A new study by Keio University School of Medicine and the Broad Institute of MIT has revealed that centenarians (people that reach the age of 100) have a unique microbiome that may protect them from certain bacterial infections including diseases caused by multi-drug resistant bacteria. This finding may help researchers develop new ways to treat chronic inflammation and bacterial disease.
The unique microbiome of centenarians
The microbiome has long been recognised as a key player in determining the health status of aging individuals. This is largely due to its role in controlling digestive function, bone density, neuronal activity, immunity and resistance to pathogen infection. Microbial consortia in elderly individuals often show increased interindividual variability and reduced diversity, and are therefore being linked to immunosenescence, chronic inflammation and frailty. Meanwhile, centenarians are less susceptible to age-related chronic diseases and have a history of surviving several bouts of infectious diseases. It has therefore been theorised that there are centenarian-specific members of the gut microbiota, which might actively contribute to resistance against pathogenic infection and other environmental factors.
In this study, the researchers aimed to identify the beneficia members of the gut microbiota of centenarians and how they increase longevity.
Secondary bile acids and the unique microbiota of centenarians
A team of researchers from the Keio University School of Medicine and the Broad Institute of MIT and Harvard studied microbes found in the faecal samples of 160 Japanese centenarians. Overall, the individuals studied had an average age of 107. They found that those aged 100 and above, compared to people aged 85 to 89 and those between 21 and 55, had increased levels of several bacterial species that produce molecules called secondary bile acids.
Secondary bile acids are short chain fatty acids that are generated by microbes in the colon. They are thought to help protect the intestines from pathogens and also regulate the body’s immune response. The unique secondary bile acids found to be elevated in centenarians include iso-, 3-oxo-, allo-, 3-oxoallo-, and isoallo-lithocholic acid (LCA). The biosynthetic pathway for isoalloLCA has not yet been described.
Characterising the biosynthetic pathway of isoalloLCA
In order to characterise the biosynthetic pathway of the previously uncharacterised isoalloLCA, the researchers sequenced and screened the genomes of 68 bacterial isolates from a supercentenarian’s (aged over 110 years old) faecal microbiota. The team identified that strains of the microbe Odoribacteraceae are effective producers of isoalloLCA both in vitro and in vivo. Furthermore, the researchers found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3βHSDH) were responsible for isoalloLCA production.
To evaluate their predicted bile acid biosynthetic pathway, the team sequenced the genomes of all 68 the bacterial isolates from the faecal microbiota of the supercentenarian. Sequences orthologous to human 5AR were identified in 21 of the bacterial strains with >30% amino acid sequence similarity. The team found clusters of genes functionally related to bile acid metabolism in all 21 strains. Their analysis also identified sequences annotated as short-chain dehydrogenase (SDR), which the team predicted to be 3βHSDH.
The antimicrobial activity of isoalloLCA in the unique microbiome of centenarians
The team also set out to identify bacterial strains and enzymes that are responsible for biosynthesis of secondary bile acids unique to centenarians. The researchers treated common infection causing bacteria with the secondary bile acids that were elevated in the centenarian population. It was found that one molecule, known as isoalloLCA, strongly inhibited the growth of Clostridioides difficile. C. difficile is a gram-positive antibiotic-resistant bacterium that causes severe diarrhoea and gut inflammation.
The team fed mice infected with C. difficile diets that were supplemented with isalloLCA. It was found that the secondary bile acid supressed the levels of the pathogen. Interestingly, the team also found that isoalloLCA potently inhibited the growth of or killed many other gram-positive pathogens. This finding suggests that isoalloLCA may help the body to retain the delicate equilibrium of microbial communities in a healthy gut.
Summary
In the study, researchers identified that centenarians have a unique microbiome that contributes to age related longevity. This unique microbiome includes specific gut microbiota signatures as well as defined bacterial species and genes/pathways that promote the generation of antimicrobial secondary bile acids, such as isoalloLCA. The action of isoalloLCA on C. difficile suggests that it is a potent antimicrobial agent selective against gram-positive microbes, suggesting that it may contribute to the maintenance of intestinal homeostasis by enhancing colonisation resistance mechanisms. This finding my enable researchers to exploit the unique bile acid-metabolising capabilities of the bacterial strains identified in this study to manipulate the bile acid pool and combat diseases.
Image credit: Jezperklauzen – canva.com
