The Journal of Infectious Diseases
VIEWPOINT
Thinking Small, Stinking Big: The World
of Microbial Odors
Tzvi Y. Pollock1, and Audrey R. Odom John1,2,
1
Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; and 2Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Keywords. infectious diseases; diagnostics; volatile organic compounds; VOCs; breathomics; mass spectrometry;
gas chromatography-mass spectrometry.
Humans live embedded in an ecosystem
of microbial life. Nowhere is this ecosys-
tem more apparent to the naked eye (or,
rather, nose) than in the world of micro-
bially derived odors. From the fungal
fragrances that sing of environmental
mold to the bacterial bouquet that warns
us off week-old leftovers, our air com-
prises a microbial miasma of informa-
tion, ripe for research and exploration.
Microbially derived odors, especially
those produced by pathogens, can prove
useful in the toolkit of both the microbe
and the diagnostician. A rapidly increas-
ing number of studies highlight the need
for further understanding of these odors
—their origins, their functions, and their
utility in our hands.
Microbial odors are mediated by vola-
tile organic compounds (VOCs), small
organic molecules with low boiling
points, generally synthesized during the
microbe’s metabolism. Multicellular or-
ganisms typically detect VOCs via dedi-
cated odor receptors, such as those in
the vertebrate nose or on arthropod an-
tennae. In the laboratory, individual
Received 14 September 2023; editorial decision 15
September 2023; accepted 19 September 2023;
published online 21 September 2023
Correspondence: A. R. Odom John, MD PhD, Department of
Pediatrics, Children’s Hospital of Philadelphia, 3501 Civic
Center Boulevard, CTRB 10100, Philadelphia PA 19104-4318
(johna3@chop.edu).
The Journal of Infectious Diseases®
© The Author(s) 2023. Published by Oxford University Press on
behalf of Infectious Diseases Society of America. All rights re-
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https://doi.org/10.1093/infdis/jiad405
VOCs produced by microbes can be
characterized using gas chromatogra-
phy/mass spectrometry, while the global
fingerprint of microbial odors can be
recognized through use of electronic
nose technology. Which microbial
VOCs mediate what odors—and to
what purpose—are topics of ongoing
investigation in the field.
WE WANT TO SMELL THEM
Why even care about the little smells of
our microscopic neighbors? Specific
odors have long been associated with hu-
man disease and have served well as rudi-
mentary and noninvasive diagnostics. As
early as 400 BCE, Hippocrates advised that
students smell their patients’ breath to
diagnose illness [1]. While our under-
standing of the underlying pathophysiol-
ogy may have advanced in the millennia
hence, conditions such as portal hyper-
tension and diabetic ketoacidosis are
readily recognized by their associated
characteristic odors. Microbial patho-
gens tend to demonstrate more subtle
odor profiles than these noninfectious
conditions, as the odoriferous insult
operates on far smaller orders of magni-
tude. This has not stopped us from
seeking out new methods of detecting
microbial infection by way of pro-
duced VOCs. Compared to other test-
ing mechanisms, testing the odor
profile of patients is minimally inva-
sive. Additionally, as the testing relies
on key metabolic products of the infec-
tion rather than easily mutated
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antigens, the prospect of microbial
mutation away from diagnostic effica-
cy is far more remote.
Detection of infection by way of scent
has already proven possible thanks to
both human technology and mammalian
cooperation. In partnership with our
four-legged friends, human clinicians
have been able to pinpoint infections
with startling accuracy on the basis of
scent alone. African giant pouched rats
(Cricetomys gambianus) in Tanzania
and Mozambique have been successfully
trained to sniff out and differentiate spu-
tum samples from patients infected with
tuberculosis, with greater accuracy than
even trained human microscopists [2].
In Canada and the Netherlands, mean-
while, odor-sniffing dogs (Canis lupus
familiaris) have been trained to identi-
fy Clostridium difficile in stool [3].
Preliminary studies additionally abound
investigating the potential of canine as-
sistance in the detection of severe acute
respiratory syndrome coronavirus 2
(SARS-CoV-2) infection [4]. Manmade
attempts are likewise promising, with
breath tests for infections such as tuber-
culosis, SARS-CoV-2, and even malaria
showing high sensitivity and accuracy
[5]. Our ability to accurately and nonin-
vasively pinpoint infection looks to be
steadily improving, in part by detecting
pungent pathogens.
THEY WANT US SMELLING THEM
In the push and pull of host-pathogen
competition, any evolutionary advantage
VIEWPOINT • JID • 1
over the adversary is liable to be main-
tained, and any disadvantage quickly dis-
carded. Why, then, might pathogenic
microbes release VOCs at all, if they
might facilitate host detection and avoid-
ance of infection? Microbial odors are
not simply an inevitable byproduct of
host metabolism during infection; patho-
gens such as Mycobacterium tuberculosis
or Plasmodium falciparum, the causative
agent of severe human malaria, are
known to directly produce similar vola-
tiles in vitro as they do in patients [6].
While many microbial VOCs are likely
unavoidable derivatives of normal patho-
gen metabolism, evidence suggests some
microbes have evolved to use odors to in-
fluence their hosts and disseminate.
The sweet, earthy scent of petrichor
that follows a light rain is mediated in
part by the VOC geosmin, which is pro-
duced by soil-dwelling bacteria such as
the spore-forming Streptomyces coelicol-
or. S. coelicolor actively synthesizes geo-
smin when sporulating, and the
resulting scent can be detected far and
wide. One study demonstrated that geo-
smin production rendered S. coelicolor
especially attractive to soil-resident ar-
thropods called springtails (Folsomia
candida) [7]. This attraction was shown
to enhance the dispersion of S. coelicolor,
as the springtails consume and spread the
spores that proved so alluring.
In a sinister parallel, similar dynamics
have been observed in human infection.
As mentioned earlier, the malaria parasite
P. falciparum is known to produce detect-
able changes in human breath metabolites
during infection [8]. Unfortunately, we
are not the only ones to have noticed.
Studies have found that the vectors of ma-
laria, Anopheles mosquitoes, are suckers
for the scent of Plasmodium spp. infection
2 • JID • VIEWPOINT
[9]. Patients infected with the parasite,
specifically during the life stage in which
the parasite requires vector uptake, are
twice as attractive to the mosquito as un-
infected patients. In this way, the parasite
manages to enhance its own transmission
with just an inviting aroma.
We float every day through a vast
ocean of smells that we are only now
learning to pick out of the ambient air.
Pathogens have clearly wasted no time
in utilizing scent to bolster their own fit-
ness. Now that we are aware of these mi-
crobial odors, which opportunities to
leverage them for human health will
bear fruit? Only the nose knows.
Notes
Financial support. A. O. J. is support-
ed by the National Institutes of
Health (grant numbers R01AI103280,
R01HD109963, R01AI171514, and
R33HD105594); the US Department of
Defense; and is an Investigator in the
Pathogenesis of Infectious Diseases of
the Burroughs Wellcome Fund.
Potential conflicts of interest.
T. P. reports no conflicts of interest.
A. O. J. reports pending patents on breath
biomarkers for malaria and SARS-CoV-2;
and receives compensation for editorial
roles from the Infectious Diseases Society
of America and the American Society for
Microbiology. Both authors have submitted
the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the edi-
tors consider relevant to the content of the
manuscript have been disclosed.
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