we found MR moderately recovered the cyclical fluctuations of the gut microbiome which was disrupted in aged mice, leading to time-specific enhancement of the abundance of short-chain fatty acid-producing and lifespan-promoting microbes. Moreover, MR dampened the oscillation of inflammation-related TM7-3 and Staphylococcaceae. In conclusion, the effects of MR on the gut barrier were likely related to alleviation of the oscillations of inflammation-related microbes. MR can enable nutritional intervention against age-related gut barrier dysfunction.

Time of Sample Collection Critical for Microbiome Replicability

“…responses: four were unable to locate the missing data 2,12,14,15 , three could not provide data in a format suitable for re-analysis [43][44][45] , and three did not respond to repeated inquiries [46][47][48] . This resulted in the acquisition of five previously published datasets in a form suitable for re-analysis underwent fragment insertion on Greengenes_13_8 via SATé-enabled phylogenetic placement 51 to create the phylogenetic tree, and weighted UniFrac distances 52 Circadian time notation is used throughout the paper to denote when samples were collected:…”

“…Of the remainder, four had incomplete datasets on ENA/EBI - 12,15,29,43 - and the rest were not publicly available. We then contacted the authors of all studies with missing or incomplete data and got the following responses: four were unable to locate the missing data 2,12,14,15 , three could not provide data in a format suitable for re-analysis 43–45 , and three did not respond to repeated inquiries 46–48 . This resulted in the acquisition of five previously published datasets in a form suitable for re-analysis 11,13,27–29 .…”

“…Of these 14 studies, four had complete publicly available data on ENA/EBI. Of the remainder, four had incomplete datasets on ENA/EBI - 12,15,29,43 -and the rest were not publicly available. We…”

“…Of these 14 studies, four had complete publicly available data on ENA/EBI. Of the remainder, four had incomplete datasets on ENA/EBI - 12,15,29,43 -and the rest were not publicly available. We then contacted the authors of all studies with missing or incomplete data and got the following C) The percentage articles where collection time was explicitly stated (yes: 8 AM, ZT4, etc.…”

Methionine restriction - Association with redox homeostasis and implications on aging and diseases

“…The above studies show that the balance of the gut microbiome and the integrity of the gut barrier are closely related to redox homeostasis in the brain. A research focus should be on the fact that MR seems to alter gut microbiome/metabolites [ 255 , 256 ] and improve the gut barrier [ 257 ]. The interaction of gut and brain function has to be taken into consideration in future MR research.…”