Journal Pre-proof

Asthma, Obesity, and Microbiota: A complex immunological

interaction

Laura Machado Menegati , Erick Esteves de Oliveira ,

Bernardo de Castro Oliveira , Gilson Costa Macedo ,
Flávia Márcia de Castro e Silva

PII: S0165-2478(23)00004-4
DOI: https://doi.org/10.1016/j.imlet.2023.01.004
Reference: IMLET 6736

To appear in: Immunology Letters

Received date: 5 October 2022

Revised date: 2 January 2023
Accepted date: 9 January 2023

Please cite this article as: Laura Machado Menegati , Erick Esteves de Oliveira ,
Bernardo de Castro Oliveira , Gilson Costa Macedo , Flávia Márcia de Castro e Silva , Asthma,
Obesity, and Microbiota: A complex immunological interaction, Immunology Letters (2023), doi:
https://doi.org/10.1016/j.imlet.2023.01.004

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Review

Asthma, Obesity, and Microbiota: A complex immunological interaction

Laura Machado Menegati1,, Erick Esteves de Oliveira2,, Bernardo de Castro Oliveira3, Gilson Costa Macedo1, Flávia Márcia de Castro e

Silva4,#
1
Faculdade de Medicina, Programa de Pós-Graduação em Saúde, Universidade Federal de Juiz de Fora - MG, Brasil
2
Instituto de Ciências Biológicas, Programa de Pós-Graduação em Biologia Departamento de Parasitologia, Microbiologia e Imunologia,

Universidade Federal de Juiz de Fora - MG, Brasil

3
Universidade de São Paulo – SP, Brasil
4
Departamento de Microbiologia, Imunologia e Parasitologia, Faculdade de Ciências Médicas - RJ, Universidade do Estado do Rio de Janeiro,

Brasil
#
Correspondence: Flavia Marcia de Castro e Silva, Departamento de Microbiologia, Imunologia e Parasitologia, Faculdade de Ciências

Médicas, Universidade do Estado do Rio de Janeiro - RJ, Brasil - e-mail: flaviamcsilva@gmail.com


These authors contributed equally

Key Messages

 Obesity increases the risk of asthma development and worsens the symptoms, affecting children and adults by different mechanisms.

 The influence of obesity can start as early as in the womb by promoting epigenetic alterations, and by affecting the bacterial

colonization of the offspring in a detrimental way.

 High-fat diet and obesity promote gut dysbiosis, however, their influence over lung microbiota is still poorly assessed.

Abstract

Obesity and allergic asthma are inflammatory chronic diseases mediated by distinct immunological features, obesity presents a Th1/Th17

profile, asthma is commonly associated with Th2 response. However, when combined, they result in more severe asthma symptoms, greater

frequency of exacerbation episodes, and lower therapy responsiveness. These features lead to decreased life quality, associated with higher

morbidity/mortality rates. In addition, obesity prompts specific asthma phenotypes, which can be dependent on atopic status, age, and gender.
In adults, obesity is associated with neutrophilic/Th17 profile, while in children, the outcome is diverse, in some cases obese children present

aggravation of atopy, and Th2 inflammation, and in others an association with a Th1 profile, with reduced IgE levels and eosinophilia. These

alterations occur due to a complex group of factors among which the microbiome has been recently explored. Particularly, evidence shows its

important role in susceptibility or resistance to asthma development, via gut-lung-axis, and demonstrates its relevance to the immune

pathogenesis of the syndrome. Few studies address the relevance of the lung microbiome in shaping the immune response, locally. However,

specific bacterias, like Moraxella catarrhalis, Haemophilus influenza, and Streptococcus pneumoniae, correlate with important features of the

obese-asthmatic phenotype. Although maternal obesity is known to increase asthma risk in offspring, the impact on lung colonization is

unknown. This review details the main key immune mechanisms involved in obesity-aggravated asthma, featuring the effect of maternal

obesity in the establishment of gut and lung microbiota of the offspring, acting as potential childhood asthma inducer.

