Better Mapping Age-Related Changes in the Human Gut Microbiome

In today's open access paper, researchers report on an improved mapping of changes in microbial populations in the gut with advancing age. Past studies have shown that significant changes start comparatively early, in the mid-30s, for reasons yet to be clearly understood. Age-related changes in diet (generally worse) and exercise (generally lessened) clearly play a role, but at the high level, the most important changes are thought to be the result of a bidirectional interaction between the immune system and the microbiome. Growing numbers of inflammatory microbes contribute to the harmful chronic inflammation of aging, expanding their populations at the expense of beneficial microbes that generate useful metabolites. Meanwhile, the age-related decline of immune function, partially caused by chronic inflammation, means that harmful microbes are less effectively suppressed, enabling their expansion in the intestinal tract.

The novel results in this work include a link between medication status in later life and changes in the gut microbiome. Most older people take one or more medications for chronic conditions. This is quite interesting and a topic that has gone largely untouched to date in investigations of how the microbiome interacts with health in later life. Given the influence of the gut microbiome on systemic inflammation, and noting that inflammation is of great importance in aging and age-related disease, this sounds like one more good reason to push for the widespread clinical use of fecal microbiota transplantation and other approaches shown to improve the quality of the aged gut microbiome.

This study examines how the duodenal microbiome changes with chronological age and with the process of aging. In this article, we have used the term aging to include chronological age, the number of concomitant diseases, and the number of medications used. Our results indicate that the duodenal microbiome changes progressively and significantly in older subjects, including a decrease in microbial diversity that was driven not only by chronological age but also by increases in the number of medications used and the number of concomitant diseases. Furthermore, this decrease in diversity is associated with increases in coliform levels. Representatives from phylum Firmicutes demonstrate stability and predictability over time, but other components of the common core duodenal microbiome change significantly with chronological age. This was driven by increases in phylum Proteobacteria, which increases to the second most abundant phylum in the duodenum in adults aged 36-50 years and remains in this position throughout adulthood. In contrast, phylum Bacteroidetes progressively decreases in RA with increasing age. The increase in RA of phylum Proteobacteria results from increases in the family Enterobacteriaceae, and specifically the genera Escherichia and Klebsiella. These changes are most pronounced when comparing young adults in their 20s and 30s to adults in their 70s and beyond, and correlated with changes in predicted microbial metabolic pathways, including the ubiquinone biosynthesis pathway, which is an antioxidant pathway whose expression is increased under stress conditions, including in anoxic environments for Escherichia coli.

We identified a significant decrease in duodenal microbial diversity in older subjects, which is consistent with previous data demonstrating reductions in microbial diversity in the stool microbiome with age, coupled with shifts in the dominant species and declines in beneficial microorganisms. However, advancing chronological age is accompanied by multiple factors that complicate microbial analysis. For example, the process of aging is associated with increases in the number of concomitant diseases present in older subjects and the number of medications used, factors that were not explored in previous studies. Through multivariate analyses controlling for these factors, we found that the decrease in duodenal microbial diversity was driven by a combination of chronological age, increases in the number of concomitant diseases, and increases in the number of medications used by older subjects, rather than solely by age alone. Our culture findings indicate that this decrease in microbial diversity in the duodenum is also associated with increased levels of coliform bacteria in the duodenum. This included increased relative abundance of the genera Klebsiella and Escherichia, a finding that is also consistent with previous findings in studies using stool, but here we show that Escherichia is associated with chronological age rather than the aging process, and that Klebsiella is associated with the number of medications used.

Previous studies have shown that the stool microbiome is dominated by bacteria from the phyla Firmicutes and Bacteroidetes. We found that the common core microbiome in the duodenum is also dominated by phylum Firmicutes, including the genera Streptococcus and Veillonella which are part of the core of the duodenal microbiome, but the relative abundance of the other major phyla differ with increasing age, including decreased relative abundance of Bacteroidetes, which is consistent with recent findings from the stool microbiome. These changes appear to be driven by increases in phylum Proteobacteria, which significantly and negatively affects the relative abundance of the phyla Firmicutes and TM7. Within phylum Proteobacteria, changes in the family Enterobacteriaceae also significantly and negatively impact the duodenal microbiome, affecting both the relative abundance of other microbial families and overall microbial diversity. These increases in Enterobacteriaceae were driven by the genera Escherichia and Klebsiella, both of which are coliforms, again supporting a link between increases in duodenal coliforms and decreased microbial diversity in older adults.

Further comparisons between the youngest and oldest groups of adults (ages 18-35 and 66-80 years, respectively) revealed that the changes in some genera were solely associated with chronological age (e.g., Escherichia, family Enterobacteriaceae), whereas others were in fact associated with the number of medications used (e.g., Klebsiella, family Enterobacteriaceae) or with the number of concomitant diseases (e.g., Clostridium, family Clostridiaceae). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of predicted microbial metabolic pathways based on 16S data suggested enrichment of microbial genes associated with the ubiquinone biosynthesis pathway in the duodenal microbiome of older adults. Ubiquinone constitutes the first line of defense in oxidative stress and plays an essential role in respiration in E. coli, so it is not surprising that this pathway could be enriched in older subjects.

In conclusion, this study examined how age and the process of aging are associated with changes in the microbiome of the small intestine, using validated sampling and processing techniques. The most significant differences are higher relative abundance of the phylum Proteobacteria and decreased relative abundance of Bacteroidetes in older subjects when compared to the youngest group. The higher relative abundance of Proteobacteria appeared to affect other duodenal microbial taxa, leading to decreased microbial diversity and increased relative abundance of coliforms and of anaerobic bacteria. The small intestine is vital to digestion, nutrient absorption, and incretin regulation, and consequently has a critical effect on host metabolism. The small intestine microbial changes reported here may play a clinically relevant role in human health and disease throughout the aging process. Further studies are needed to understand the causes and implications of these microbial changes with advancing age.


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