The human gut microbiome is a complex microbial ecosystem that plays an important role in our health.
For example, these microbes – bacteria, viruses, fungi – help regulate metabolism, fend off infections, produce essential vitamins and break down dietary fiber.
They may also be biomarkers of health and disease.
The human microbiota consists of the 10-100 trillion symbiotic microbial cells harbored by each person, primarily bacteria in the gut; the human microbiome consists of the genes these cells harbor[1].
Microbiome projects worldwide have been launched with the goal of understanding the roles that these symbionts play and their impacts on human health[2, 3].
Just as the question, “what is it to be human?”, has troubled humans from the beginning of recorded history, the question, “what is the human microbiome?”
has troubled researchers since the term was coined by Joshua Lederberg in 2001 [4].
Specifying the definition of the human microbiome has been complicated by confusion about terminology: for example, “microbiota” (the microbial taxa associated with humans) and “microbiome” (the catalog of these microbes and their genes) are often used interchangeably.
In addition, the term “metagenomics” originally referred to shotgun characterization of total DNA, although now it is increasingly being applied to studies of marker genes such as the 16S rRNA gene.
More fundamentally, however, new findings are leading us to question the concepts that are central to establishing the definition of the human microbiome, such as the stability of an individual’s microbiome, the definition of the OTUs (Operational Taxonomic Units) that make up the microbiota, and whether a person has one microbiome or many.
In this review, we cover progress towards defining the human microbiome in these different respects.
Studies of the diversity of the human microbiome started with Antonie van Leewenhoek, who, as early as the 1680s, had compared his oral and fecal microbiota.
He noted the striking differences in microbes between these two habitats and also between samples from individuals in states of health and disease in both of these sites [5, 6].
Thus, studies of the profound differences in microbes at different body sites, and between health and disease, are as old as microbiology itself.
What is new today is not the ability to observe these obvious differences, but rather the ability to use powerful molecular techniques to gain insight into why these differences exist, and to understand how we can affect transformations from one state to another.
Culture-independent methods for characterizing the microbiota, together with a molecular phylogenetic approach to organizing life’s diversity, provided a fundamental breakthrough in allowing researchers to compare microbial communities across environments within a unified phylogenetic context (reviewed in [7]).
Although host-associated microbes are presumably acquired from the environment, the composition of the mammalian microbiota, especially in the gut, is surprisingly different from free-living microbial communities [8].
In fact, an analysis of bacterial diversity from free-living communities in terrestrial, marine, and freshwater environments as well as communities associated with animals suggests that the vertebrate gut is an extreme [8].
In contrast, bacterial communities from environments typically considered extreme, such as acidic hot springs and hydrothermal vents, are similar to communities in many other environments[9].
This suggests that coevolution between vertebrates and their microbial consortia over hundreds of millions of years has selected for a specialized community of microbes that thrive in the gut’s warm, eutrophic, and stable environment[8].
In the human gut and across human-associated habitats, bacteria comprise the bulk of the biomass and diversity, though archaea, eukaryotes, and viruses are also present in smaller numbers and should not be neglected[10, 11].
Interestingly, estimates of the human gene catalog and the diversity of the human genome pale in comparison to estimates of the diversity of the microbiome.
For example, the Meta-HIT consortium reported a gene catalog of 3.3 million non-redundant genes in the human gut microbiome alone[3], as compared to the ∼22,000 genes present in the entire human genome[12].
Similarly, the diversity among the microbiome of individuals is immense compared to genomic variation: individual humans are about 99.9% identical to one another in terms of their host genome[13], but can be 80-90% different from one another in terms of the microbiome of their hand[14] or gut[15].
These findings suggest that employing the variation contained within the microbiome will be much more fruitful in personalized medicine, the use of an individual patient’s genetic data to inform healthcare decisions, than approaches that target the relatively constant host genome.
Many fundamental questions about the human microbiome were difficult or impossible to address until recently.
Some questions, such as the perennially popular “how many species live in a given body site?”, are still hard to answer, due to problems with definitions of bacterial species and with the rate of sequencing error.
Other questions, such as “how does the diversity within a person over time compare to the diversity between people?”, or “how does the diversity between sites on the same person’s body compare to the diversity between different people at the same site?”, or “is there a core set of microbial species that we all share?”, can now be answered conclusively. In the next section, we discuss some of the tools that have allowed these long-standing questions to be answered.
A recent study by researchers at University of California San Diego School of Medicine, San Diego State University and the Max Planck Institute for Developmental Biology found that the age and sex of an individual strongly influences the bacterial diversity of the gut microbiome.
The study, published online May 14, 2019 in mSystems, found younger age is positively associated with gut bacterial diversity in both men and women, but young women display greater biodiversity than young men.
“It is well known that the microbiome changes from childhood to adulthood.
We wanted to look at changes that happen in adulthood, from young adults to middle-aged adults, and if those changes are influenced by sex and age,” said senior author Varykina Thackray, Ph.D., associate professor in the Department of Obstetrics, Gynecology and Reproductive Sciences at UC San Diego School of Medicine.
“Our findings show a woman’s microbiome may be more diverse than a man’s and mature sooner.”
Greater microbial diversity in the female gut may be associated with sex hormones.
“Our results suggest that, because girls go through puberty earlier than boys, the microbiome of men may need time to catch up,” said Thackray, who is also a faculty member in the Center for Microbiome Innovation at UC San Diego.
The research team analyzed the gut bacterial diversity of approximately 8,900 adults, ages 20 to 69 from four geographic regions: the United States and United Kingdom – part of the American Gut Project citizen-science initiative based at UC San Diego – and two independent cohorts from Colombia and China.
In terms of age, researchers found that in the U.S., U.K. and Colombia cohorts, bacterial biodiversity correlated positively with age in young adults (ages 20 to 45) but plateaued around age 40, with no positive association observed in middle-aged adults (ages 45 to 69).
“We were intrigued to see that the differences we detected between men’s and women’s microbiome in young adulthood were less obvious in middle age,” said Thackray.
“One way of thinking about this is like the growth of plants in a newly cleared field.
Over a period of time, a diverse ecosystem of plants would become established and grow in the field until no more space was available.
Our study suggests that the human gut microbiome continues to diversify until age 40 or so when it seems to plateau, as opposed to continuing to become more and more diverse over a lifetime.”
Of note, researchers found little association of biodiversity with age or sex in the Chinese cohort.
“The idea that sex and age play a role in microbiome diversity may not be universal.
There is a lot more work that needs to be done with future longitudinal studies to understand the effects of factors like puberty, steroid hormone levels and hormonal contraceptives on diversification of the gut microbiome during adolescence and young adulthood,” Thackray said.
More information: Jacobo de la Cuesta-Zuluaga et al, Age and sex-dependent patterns of gut microbial diversity in human adults, (2019).DOI: 10.1101/544270
Provided by University of California – San Diego
