The relationship between health and the microorganisms living in the gut has increasingly reached the spotlight in the last few years, and a new study led by researchers at Nanyang Technological University, Singapore (NTU Singapore) sheds more light on the gut microbiome and how it can influence aging.
The gut microbiome
The gut microbiome is a complex ecosystem that includes a varied community of bacteria, archaea, eukarya, and viruses that inhabit our guts. The four bacterial phyla of Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria comprise 98% of the intestinal microbiome.
The activity of the microbiome community regulates a number of functions in the gut and interacts with the immune system and energy metabolism. The beneficial bacteria in our guts also help to prevent the growth of harmful bacteria, protect us from invasive microorganisms, and help to maintain the integrity of the intestinal barrier.
One of the microbiome’s more important activities is to facilitate energy production and metabolic function, which it achieves by the creation of short-chain fatty acids (SCFAs) and their conjugate bases (acetate, propionate, and butyrate). A number of bacteria, including Faecalibacterium prausnitzii, Roseburia faecis, Anaerostipes butyraticus, Ruminococcaceae, and Christensenellaceae, break down fiber and ferment it to make these SCFAs, which are then used as an energy source for the microbiome and by gut membrane cells such as colonocytes. This, in turn, supports the integrity of the intestinal barrier and stimulates the inflammasome pathway in gut homeostasis .
The gut microbiome helps facilitate immune function and development, and studies have shown that when the microbiome is absent, such as in animals kept in a sterile environment, the immune system does not develop and mature properly . Gut bacteria such as Candida albicans and Citrobacter rodentium also help with pathogen control by activating T cells and summoning neutrophils and other immune cells. Bacteroides fragilis and Clostridium help to regulate inflammation by inducing the differentiation of regulatory T cells (FoxP3-positive) and the production of interleukin-10 and transforming growth factor ß .
Butyrate spurs neurogenesis in young mice
The new study transplanted gut microbes from aged, 24-month-old mice into the guts of 6-week-old germ-free mice, and a control group of 6-week-old germ-free mice received microbe transplants from normal 6-week-old mice . Unexpectedly, after just eight weeks, the mice that had received transplants from the older mice showed an increased level of intestinal growth and higher levels of neurogenesis, the creation of new neurons in the brain, compared to the mice that had received transplants from their same-aged counterparts. This was due to an increased supply of a compound known as butyrate.
Butyrate is a type of short-chain fatty acid (SCFA) and has been shown to reduce inflammation and improve cognitive functions in other animal studies, and the production of butyrate by gut bacteria stimulates the production of the hormone FGF21, which has been associated with longevity and regulates energy metabolism.
A fiber-rich diet supports the butyrate-producing gut bacteria and helps them to thrive, unlike diets more rich in fat or protein, which appear to influence the gut microbiome negatively. It is less clear that supplementing directly with butyrate has the same benefits for humans, though some animal studies suggest it might .
As humans age, levels of butyrate generally fall due to changes in the populations of gut bacteria producing it, and some researchers believe it could be the origin point of inflammaging, the chronic background of low-grade inflammation typically found in older people.
In the next step in the study, the researchers gave young germ-free mice butyrate directly and observed the same neurogenesis effect that transplanting gut microbes from old mice achieved.
Butyrate changes the digestive system
Finally, the research team took a look at the effects of gut microbe transplants from aged to young mice on the digestive system. In general, the decline with age of butyrate production in the gut contributes to loss of intestinal wall integrity, so called leaky gut, and the death of the cells lining it. However, butyrate appears to improve the situation by helping the intestinal barrier function and reducing its inflammation.
The researchers found that the young mice saw improvement to their digestive system with increased length and width of the intestinal villi, small finger-like structures in the small intestine that help to absorb digested food.
The young mice given the microbes also had longer small intestines and colons, which means that their digestive systems would be better at processing nutrients given the extra surface area.
The researchers suggest that adjusting populations of gut microbes can somewhat compensate for an aging body and that this opens to the door for using butyrate to counter some of the negative effects of aging.
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.
This is tantalizing evidence that direct supplementation with butyrate may be useful for health and could potentially translate to humans; if it does, then it could be used to support tissue regeneration following strokes or spinal damage and perhaps even slow down cognitive decline.
While it is still unclear if the same benefits will be observed in humans through increasing butyrate via dietary intervention, fecal transplant, butyrate supplementation, or other methods, it is certainly plausible. If nothing else, this study is a good case for including plenty of plant fiber in your diet now while we wait for human studies to be done.
If you are interested in delving deeper into the fascinating world of the microbiome and its relation to health and aging, you may enjoy the microbiome webinar we did earlier this year with leading microbiome researchers Dr. Mike Lustgarten, Dr. Amy Proal, and Dr. Cosmo Mielke.
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