Inside you, there are two wolves … one is evil, the other one is good … they are having
a terrible fight … This is how a proverb of fuzzy origins1
starts, which has lately been extensively parodied on the internet. The original version
is one of countless moralistic-metaphorical tales about the internal fight between
an individual’s positive and negative emotions, similar to the depiction as angel-and-demon
versions of the same subject in the Western comic culture.
Most religions and mythical beliefs concord on the existence of an immaterial essence
of living beings, in charge of the higher, noble mental abilities such as reason,
morality, and consciousness – the soul.
My personal experience with the soul is mainly one of linguistic confusion though,
as I happened to be born in the south-western region of Germany named Swabia, where
the term Seele designated not only the ethereal essence of human creatures, but also
a local food specialty, more precisely a baguette-shaped bread made from spelt and
traditionally coated in large grain salt and caraway. Therefore, when introduced to
the idea of the immortal soul, three-year-old me instantly created a very vivid mental
image of some sort of luminous, shiny piece of bread stuck inside the human ribcage,
which still comes to my mind three decades later, whenever someone mentions souls.
Beyond doubt more attracted to food than metaphysical concepts, I nonetheless entered
“soul” into PubMed, out of sheer curiosity. The result exceeded the wildest expectations
of the cynical mind, as the second result turned out to be a paper proudly claiming
to elucidate the neurobiology of the soul . In a delightful mashup of malarkey
and flamboyant scientific terms, “The Soul, as an uninhibited mental activity, is
reduced into consciousness by rules of quantum physics” details how the amorphous
soul, initially lacking spatial and temporal information, is squeezed into unconscious
and mental events by the maturation of the frontal cortex and the rise of γ-aminobutyric
acid (GABA) to the rank of main inhibitory neurotransmitter. Quantum physics kick
in once the reader is instructed that the universe and the brain share the same structural
properties, and that “the universe fills the soul by quantum, and the soul fills the
brain by physics”.
At this stage I was seriously wondering if I hadn’t stumbled by chance across another
Alan Sokal affair2
– back in 1996, the professor of mathematics had managed to get an intentionally nonsensical
paper titled “Transgressing the Boundaries; Towards a Transformative Hermeneutics
of Quantum Gravity”, explaining that the physical reality is no more than a mere social
and linguistic construct, published in a renowned academic journal. Sokal’s (achieved)
goal was to demonstrate the ideological bias and negligence of the editorial process,
as well as the thriving anti-intellectual, deconstructionist critique of science.3
It is however much more likely that I found an explanation why random strangers in
a bar keep trying to convince me that genetic information can be transmitted by the
memory of water via soundwaves.4
Quantum physics aside, the idea of several (im)material entities sharing and controlling
one single body is extremely widespread. With time, the concept of a soul has strayed
away from the ideological focus and spread into psychology and fiction (often as an
equivalent of consciousness), and apparently undergone mitosis. Sigmund Freud for
example structured the “psychic apparatus” into the instinct-driven id, critical super-ego,
and realistic, diplomatic ego mediating between the two.
Fiction in turn has popularised the individualisation of contrasting emotions, such
as in the highly acclaimed 2015 animated movie “Inside Out”, where a little girl is
piloted by colourful, anthropomorphic personifications of joy, fear, anger & Co. inside
her head, and extensively explored the idea of mind coalescence or hive minds: from
superorganism like Isaac Asimov’s Gaia planet in the Foundation series, to aliens
overtaking human bodies, typically leading to a fight between two minds over the controls
of one organism, for instance in the 2013 The Host movie.
Just like the terrible fight between the two wolves inside us, and the pending question
“which one will win?”. The official answer is “the one you feed”, and this leads us
straight down the oesophagus to what actually comes closest to the only scientifically
proven set of separate entities inhabiting one human body and influencing an impressive
amount of processes in there. Actually, “Inside you are about two kilograms of microorganisms”
would make for a much more accurate start into the proverb, and the conclusion would
still hold true.
