By: Johnny Kung
16 Mar, 2020
Understanding How the Microbiome Impacts Public Health via a Multidisciplinary Approach
March 16, 2020
Background
Recent research on the microorganisms that live in or on our bodies — collectively known as the “microbiota” or “microbiome” — is changing the traditional perception in medical science and public health that microorganisms primarily act as causes of infectious diseases that must be eliminated in order to protect human health. Instead, there is a growing understanding that the microbiome is a crucial component of the holobiont, interacting with the physiology and genetics of the host in complex, bidirectional ways, and possibly helping to mediate the effects of the ecological and social environments on the host’s biology. An understanding of the human microbiome, and how social/cultural practices and environmental factors affect the microbiome, thus have a major role to play in an integrated, systems-level approach to public health policy and practice, particularly as they relate to the “bookends” of life — childhood and old age. Recent work by CIFAR fellows in the Humans & the Microbiome program, which draws together expertise from microbiology, evolutionary biology, anthropology and more, illustrate the importance of using a truly interdisciplinary lens to study the role of the microbiome in shaping human health.
Why this matters
The work summarized in this brief highlights important insights from frontier research on the human microbiome that public health practitioners should consider when developing programs and policies. Many of these studies uncover significant and specific changes in the microbiome due to social and environmental factors — diet, lifestyle, antibiotic use, built environment, etc. The resulting changes in the microbiome, in turn, are found to be correlated with a range of health outcomes that are often the focus of public health research and measures, including childhood malnutrition and stunting, susceptibility to infections, noncommunicable diseases such as asthma and cardiovascular diseases, and aging-related conditions such as Alzheimer’s disease. Working towards a more causative or mechanistic understanding of how social and environmental factors affect health via the microbiome may thus create additional avenues of interventions to tackle the social determinants of health, and at the same time, practitioners will need to take into account the effects that health policies and clinical practice may have on the microbiome.
Key insights
The interplay of environmental factors, the microbiome and health outcomes
- A study led by Eran Elinav provides support for the notion that the microbiome plays a significant role in mediating the effects of environmental factors on health outcomes. In an analysis on an Israeli cohort with varied ancestries, the researchers found that it is not host genetics — as reflected by ancestry, the genetic kinship of relatives or an individual’s genetic markers — but instead environmental factors (such as diet, lifestyle or sharing the same household) that are significantly associated with differences in the gut microbiome. The authors also found that, compared with host genetic differences, it is microbiome composition that is more strongly associated with the differences in a number of health-related phenotypes, including body-mass index, the levels of HDL cholesterol or blood sugar.
- In a review in Environmental Microbiology , Brett Finlay and colleagues examine the current understanding of the link between early-life environmental exposure, the gut microbiome and incidence of asthma or allergies later in life. The authors look at the evidence for a “critical window” in the first 100-days of life when the gut microbiota can modulate the host’s immunity, by limiting the development of proinflammatory immune cells and promoting anti-inflammatory ones, and in turn affect the occurence of allergy in later life. Additionally, certain bacterial metabolites released from the degradation of dietary fibres seem to protect against allergies. Finally, research on a number of “natural experiments” involving communities with similar geography and population make-up, but different degrees of industrialization, suggest that living in rural areas or near farms or parks, where there is higher microbial diversity (also reflected in the increased microbial diversity in household dust), seems to protect against allergies.
The microbiome and the transmissibility of chronic diseases
- A team of Humans & the Microbiome fellows propose in a perspective article in Science that certain chronic diseases traditionally considered to be noncommunicable, such as type 2 diabetes, cardiovascular diseases and inflammatory bowel diseases, may in fact have a communicable component via the microbiome, which can have significant implications for public health in terms of both preventive measures and treatments. The authors give an overview of the evidence that the microbiome is often in a state of imbalance or dysbiosis in individuals with these chronic diseases; data showing that individuals sharing a household or similar geography with others with such diseases often quickly acquire the same conditions and similarly dysbiotic microbiomes; as well as experimental results demonstrating that the transfer of dysbiotic microbiota from humans or animal models to non-diseased animals can result in similar disease phenotypes. While the links are tantalizing, the authors acknowledge the difficulty in many cases of teasing apart the direct effects of environmental factors from those of the microbiome, and hope to spur further conversations and experiments to more rigorously test the causal effects of transmissible microbiomes on chronic diseases.
