Disappearance of the Human Microbiota: How We May Be Losing Our Oldest Allies
"The microbiota is not accidental," says Dr. Martin Blaser, Director of the Center for Advanced Biotechnology and Medicine at Rutgers University and author of Missing Microbes. "The microbiota has co-evolved with us over very long periods of time, and it performs beneficial functions for us, just as we perform beneficial functions for it…We are all working together as an ecological unit." Since our species–and all of life–has existed on earth, we have been in the company of microbes: microbes reside in our intestines, on our skin, and in the environments we live in. These bugs have at times been opportunistic pathogens, preying on the vulnerabilities of individuals and populations, but they have more frequently been some of our oldest evolutionary friends.
The trouble is, the microbiota as we’ve known it is disappearing.
Why are microorganisms disappearing? One popular explanation is the hygiene hypothesis, which suggests that people are not encountering enough microbial stimuli early in life. Blaser suggests that rather than the hygiene hypothesis alone, a more appropriate hypothesis may be that the microbes themselves are being depleted from generation to generation through a number of modern practices that disrupt our ancestral relationships to them. Instead of active hunter-gatherers subsisting on large quantities of fiber and in close contact with each other and the environment–like our ancestors–humans in the West have adopted increasingly sedentary urban existences that include processed foods, antibiotic exposure and lifestyle factors that differ widely from our evolutionary origins.
These practices, which limit the diversity of the microbiome, result in a loss of vertical transmission as each successive generation has fewer types of organisms to pass on to the next one. Blaser and others have suggested that this fundamental loss of microbes, particularly during early life, is behind the rapid rise of non-communicable disease in the 20th and 21st centuries.
The Importance of the Microbiota
From conception, our development is likely under the influence of microbial symbionts. Whether there exists a unique placental microbiota is under active research, but one animal study demonstrates that even a transient in utero exposure to maternal microbes can reprogram and strengthen the neonatal immune response. Babies are first introduced to the microbiota at birth, when they are bathed in the Lactobacillus-rich microbial community of the birth canal, which ultimately seeds their gut microbiota. The indigestible oligosaccharides in breast milk reinforce and select for symbiotic microbial species, while the microbes digest the glycans for the infant and participate in critical priming of the immune system. As infants explore (and taste) their environments, and as solid foods are introduced, the microbiota matures and forms a lifelong communication interface at the mucosal surfaces of the body.
These microbes, especially in the rich and diverse incubator of the gut, have many effects on human health:
- Influencing metabolic function.
- Protecting against opportunistic infection.
- Breaking down compounds that are indigestible to humans.
- Modifying gene expression.
- Communicating with the immune system.
- Producing neurotransmitters that impact neurological function and behavior.
Comparisons to the gut microbiota of cultures more reflective of ancestral lifestyles, such as those in the Amazon, Malawi, Tanzania and Papua New Guinea, consistently demonstrate an enriched diversity of microbes compared to that of Western societies. Specifically, societies with more ancestral ways of life consistently have a higher abundance of fiber-fermenting genera such as Prevotella and display significant functional differences in the metabolic potential of their gut microbiota. Hunter-gatherer and agrarian societies show some compositional differences between one another, but together are more similar and more species rich than those of U.S. communities. This suggests that Western societies have diverged significantly from the microbiota we coevolved with, both through compositional changes and changes in the number of species present.
Many Lifestyle Factors Affect Microbial Diversity
While often medically necessary, modern practices such as perinatal antibiotics, Cesarean section, and formula feeding all impact the fragile window during which immunological and metabolic patterning is established. "There’s a developmental trajectory that’s set in the first couple years of life," says Blaser. "This is just when the intergenerational transfer [of microbiota] is going on. It’s been going on for millions of years. We’re thwarting that." More and more evidence suggests that the effect of antibiotic disruption is important at any life-stage, but is especially dramatic in early life. Children who receive antibiotics within the first 2 years of life, for example, are at substantially higher risk for allergy, asthma, obesity and inflammatory bowel disease later on. Although often times antibiotics are life-saving interventions, we now appreciate that rather than returning to normal following antibiotic treatment, the microbiota may never completely recover.