While the nature and exact location of the soul have been the matter of vehement debate,
no doubt persists regarding the identity of countless genera of bacteria, archaea,
protists, fungi, and viruses, as well as their presence on almost all body surfaces,
with the bowels for headquarters . As a consequence of the last fact, the gut microbiome
is the most intensely studied department among the unicellular population of the human
body, including its role in development, physiological functions, and disease [3,4].
Namely two processes have made the headlines over the past decades – first its involvement
with the education and upkeep of the host immune system, inflammation control, and
autoimmunity prevention ; second the “gut–brain axis”, comprising the role of the
microbiota in behaviour, mood, and neurodegenerative diseases .
But as seemingly all roads lead to the gut, more and more connections come into sight,
including the “gut-lung” axis, which stands at the centre of the highlighted article
by Jilin Yu’s team in this issue of Microbes & Infection . Here, the authors demonstrate
that antibiotic pre-treatment in mice causes dysbiosis of the gut microbiota and impairs
the host immune response to Pseundomonas aeruginosa, one of the leading causes of
nosocomial infections, notably hospital-acquired pneumonia .
Coincidentally, since the start of the ongoing COVID19 pandemic, pneumonia has been
on the tip of everyone’s tongue, as one of the main complications caused by the novel
coronavirus consists in severe pneumonia and acute respiratory failure . That said,
pneumonia had already quite the portfolio, even before SARS-CoV-2 entered the stage
– with approximately 4.5 million cases and 4 million deaths worldwide per year, it
is the currently deadliest infectious disease [10,11].
This aside, the present study by Wang et al. adds several valuable new elements to
previous studies regarding the gut-lung connection [, , ].
Namely the fact that the authors do not observe any changes in the composition of
the lung microbiome following antibiotic treatment is of particular interest, as this
seems to have been a point of dispute in previous studies. For instance, Schuijt et al.
published a study advocating for the existence of the gut-lung axis in 2016, where
they depleted the gut microbiota in mice with an antibiotic cocktail and then infected
the animals with Streptococcus pneumoniae, the pathogen responsible for half of all
pneumonia cases . Compared to controls, these mice displayed higher bacterial
dissemination, inflammation, organ damage, and mortality. Faecal microbiota transplantation
(FMT) from untreated animals resulted in the normalisation of the infection and inflammatory
status. Additionally, the authors observed that alveolar macrophages derived from
mice pre-treated with antibiotics exhibited a reduced ability to phagocytose S. pneumoniae,
as well as a reduced responsiveness towards lipoteichoic acid and lipopolysaccharides.
The report received , and addressed , some criticism for not verifying any
potential impact of the antibiotic treatment or the FMT on the lung microbiota, leading
thus to a “premature invocation of a gut-lung axis”, shifting the debate to the actual
existence of the lung microbiota itself.
As a matter of fact, the respiratory tract was considered sterile until quite recently
, when the overall gain of interest in the microbial populations hosted by the
human body promoted researchers to screen other organs than the intestines for inhabitants
, the lung being one of the latest recruits .
Studies converge so far on the presence of a low density microbial population, principally
bacteria, displaying a considerable heterogeneity between individuals and lung regions.
What mixture counts as healthy is still a matter of debate, but in any case, it is
expected to change in, and potentially modulate, the lung affected by cigarette smoke,
chronic obstructive pulmonary diseases, asthma, fibrosis, and lung cancer [16,17,19].
However, both the small amounts of microorganisms in the lung and the reduced accessibility
of the lower respiratory tract, especially in studies on human subjects, represent
obvious technical hurdles for the routine assessment of the lung microbiota .
Wang et al. themselves advise caution regarding their results, quoting the difficulties
involved in sampling the lungs for microbiota sequencing .
As expected, human studies related to the gut-lung axis are yet rare . Shimizu
et al. performed a randomized controlled trial in 2018 in order to determine if the
administration of synbiotics would benefit mechanically ventilated patients with sepsis.