The effect of early-life antibiotics exposure on health
- There is growing evidence for the potential consequences of antibiotic overuse that calls for a change to public policy and medical practice, including how antibiotics-triggered dysbiosis in newborns may significantly increase the later-life risk of asthma. At the 2019 Annual Conference of the International Society for Environmental Epidemiology, Brett Finlay and his colleagues presented data from the ongoing Canadian Healthy Infant Longitudinal Development (CHILD) prospective cohort study of almost 3500 children tracked since before birth. Their data show that systemic antibiotics use in the first year of life is correlated with a decrease in gut microbiome diversity and an increased risk of asthma in 1-4 y.o.
- A recent paper from the lab of Martin Blaser provides further support for the effects of early-life antibiotic use on later-life health outcomes. In this experiment, 5-10-day old mouse pups that were exposed to antibiotics via their mothers’ milk were found to suffer more severe colitis when infected by a pathogenic strain of gut bacteria as late as 80 days after the exposure. The composition and diversity of the gut microbiota was significantly changed in these mice, and when transferred to germ-free animals that were not exposed to antibiotics in early life, the affected microbiota were found to lead to similar susceptibility to enhanced colitis.
The link between the microbiome and stunting
- In a led by Philippe Sansonetti and also involving Brett Finlay and Tamara Giles-Vernick , the researchers investigated children’s microbiome in the context of stunting, or delayed linear growth, a major global health problem that affects a quarter of the world’s children. By analyzing the gut and faecal microbiota from more than 400 children in Madagascar and the Central African Republic, the study found that in stunted children the microbiome of the upper gut (stomach and small intestine) is more similar to the microbiome usually found in the oral cavity and oesophagus. The researchers also observed a decrease in bacterial species that produce the nutrient-rich metabolite butyrate, as well as an increase in enteropathogenic strains, suggesting a vicious cycle where gut dysbiosis leads to further malnutrition and infection. These results shed new light on the pathophysiology of stunting and potential ways to intervene in the condition.
Probiotics and the gut microbiome
- Probiotics is increasingly being used as a health supplement or treatment, e.g., to prevent dysbiosis following antibiotics use, but the actual health benefits and side effects of probiotics are still often poorly characterized. A paper by Eran Elinav and colleagues reports on a prospective longitudinal study that investigated how probiotics affect the reconstitution of the gut microbiome after antibiotics treatment. Study volunteers were given a course of broad-spectrum antibiotics, and then received either a commercially available probiotics formulation with 11 strains of bacteria or an autologous fecal microbiome transplantation (aFMT, in which the individual’s own fecal sample taken before antibiotics treatment was transplanted back into their gut), or allowed to recover spontaneously. Those who received aFMT saw a return of their original, “indigenous” microbiota in as soon as one day, while those allowed to recover spontaneously did so after three weeks. However, in individuals receiving the probiotics, while several of the probiotic strains successfully colonized the gut, the microbiome did not return to its indigenous state for at least five months. These results suggest an important tradeoff to consider regarding the use of probiotics following antibiotics treatment. While the widespread clinical use of aFMT is logistically challenging, further research may identify specific components of individuals’ microbiome that can be used to create defined, personalized probiotics treatment.
The role of the microbiome in aging-related conditions
- A review article in Bioessays by Brett Finlay, Sven Pettersson, Melissa Melby and Thomas Bosch gives an overview of research exploring the many links between the microbiome and old age, which can have important implications for the wellbeing of an aging population and its impact on the health care system. Studies have shown that a number of microbial metabolites play a role in upregulating the growth factor FGF21, which regulates host metabolism and longevity, and experiments in animal models suggest that transplanting gut microbiomes from young to older individuals can induce lifespan extension. The production of these metabolites, in turn, has been found to be affected by lifestyle factors such as diet and exercise. At the same time, social and environmental factors may also influence the psychological and behavioural responses to aging through their effects on the gut microbiota, which produce neuroactive molecules that influence the central nervous system via the gut-brain axis (the neural and hormonal connection between the gastrointestinal tract and the central nervous system). An example is the strong correlation between a high soy diet (specifically, the isoflavone found in soy) with longevity and a more positive experience of the menopause among Japanese people, compared with North American populations which seem to derive less benefit from isoflavone intake. This observed difference may be related to the higher prevalence of bacterial strains, in the gut microbiome of Japanese populations, that can metabolize isoflavone to equol.
