@article{
author = "Popovic, Dusanka and Kulas, Jelena and Tucovic, Dina and Popov Aleksandrov, Aleksandra and Malesevic, Anastasija and Glamoclija, Jasmina and Brdarić, Emilija and Soković Bajić, Svetlana and Golić, Nataša and Mirkov, Ivana and Tolinački, Maja",
year = "2023",
abstract = "While the effect of gut microbiota and/or inflammation on a distant body
site, including the lungs (gut–lung axis), has been well characterized, data about the
influence of lung microbiota and lung inflammation on gut homeostasis (lung–gut
axis) are scarce. Using a well-characterized model of pulmonary infection with the
fungus Aspergillus fumigatus, we investigated alterations in the lung and gut microbiota
by next-generation sequencing of the V3–V4 regions of total bacterial DNA. Pulmo-
nary inflammation due to the fungus A. fumigatus caused bacterial dysbiosis in both
lungs and gut, but with different characteristics. While increased alpha diversity and
unchanged bacterial composition were noted in the lungs, dysbiosis in the gut was
characterized by decreased alpha diversity indices and modified bacterial composition.
The altered homeostasis in the lungs allows the immigration of new bacterial species of
which 41.8% were found in the feces, indicating that some degree of bacterial migration
from the gut to the lungs occurs. On the contrary, the dysbiosis occurring in the gut
during pulmonary infection was a consequence of the local activity of the immune
system. In addition, the alteration of gut microbiota in response to pulmonary infection
depends on the bacterial composition before infection, as no changes in gut bacterial
microbiota were detected in a rat strain with diverse gut bacteria. The data presented
support the existence of the lung–gut axis and provide additional insight into this
mechanism.
IMPORTANCE Data regarding the impact of lung inflammation and lung microbiota
on GIT are scarce, and the mechanisms of this interaction are still unknown. Using a
well-characterized model of pulmonary infection caused by the opportunistic fungus
Aspergillus fumigatus, we observed bacterial dysbiosis in both the lungs and gut that
supports the existence of the lung–gut axis.
KEYWORDS fungal lung infection, gastrointestinal microbiota, lung microbiota,
lung-gut axis, rats
B
acteria inhabit every part of the human body, but most of them are found in the gut.
Gut microbiota are responsible for many functions, including nutrient metabolism,
immunomodulation, maintenance of host physiology, and protection against pathogen
overgrowth (1). To date, numerous scientific studies confirm the important role of
gut bacteria in health and disease. This microbial community impacts not only local
immunity but also a distant body site, such as the lungs. Disturbances in gut bacterial
composition have been linked to asthma (2), chronic obstructive pulmonary disease
(3), cystic fibrosis (4), and lung cancer (5). Furthermore, pulmonary involvement was
noted in inflammatory gastrointestinal disease characterized by microbial dysbiosis (6),
Month XXXX Volume 0 Issue 0 10.1128/spectrum.01990-23 1
Editor Agostinho Carvalho, University of Minho,
Braga, Portugal
Address correspondence to Maja Tolinacki,
maja_tolinacki@imgge.bg.ac.rs.
The authors declare no conflict of interest.
See the funding table on p. 15.
Received 11 May 2023
Accepted 25 July 2023
Published 25 August 2023
Copyright © 2023 Popovic et al. This is an open-
access article distributed under the terms of the
Creative Commons Attribution 4.0 International
license. Downloaded from https://journals.asm.org/journal/spectrum on 09 October 2023 by 147.91.199.205.
supporting the existence of a gut–lung axis. The gut bacterial microbiota or some of
their constituents impact the immune response in the lungs against viruses (7–9),
bacteria (10–13), fungi (14), and allergic airway inflammation (15) mainly through the
effect of the gut microbiota (or their metabolites) on the immune cell activity.
While the gut–lung axis is well characterized, the influence of the lung microbiota
as well as lung inflammation on gut homeostasis has attracted much more attention in
recent years. The first indication of the lung–gut axis was a higher prevalence (compared
to healthy subjects) of gastrointestinal symptoms in patients with asthma (16) and
chronic obstructive pulmonary disease (17). The existence of gastrointestinal symptoms
in patients with pulmonary virus infection has also been documented (18). Gastrointesti-
nal symptoms (abdominal pain, nausea, vomiting, and diarrhea) were noted in 11.6%
of children with influenza infection (18), and a later study showed a decrease in alpha
diversity in the feces of influenza-infected patients compared to healthy controls (19).
Fecal bacterial samples from patients with COVID-19 infection were shown to cluster
separately from those in healthy controls as well, but in the majority of these patients,
SARS-Cov-2 could be detected in the feces (20). Experimental studies in mice confirmed
the occurrence of gut dysbiosis following respiratory influenza virus infection (21–25)
and respiratory syncytial virus infection (24), despite the fact that the virus has not
been detected in the gut (21, 22, 24, 25). It has been shown that the alteration of gut
microbiota is a consequence of infection with live virus particles, as administration of an
attenuated influenza vaccine had no effect on the microbiota (24).
Bacterial dysbiosis in the gut also occurs following pulmonary bacterial infection. A
decrease in alpha diversity indices and differential relative abundance of fecal microbiota
were noted in patients with pulmonary tuberculosis (26, 27) and in mice infected with
Mycobacterium tuberculosis (28) and Klebsiella pneumoniae (29). Even administration of
the major component of the outer membrane of Gram-negative bacteria, lipopolysac-
charide, to the lungs caused gut bacteria dysbiosis (30).
In addition to pulmonary infections caused by viruses or bacteria, alteration of the gut
microbiota was noted in mice exposed to hyperoxia (31) and in patients with lung cancer
(compared to healthy individuals) (32) indicating that pulmonary inflammation/injury
affects the gut microbiota regardless of its origin. Despite a growing body of evidence
for interaction between the lungs and gut, there is still a lot of work to be done to
understand this crosstalk. There are virtually no data regarding gut microbiota changes
during pulmonary infection caused by fungi. Our previous study showed an alteration
in immune-mediated homeostasis of the gut in a rat model of sublethal pulmonary
infection with A. fumigatus (33). Using the same experimental model of infection in Dark
Agouti (DA) rat strain, we aimed to investigate changes in the lung and gut microbiota
by next-generation sequencing of the V3–V4 regions of total bacterial DNA in these
two organs. Possible mechanisms of lung–gut communication were also investigated. In
addition, to examine whether gut dysbiosis is a general characteristic during pulmonary
fungal infection, we analyzed feces from infected Albino Oxford (AO) rats, a strain that
develop quantitatively different immune response to fungus A. fumigatus (34) and whose
gut microbiota was previously shown to respond differently to oral cadmium administra-
tion (35) compared to DA rats.",
journal = "Microbiology Spectrum, Microbiology spectrum",
title = "Gut microbial dysbiosis occurring during pulmonary fungal infection in rats is linked to inflammation and depends on healthy microbiota composition",
pages = "23-e01990",
number = "n/a",
volume = "n/a",
doi = "10.1128/spectrum.01990-23"
}
