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Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice

microbioma mice neurogenesis prolongevity

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#1 Engadin

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Posted 14 November 2019 - 06:47 PM


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F U L L   T E X T   S O U R C E :    Science Translational Medicine

 

 

 

 

 

Hidden benefits of a fecal transplant
 
Our gut microbiota evolves as we age, yet its effects on host physiology are not clearly understood. Kundu et al. now attempt to elucidate these effects by transplanting the gut microbiota of either young or old donor mice into young germ-free recipient mice. They report that young germ-free mice receiving gut microbiota transplants from old mouse donors exhibited increased hippocampal neurogenesis, intestinal growth, and activation of the prolongevity FGF21-AMPK-SIRT1 signaling pathways in the liver. Subsequent metagenomic analysis revealed the potential role of butyrate-producing microbes in mediating these effects. These findings collectively suggest that the gut microbiota of an old mouse host may have beneficial effects in a young mouse recipient.
 
 
Abstract
 
The gut microbiota evolves as the host ages, yet the effects of these microbial changes on host physiology and energy homeostasis are poorly understood. To investigate these potential effects, we transplanted the gut microbiota of old or young mice into young germ-free recipient mice. Both groups showed similar weight gain and skeletal muscle mass, but germ-free mice receiving a gut microbiota transplant from old donor mice unexpectedly showed increased neurogenesis in the hippocampus of the brain and increased intestinal growth. Metagenomic analysis revealed age-sensitive enrichment in butyrate-producing microbes in young germ-free mice transplanted with the gut microbiota of old donor mice. The higher concentration of gut microbiota–derived butyrate in these young transplanted mice was associated with an increase in the pleiotropic and prolongevity hormone fibroblast growth factor 21 (FGF21). An increase in FGF21 correlated with increased AMPK and SIRT-1 activation and reduced mTOR signaling. Young germ-free mice treated with exogenous sodium butyrate recapitulated the prolongevity phenotype observed in young germ-free mice receiving a gut microbiota transplant from old donor mice. These results suggest that gut microbiota transplants from aged hosts conferred beneficial effects in responsive young recipients.
 
 
INTRODUCTION
 
Aging is a biological process associated with gradual impairment in physiological functions. It is likely that the changes associated with aging are recognized by the indigenous gut microbiota that has coevolved together with its host as part of the “holobiont” (1, 2). The composition of the gut microbiota changes with age in both humans and in genetically homogeneous mice raised under controlled experimental conditions (1). Recently, a number of studies involving nonmammalian model organisms such as worms, flies, and fish have documented the functional relevance of the gut microbiota in the host aging process (1, 3–5). Shifts in the gut microbiota of an aged host are thought to contribute to typical aging phenotypes, including decreased gut epithelial barrier integrity and associated low-grade systemic inflammation (6, 7). However, the unique microbial signatures in centenarians characterized by an enrichment in health-associated microbes (8), and the recent findings of adult neurogenesis in the brains of healthy elderly individuals (9) underscore the limits of our current understanding of how the gut microbiota changes during aging.
 
 
RESULTS
 
Age-dependent alterations in the gut microbiota of mice
 
To assess the influence of the gut microbiota on host aging, we transplanted the gut microbiota from healthy old (~24-month-old) donor mice into young (5- to 6-week-old) germ-free recipient mice (Fig. 1A). Groups of germ-free mice (recipients) were “conventionalized” by both fecal transplantation via gavage and short-term cohousing with respective donors to allow transfer of both the gut and skin microbiota. The ex–germ-free recipient mice were subsequently raised in a contained environment (i.e., in germ-free isolators) and received a defined diet to reduce the influence of confounding factors such as diet or environment. Mouse recipients transplanted with the gut microbiota of age-matched (5- to 6-week-old) young donors served as experimental controls. Metagenomic analysis of stool samples from the young and old donors revealed distinct differences between their gut microbiotas (fig. S1, A and B), in line with previous reports (6, 10). For instance, old donors showed a reduced abundance of bacteria of the Akkermansia and Alistipes genera in their stool samples (fig. S1B).
 
 
F1.large.jpg
 
 
Fig. 1 Gut microbiota transplants from old donor mice promote hippocampal neurogenesis in germ-free recipient mice.
(A) Gut microbiota transplants (MTs) from ~24-month-old or 5- to 6-week-old mice were transplanted into 5- to 6-week-old germ-free young recipient mice. The transplanted mice were subjected to short-term cohousing with donors and then were housed in a controlled environment for 8 or 16 weeks before being euthanized. (B) Shown are representative images of doublecortin (DCX)–stained neurons in the dentate gyrus of young recipient mice receiving a gut microbiota transplant from old or young donors, referred to as old MT recipients or young MT recipients, respectively. DCX staining is red, and DAPI counterstain is blue. The white arrows indicate DCX+ neurons, and the red boxes indicate the area magnified in the two left panels. Scale bars, 100 μm. © Shown is quantification of the number of DCX+ neurons in the dentate gyrus of old MT and young MT recipient mice (n = 5 per group). (D and E) Shown is the expression of Sox9 (D) and CD133 (E) mRNA in the hippocampus of old MT and young MT recipient mice (n ≥ 5 per group). (F) Western blot analysis and quantification of BDNF protein expression in the hippocampus of old MT and young MT recipient mice (n = 4 per group). Actin was used as the loading control. (G) Differences in hippocampal metabolites between old MT and young MT recipient mice (n = 8 per group). The model is composed of one predictive (tcv [1]) and one orthogonal (tocv [1]) principal components. Data are reported as means ± SEM. *P calculated using the Student’s t test.
 