The treatment reduced significantly the incidence of enteritis, as fairly expected,
but also of ventilator-associated pneumonia , although the methodology encountered
some scepticism . Moreover, Shenoy et al. examined both the gut and lung microbiota
in HIV-infected patients with pneumonia. Interestingly, they found that the gut, but
not the lung microbiota, composition correlated with CD4 cell counts, and thus diseases
severity, prompting them to hypothesise that the intestinal microbiome modulates peripheral
immune function and response to lung infection .
Another interesting point of the highlighted paper is the focus on neutrophils as
a target population of the antibiotic pre-treatment . Indeed, most previous studies
have primarily examined the behaviour of alveolar macrophages, the resident pulmonary
immune cells, following the disturbance of the intestinal microbiome , omitting
the recruitment of circulating members of the host immune system upon pulmonary infection.
Evidence for the importance of a healthy gut microbiome for adequate neutrophil development
can be found in a study by Deshmukh et al. from 2014, where pregnant mice were exposed
to antibiotics, leading to a reduced number and diversity of the neonate intestinal
microbes. The new-borns displayed in addition fewer circulating and bone marrow neutrophils
and granulocyte/macrophage-restricted progenitor cells compared to controls, as well
as an impaired host defence and increased susceptibility to Escherichia coli and Klebsiella
pneumoniae . Fittingly, Wang et al. observe less neutrophil recruitment in the
P. aeruginosa-infected lungs of mice that had been subjected to antibiotic pre-treatment
. Hence, neutrophils are good candidates for at least one cellular intermediate
between the physically separate gut and lung, migrating either through blood or lymph
inside the so-called “mucosal immune system” [17,24]. Upstream of neutrophils, the
authors identified the lack of activation and expansion of γδ T-cells, in charge of
producing the pro-inflammatory IL-17 cytokine . γδ T-cell abundance is the highest
in the gut mucosa , where dendritic cells sample antigens from the gut lumen to
stimulate the proliferation and expansion of T-cells , and although it is yet
unclear which specific antigens drive their activation, it is tempting to speculate
that at least some derive from the intestinal microbiome. In accordance with the present
results, Deshmukh et al. also observed a reduction of IL-17-producing cells in the
antibiotic-treated mouse intestine .
To note, the road from gut to lung might very well be a two-way street. Coopersmith
et al. showed in 2003 that pneumonia-induced sepsis by P. aeruginosa in mice caused
apoptosis and impaired proliferation of gut epithelial cells , which in turn would
quite probably impact on the intestinal microbiome .
Should feeding the right microbes thus also be part of respiratory tract-related therapies?
Probably, claims the literature. Although concrete proof has still to be delivered,
prospects are good for healthy diets and probiotics to reduce asthma risk, support
chemotherapy, and curtail lung infections [16,17].
At least, “food for the soul” makes much more sense now.
Pneumonia affects 4.5 million individuals and causes 4 million deaths every year
It accounts for 15% of all deaths of children under 5 years old
Pseudomonas aeruginosa is a Gram-negative bacterium causing disease in plants and
animals, and notably nosocomial infections in humans
The bacterium’s ability to form biofilms accounts for its enhanced drug resistance
In a nutshell
Antibiotic treatment of mice prior to Pseudomonas aeruginosa infection doubled the
mortality rates and led to appreciably higher bacterial burden
Substantial alterations of the gut, but no the lung microbiota is observed in antibiotic
pre-treated mice, including a decrease of microbial diversity, and an increase in
the abundance of Proteobacteria
TNF-α as well as IL-6 protein and mRNA levels were reduced, and IL-10 levels elevated
in the antibiotic treatment group
IL-17 levels are lower in pre-treated mice, leading to a reduced production Cxcl1/2,
and thus fewer neutrophils in their lungs
Antibiotics decreased the steady state percentage of γδ T17 cells and prevented their
activation and expansion upon P. aeruginosa infection, as well as their IL-17 production
Blocking γδT cells in mice with antibodies closely mimicked the phenotype of antibiotic-treated
Conflict of interest
The author declares no conflict of interest.