- Another recent study led by Martin Blaser lends support to the idea that the microbiome plays a role in the development of Alzheimer’s disease in aging individuals. Conducting the experiments in a strain of mice genetically engineered to be more prone to Alzheimer’s-like symptoms, the researchers found that the composition of the gut microbiome changes with aging, but some of these changes were reversed if the mice were put through a calorie-restricted diet. In particular, the researchers found that the deposition of amyloid β plaques in the brain (a common marker of Alzheimer’s disease) was decreased in calorie-restricted mice, along with the decreased expression of proinflammatory genes in the gut. When the scientists added to young mice one of the bacterial strains that showed the highest increase with aging ( Bacteroides fragilis ), they observed increased sizes of amyloid β plaques in the brain, suggesting a direct biological effect potentially via the gut-brain axis. If confirmed in humans, these results may point to the possible role of diet as an intervention for Alzheimer’s disease. Importantly, these effects were only observed in female mice and not male ones.
Looking forward
- Building on the work above, members of the Humans & the Microbiome program have identified a number of key questions or research directions that will further elucidate the role of the microbiome in human health and the extent to which it mediates or buffers the effects of environmental factors:
- Better establishment of the causal role of microbial diversity and dysbiosis in health and disease;
- Improved characterization of the microbial metabolites and genetic pathways that may mediate the microbiota’s effects on health;
- Further exploration of the microbiome outside the gut, in other organs such as the lungs and skin;
- Expanding the investigation of other components of the microbiota beyond bacteria, such as viruses, fungi and parasitic worms; and
- The use of multidisciplinary methods that can complement lab-based studies on germ-free animal models, such as ecological “field studies” of animals with natural variations in genetics and microbiome, studies of non-human primates, and anthropological and historical approaches to investigate how the microbiome may vary with social and cultural practices.
References
Amato K et al. 2019. Multidisciplinarity in microbiome research: A challenge and opportunity
to rethink causation, variability, and scale. Bioessays 41:1900007.
Cox L et al. 2019. Calorie restriction slows age-related microbiota changes in an
Alzheimer’s disease model in female mice. Sci. Rep. 9:17904.
Finlay B et al. 2020. Are noncommunicable diseases communicable?
Science 367:250-251.
Finlay B et al. 2019. The microbiome mediates environmental effects on aging. Bioessays
41:1800257.
Rothschild D et al. 2018. Environment dominates over host genetics in shaping human gut
microbiota. Nature 555:210-215.
Roubaud-Baudron C et al. 2019. Long-term effects of early-life antibiotic exposure on
resistance to subsequent bacterial infection. mBio 10:e02820-19.
Sbihi H et al. 2019. Thinking bigger: How early‐life environmental exposures shape the gut
microbiome and influence the development of asthma and allergic disease. Allergy
74:2103-2115.
Sbihi H et al. 2019. Early-life antibiotic exposure, the gut microbiome, and the risk of
childhood asthma. Environ. Epidemiol. 3:351-352.
Suez et al. 2018. Post-antibiotic gut mucosal microbiome reconstitution is impaired by
probiotics and improved by autologous FMT. Cell 174:1406-1423.
Vonaesch P et al. 2019. Stunted childhood growth is associated with
decompartmentalization of the gastrointestinal tract and overgrowth of oropharyngeal
taxa. Proc. Natl. Acad. Sci. 115:E8489-E8498.
Further reading
CIFAR resources:
The Future of the Microbiome in Public Health (event brief)
The Human Microbiome & Public Health: Supporting Healthy Development and Aging (event brief)
The Microbiome in Human Health (event brief)
Antibiotic treatment in infancy can hasten the onset of type-1 diabetes in mice (research brief)
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