‘Timely, interesting and important’: Study links gut microbe metabolism to longevity

Data published in Nature​ indicated that centenarians have a distinct gut microbiome enriched in bacteria that can generate unique secondary bile acids.

Specifically, the researchers reported that Odoribacteraceae​, a gram-negative family of bacteria found in the feces of centenarians, may produce a specific bile acid (BA) called isoallo-lithocholic acid (isoalloLCA), which exerts potent antimicrobial effects against gram-positive (but not gram-negative) multidrug-resistant pathogens, such as Clostridioides difficile​ and Enterococcus faecium​.

“To our knowledge, isoalloLCA is one of the most potent antimicrobial agents selective against gram-positive microbes, including multidrug-resistant pathogens, suggesting that it may contribute to the maintenance of intestinal homeostasis by enhancing colonization resistance mechanisms,” ​wrote researchers led by Kenya Honda, MD, PhD, from the Keio University School of Medicine in Tokyo and the RIKEN Center for Integrative Medical Sciences in Yokohama.

The study, which compares the gut microbes of centenarians, elderly individuals (85–89 years old), and younger people (21–55 years old) in Japan, raises the possibility of manipulating the bile acid pool for health benefits.

Correlation and not causality, but…​

Commenting independently on the study’s findings, Prof Kim Barrett, Distinguished Professor of Medicine at UC San Diego, said: “This work seems timely, interesting and important, and to have been carefully conducted.  Like many studies that seek to implicate specific microbiome signatures with particular conditions in humans, as yet the work mostly reveals correlations rather than causality. ​

“On the other hand, bile acids are emerging as a new class of “enterohormones” beyond their classic role in fat digestion and absorption.  It is certainly conceivable that manipulating concentrations of specific bile acids, whether microbially or by giving them directly, could exert health benefits.”​

Study details​

Dr Honda and his co-workers studied three groups of Japanese people: 160 centenarians; 112 elderly people; and 47 younger people and found that there were distinct differences in several taxa between the centenarians and the other two groups. These differences could be classified in three ways or signatures, they said:

“The first signature included taxa whose abundance was increased or decreased with age; The second signature included taxa whose abundance was similar in centenarians and young controls, but distinct from the elderly; The third signature included centenarian-specific taxa whose abundance was significantly different between centenarians and both the elderly and young control groups, but not between these two control groups.”​

Those taxa that were enriched in the centenarians included Alistipes, Parabacteroides, Bacteroides, Clostridium​, and Methanobrevibacter​ species, said the researchers.  

The researchers then focused attention on strains of Odoribacteraceae​, species of bacteria within the phylum Bacteroides,​ and found that these bacteria were effective producers of isoalloLCA, and that this production was due to two enzymes: 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3βHSDH)

The study’s findings should be viewed in the context of some confounding factors, which limited the researchers ability to tease apart why centenarians have higher levels of these isoalloLCA-producing organisms.

“Also, the causal relationship between centenarians’ unique BAs and longevity needs to be validated with longitudinal surveys, additional participants, and long-term analyses of animal models,”​ they added. “Regardless, we may be able to exploit the unique bile acid-metabolizing capabilities of the bacterial strains identified in this study to rationally manipulate the bile acid pool and combat diseases caused by gram-positives like antibiotic-resistant ​C. difficile and VRE [vancomycin-resistant ​E. faecium].”​

Is the gut microbiome a primary or secondary driver of longevity? ​

Mark Miller, PhD, principal at Kaiviti Consulting, LLC, told NutraIngredients-USA that we need to interpret the data with caution.

“The study is comprehensive and highlights the association of a gut microbial profile of Centenarians that favors the production of secondary bile acids with antimicrobial properties for pathogenic species,” ​Dr Miller told us.

“This association does not prove cause-effect, but yet, it remains an intriguing association. While the publication has received much attention as a possible roadmap for those wishing to live over 100 years, but let’s be cautious,” ​he added.

Dr Miller noted that there are several points to consider that go beyond the production of secondary bile acids. The first of which is that there were two control groups: Young (ages 21-55) and Elderly (ages 85-89), and this elderly group exceeds the median age for most Western Countries, so they too qualify as examples of longevity.

Even so, the Centenarians differed from the Elderly in multiple ways, said Dr Miller, with Centenarians displaying: More physical activity;
A higher fecal pH which is most likely linked to lower production of butyrate, propionate (SCFA) and a higher production of ammonia;
Numerous differences on blood tests – lower RBCs, Albumin, total protein and Higher levels of CRP (inflammation) and lower kidney function (BUN); and
A lower BMI.

“Apart from physical activity and BMI, these are not usually ideal wellness characteristics,” ​noted Dr Miller.

“To my mind there is an anomaly given that the elderly group (85-89 years old) did not display high levels of secondary bile acids, yet they qualify as examples of longevity. ​

“There is affirmation that enhanced activity and lower BMI is a hallmark of centenarians, this should be emphasized. For some time now the Japanese diet and lifestyle have been regarded as important drivers of longevity. What remains to be determined is the role of the gut microbiome – is it a primary or secondary driver of longevity?”​

Source: Nature​
2021, Published online ahead of print, doi: 10.1038/s41586-021-03832-5​
“Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians”​
Authors: Y. Sato, et al.