 
Similarities in the gut microbiotas of young donors and their corresponding recipients [young microbiota-transplanted recipient mice (young MT recipients)] and between the old mouse donors and their recipients [old microbiota-transplanted recipient mice (old MT recipients)] confirmed successful gut microbiota transfer (fig. S1C). Metatranscriptomic analysis revealed distinct gene expression patterns for the gut microbiotas of young versus old donors and for young MT recipients versus old MT recipients, suggesting functional divergence in the gut microbiotas of young compared to old mice (fig. S1D). Compared to the gut microbiota transcriptomes of young donors and young MT recipients, those of the old donors and old MT recipients showed elevated expression of fumarate reductase, an enzyme required for anaerobic respiration (fig. S1E).
 
Colonization of germ-free recipients with the gut microbiota from healthy old donors had no adverse effects on age-associated weight gain (fig. S2A), food intake (fig. S2B), or muscle weight gain (fig. S2C). Likewise, there were no differences in blood glucose (fig. S2D), serum insulin (fig. S2E), triglycerides (fig. S2F), or cholesterol (fig. S2G) in young MT recipients versus old MT recipients. Similarly, multiple behavioral tests showed no notable differences in phenotypes such as anxiety between these two groups (fig. S2, H to J).
 
 
Mouse recipients of gut microbiota transplants from old donors show an increase in doublecortin-positive hippocampal neurons
 
Aging is typically associated with reduced adult neurogenesis in the brain and gradual changes in inflammatory gene expression signatures in various organs including the brain and gut (1, 11). Furthermore, abnormal changes in gut microbiota composition have been linked to age-associated neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease (12, 13). This prompted us to investigate adult neurogenesis in the dentate gyrus of the hippocampus of young MT recipients compared to old MT recipients. Unexpectedly, 8 weeks after gut microbial transplantation, old MT recipients had more doublecortin-positive (DCX+) neurons in the dentate gyrus than did young MT recipients, indicating increased neurogenesis in the brains of old MT recipients (P = 0.0137) (Fig. 1, B and C). This increase was even more pronounced 16 weeks after gut microbial transplantation (P < 0.0001) (Fig. 1, B and C). There were also significant increases in the expression of markers of cellular stemness, including Sox9 (P < 0.0001) and CD133 (P = 0.0002) in the hippocampus of the brains of old MT recipients compared to young MT recipients (Fig. 1, D and E). However, the number and soma size of microglia, the key immune cells in the brain, were comparable between the two groups with no obvious difference in microglial morphology (fig. S3, A to C). In addition, the expression of hippocampal pro- and anti-inflammatory cytokines including tumor necrosis factor–α (TNFα), interleukin-6 (IL-6), and IL-10 was similar between the two groups (fig. S3, D to F).
 
We speculated that changes in brain-derived neurotrophic factor (BDNF), a known neurogenic factor regulated by the gut microbial metabolite butyrate (14–16), might underlie the increased neurogenesis observed in the dentate gyrus of old MT recipients. As expected, the expression of hippocampal BDNF was significantly higher (P < 0.0001) in the old MT recipients compared to young MT recipients (Fig. 1F). However, hippocampal expression of tyrosine receptor kinase B (TrkB), the BDNF receptor, was similar among the two groups (fig. S3G). Further, metabolic profiling of hippocampal tissue (Fig. 1G) revealed increased abundance of metabolites such as taurine, choline, glutamate, and γ-aminobutyric acid (GABA) in old MT recipients compared to young MT recipients (Table 1). These metabolites are known to be associated with neurogenesis and maturation of neurons (17–21). As expected, the number of DCX+ neurons in the dentate gyrus was lower in the old donor mice compared to the young donor mice (P < 0.0001; fig. S3, H and I), confirming that the old donors did not show aberrant neurogenesis. Furthermore, hippocampal expression of the tight junction markers claudin 1, occludin, and zonula occludens-1 (fig. S3, J to L) indicated that there were no major differences in the integrity of the blood-brain barrier between the young MT recipients and old MT recipients (22). Together, these results suggested that the gut microbiota of the old donor mice had the ability to support adult hippocampal neurogenesis when transplanted into young mouse recipients.
 
 
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Edited by Engadin, 14 November 2019 - 06:49 PM.

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