The Western diet also has a critical influence on the microbiota. Western diets high in saturated fats, refined carbohydrates and sugars, and low in fresh foods and fiber are associated with reduced microbial complexity, an imbalance of the gut ecosystem and disease. Part of this loss may stem from nutrient competition, loss of indigestible bulk making it to the colon where the richest communities of bacteria live, changes to the inflammatory milieu at the host-microbe interface, and other environmental alterations such as pH. Each of these changes slowly selects away from microbes adapted to survive on nutrient-rich food in a stable host environment. Animal studies have demonstrated that such "diet-induced extinctions" can severely limit the diversity of the microbiota in increasingly aggressive ways over successive generations. The loss is not benign. Within a generation, immigrants from low-risk countries to Western societies achieve the same risk as Westerners of microbiota-associated chronic diseases like inflammatory bowel disease.
How Can We Recover Microbiome Diversity?
First, staunch the wound. Antibiotic over-prescription and misuse must be reined in as quickly as possible. Governments should monitor and restrict over-the-counter antibiotic sales and educate both the public and care-providers about the importance of antibiotic stewardship. In light of current research, early-life antibiotic therapy must especially be weighed against the mounting evidence of the long-term risks to young children. Medical organizations should critically review standards of care which may promote unnecessary courses of antibiotics, especially in infants.
We may also shift our medical focus toward narrow-spectrum antibiotics that properly target the infection, leaving the remainder of the microbiota unscathed. Where antibiotics used to be praised for the breadth of their spectrum, it may be that the antibiotics of the future are prized for their specificity. Waiting for a specific bacterial identity for narrow-spectrum treatment may be tricky in the hospital setting, where there is not always time to wait for a complete culture to come back, but this dilemma underlines the need for rapid clinical diagnostics.
Changing medical practices outside of antibiotics may help, too. In the case of Cesarean section (C-section), the World Health Organization agrees that it should be limited to medical necessity. In the case that C-section is necessary, babies can potentially be ‘seeded’ with the mother’s vaginal flora to mimic a natural exposure to the microbiota. Early data suggests that this technique has been able to partially abrogate the microbial loss to C-section. Supporting and providing safe spaces for new mothers to continue breastfeeding is also an important way to help raise breastfeeding rates. Breastmilk remains a key reinforcement for the infant microbiota and developing immune system.
We must also consider lifestyle choices. Few diets have been so universally dismal for human health as the Western diet. The vital importance of fiber and its conspicuous lack in the Western diet cannot be overstated. Fiber acts as a "prebiotic" which reinforces populations of beneficial microbes. It is simultaneously metabolized by them into short-chain fatty acids, with multiplicative health benefits. Fresh fruits and vegetables provide a variety of dietary fiber types that promote microbial diversity, yet only about 5% of Americans are consuming the recommended 19-38 g per day. Probiotics, by contrast, are living organisms consumed in supplements or foods like yogurt, and are popular health products. While they have shown a variety of health benefits, clinical evidence that they are able to modify the composition of the microbiota in healthy subjects is sparse. Still, along with prebiotics, they can be part of a healthy diet. Exercise also enhances gut microbiome diversity and should be considered a part of any healthy lifestyle.
It may be possible to recover some of the microbial taxa that have gone missing from the Western gut microbiota. Groups such as the Global Microbiome Conservancy are actively seeking to sample, study and save the organisms that we are losing from around the world in an active ‘seed bank.’ Their work gathers samples from diverse and underrepresented populations from more than 30 countries worldwide, including those from ancestral ways of life such as hunter-gatherer populations. With their dedication, and a bit of luck, we may be able to both understand and preserve the ancestral microorganisms that provide benefits to human health.
"It will take remediation," says Blaser. "The first point is to stop the damage, then rebuild."
Milani C. et al. The First Microbial Colonizers of the Human Gut: Composition, Activities, and Health Implications of the Infant Gut Microbiota. Microbiology and Molecular Biology Reviews.2017.
Halfvarson J. et al. Dynamics of the Human Gut Microbiome in Inflammatory Bowel Disease. Nature Microbiology. 2017.