Aging-associated microbiota changes may be key to susceptibility
rather than aging itself
Age is clearly one of the primary factors correlated with severe
outcomes of COVID-19 and may be related to immunosenescence–the
gradual reduction in immune function typically observed with
age[14]. However, chronological age alone may not be the most
important factor in recovery from the viral infection, since people
under 40 years old have died, while others, who are over 90, have
recovered. It is hypothesized here that factors that are often, but not
always, related to aging are more important than age itself.
Clues as to these age-associated factors may come from the observation
that individuals with the most severe outcomes frequently had
preexisting conditions, including cardiovascular disease, hypertension,
Type 2 diabetes mellitus and chronic lung diseases, such as chronic
obstructive pulmonary disease (COPD) or asthma[1,3]. Thus, a brief
examination of some of these diseases in relation to the microbiome and
respiratory infections might be useful.
All these diseases are associated with inflammation and have been linked
to various types of imbalances, or “dysbiosis,” in the gut
microbiota([15,16]. Microbes are also found in tissues in healthy
controls, e.g., the blood[17] and lungs[18]. It has been
hypothesized that what distinguishes the diseased state from a healthy
state is increased levels of potentially pathogenic species from a
variety of endogenous or exogenous sources[12].
Extensive evidence for the role of the microbiome comes from studies of
the interactions between immune responses to various respiratory
infections and the intestinal microbiome in animal models. A recent review[4] comprehensively surveys the research regarding a
wide array of types of microbiome-viral interactions, noting that
evidence supports the idea that a normal healthy microbiome tends to
lead to resistance to viral infections. For example, in a chicken model
of influenza, antibiotic-treated mice are more susceptible to influenza
infection[19]. In a mouse model, the commensal bacteria, Clostridium
orbiscendins, produces desaminotyrosine, which primes Type I interferon
signaling, thus mediating protection from influenza[20]. In a model
of respiratory syncytial virus, a probiotic was able to restore
protection from viral infection in germ-free mice[21].
Many different microbes, including oral microbes associated with
periodontal disease[22] and Chlamydia pneumoniae[23], have been
found in atherosclerotic plaques, and these microbes have been proposed
to lead to the chronic low-grade inflammation typical of
atherosclerosis. COPD is associated with an abnormal or dysbiotic
microbial community in the lungs[18] and the gut[24]. Diabetes
and the obesity that is often associated with it are also characterized
by inflammation and imbalanced microbial communities[25]. Although
it is a low-grade inflammation, elevations of IL-6 and CRP indicate that
an inflammatory process is occurring[26]. Although these
inflammatory markers tend to increase with age, along with rates of
aging-associated diseases, they can be normal in those experiencing
healthy aging[26] and can be high in younger people under certain
circumstances[27].
Although not the topic of this article, it should be noted in passing
that there are other factors that might influence susceptibility to
COVID-19. A few of the possibilities include genetic effects on immune
responses, nutritional status, prior chronic disease or therapy effects
on immune responses and immune memory to coronaviruses or other
potentially cross-reacting viruses. The infectious dose of the virus may
also be important in determining outcomes.