Keywords

Asthma, maternal obesity, microbiota, immune response

List of abbreviations: AHR, Airway hyperresponsiveness; BMI, Body mass index; CCL, C-C motif chemokine; CD, Cluster of

differentiation; DC, Dendritic cell; DNA, Deoxyribonucleic acid; FCRI, Fc epsilon receptor I; FEV 1, Forced expiratory volume in 1-second;

FVC, Forced vital capacity; GIT, Gastrointestinal tract; GPCRs, G-protein coupled receptors; GWAS, Genome-Wide Association Study;

HDCA, Histone deacetylase; ICAM, Intercellular adhesion molecule; IFN, Interferon gamma; Ig, Immunoglobulin; IL, Interleukin; ILC,

Innate lymphoid cell; IP-10, Interferon gamma-induced protein; JAK, Janus Kinase; LPS, Lipopolysaccharide; LRT, Lower respiratory tract;

M1, Type one macrophage; MAPK, Mitogen-activated protein kinase; MMP, Metalloproteinase; mTOR1, Mammalian target of rapamycin

complex 1 (mTOR1); NETs, Neutrophils extracellular traps; NLRP3, Nucleotide-binding oligomerization domain-like Receptor Family Pyrin

Domain Containing 3; Ob-R, Leptin receptor; PDL-1, Programmed cell death ligand; PFTs, Pulmonary function tests; PUFA, Polyunsaturated

fatty acid; RNA, Ribonucleic acid; RORT, Retineic-acid-receptor-related orphan nuclear receptor gamma; RSV, Respiratory Syncytial Virus;

RV, Rhinovirus; SARP, Severe Asthma Research Program; SCFAs, Short-chain fatty acids; STAT, Signal transducer and activator of

transcription; T2, Type two; Tfh, T folicular helper; TGF-β, Transforming growth factor; Th, T helper; TLC, Total lung capacity; TLR, Toll

like receptor; TNF-, Tumor necrosis factor; TReg, T regulatory; TSLP, Thymic stromal lymphopoietin

1. Introduction
 Asthma is a chronic inflammatory disease of the lungs. Its clinical manifestations include airway hyperresponsiveness (AHR), with

recurrent episodes of breathlessness, wheezing, chest tightness, and cough, which can vary in intensity over time [1]. Chronic inflammation

results in life-threatening progressive loss of pulmonary function, which is related to disease severity. Its prevalence and incidence have been

increasing considerably in recent years, affecting 1-18% of the world population [1], and being responsible for approximately half-million

deaths in 2019 [2], although most patients present manageable symptoms, quality of life is still impacted, causing a significant financial and

social burden on the health system [1].

Atopic asthma (T2high asthma endotype) is the most known form of the disease, affecting subjects with a strong genetic predisposition

to produce great amounts of antigen-specific immunoglobulin-E (IgE) in response to innocuous environmental antigens (allergens). In

susceptible subjects, the immune response begins with epithelial barrier disruption, and contact with allergen triggers alarmins such as

interleukin (IL)-25, IL-33, and Thymic Stromal Lymphoietin (TSLP) production, leading to innate lymphoid cells (ILC)2, basophils, mast

cells, and dendritic cells (DCs) activation. Antigen-bearing DCs migrate to lymph nodes priming naiveT helper cells into (Th)2 lymphocytes

which will produce the classic IL-4, IL-5, and IL-13 cytokines; as well as T follicular helper (Tfh) cells that in turn will stimulate the class

switch from IgM to IgE by B cells. IgE will coat mast cells that will degranulate under subsequent expositions to the allergen. Meanwhile, the

cytokines produced by both activated mast cells and Th2 cells will be responsible for bronchoconstriction, eosinophil recruitment, and mucus

hypersecretion [3]. Consecutive expositions will lead to tissue damage, remodeling, and progressive loss of lung function (Figure 1).

T2high asthma is extensively studied, however, the immunopathogenesis of T2low asthma is comparatively less clear, but the underlying

mechanism can involve the increase of Th1/Th17 immunity [3]. Genetic background, epigenetic alterations, and environmental factors are

decisive to set cellular and molecular mechanisms of these endotypes. Those umbrella terms shelter many other phenotypes, which can be

influenced by external factors such as air pollution, smoking, viral infections, or by host factors such as natural atopic status, age of onset,

gender, and obesity [4]. In that sense, obesity can be either a risk factor for the development of asthma, or can be an aggravating factor for the

already installed disease. In both cases, the low-grade inflammation promoted by fat accumulation, leptin secretion, and dysbiosis seems to

shape the immune response in the asthmatic patient's lung. This review will summarize the mechanisms by which obesity influences asthma,

giving special focus on the role of gut, lung, and maternal microbiota.

2. Obesity-asthma interplay
 Obesity is a rising global health problem, affecting more than 650 million adults and 124 million children around the world [5], and

like asthma, its prevalence increased substantially in the last years. This systemic inflammatory chronic disease has multifactorial origins and

is characterized by abnormal body fat accumulation, usually demonstrated by a body mass index (BMI) equal to, or greater than 30 kg/m2 [5].

Meta-analysis of prospective studies indicate a positive and causal association between obesity and asthma, as well as showing a dose-

dependent effect between abdominal fat accumulation and asthma severity [6, 7], with recurrent episodes of exacerbations and reduced

responsiveness to conventional therapy [8]. This relation can be mediated by several mechanisms acting in an independent or additive

manner, such as common genetic factors, mechanical factors, metabolic disturbance, inflammatory markers, specific diets, dysbiosis, and

maternal obesity.

2.1. Common genetic factors

Although extrinsic factors strongly support the development of asthma and obesity, these diseases have important genetic components,

and nearly 8% of them are shared between both conditions [9]. For instance, polymorphisms of the β3-adrenergic receptor, located in the

adipose tissue, are associated with increased weight gain, as well as with severe asthma phenotype, characterized by a poor response to β-

agonist [10]. In addition, tumor necrosis factor (TNF)-α haplotypes are also associated with asthma incidence, AHR, and obesity [10]. A

Genome-Wide Association Study (GWAS) found a positive association between obesity and non-atopic late-onset asthma, curiously the

majority of loci shared between them were involved in the regulation of inflammation and remodeling, as Smad3, linked to transforming

growth factor-β pathway; and FOXA3 relevant to goblet cell metaplasia and body mass regulation [9]. In addition, leptin can act as a risk

factor for asthma independently of obesity [11], as genetic polymorphisms in the leptin gene (LEP) have been associated with the disease [12,

13].

2.2. Mechanical factors

Although several molecular mechanisms participate in the interaction of obesity and asthma, the structure of an obese body can also

have implications for the physiology of the respiratory tract. Fat accumulation in both chest and abdomen can dampen lung activity, restricting

diaphragm mobility, increasing pleural pressure, decreasing lung compliance, and causing airway resistance [14]. In fact, obese individuals

present a poor performance in pulmonary function tests (PFTs), displaying decreased forced expiratory volume in 1-second (FEV1), forced

vital capacity (FVC), and total lung capacity (TLC), in adults [15]. However, obesity affects children differently, as they present an obstructive
pattern, with normal or higher FEV1 and FVC, but a lower FEV1/FVC ratio. This effect can be explained in part by disproportional growth of

the lungs compared to airway caliber, an event known as dysanapsis, which is associated with higher morbidity rates [16]. In that way, natural

weight loss [17] or bariatric surgery [18], improves respiratory functions and asthma control.

2.3. Low-grade inflammation

The effects of obesity go beyond mechanical factors, as the adipose tissue is an active endocrine organ, acting in the regulation of both

inflammation and metabolism. Metabolic disorders, such as dyslipidemia [19] and insulin resistance [20], have also been associated with

asthma occurrence, although it is not clear whether this association is dependent on obesity [21]. In addition, excessive fat accumulation leads

to the reduction of the anti-inflammatory adipokine, adiponectin, while increasing leptin production, which acts as a pro-inflammatory

mediator, being associated with asthma occurrence [22]. In that regard, immune and structural cells that participate in the pathogenesis of

asthma express the leptin receptor (Ob-R) and can be modulated by it [23, 24]. Interestingly, leptin can be detected in the lungs, suggesting its

diffusion from blood to this organ in experimental model [25].

The mere expansion of adipose tissue leads to capillaries constriction, inducing hypoxic cell death, and inflammatory macrophages

recruitment, to remove debris, leading to IL-6, TNF-α, and IL-1β overproduction [26]. These cytokines are common mediators of asthma [27–

29]. In addition, the accumulation of CD8 T cells and CD4 T cells in the adipose tissue play a critical role in maintaining higher IFN-

systemic levels, which are implicated in Th1 immune response in obesity dysfunction [30]. The systemic circulation of these factors is

considered the hallmark of low-grade chronic inflammation, typical of obesity, which can be associated with a break in lung homeostasis and

asthma development. Moreover, obesity frequently acts as an asthma modifier, leading to distinct phenotypes, with its peculiarities [31].

3. Obesity-asthma endotypes

3.1. Obesity in asthma T2high endotype

In early-onset asthma, in children under 12 years old, obesity has a bidirectional effect, either aggravating pre-existent allergic asthma

or increasing the risk for its development [32]. This obese-asthma endotype has a positive association with IgE titers [33, 34], and eosinophils

activity [35]. The higher leptin levels contribute to asthma immunopathogenesis acting as a survival and expansion factor for ILC2 and Th2

cells, by targeting multiple cellular pathways including mammalian target of rapamycin complex 1 (mTOR1), mitogen-activated protein

kinase (MAPK), and Janus Kinase/signal transducer and activator of transcription (JAK-STAT3) pathway which contribute to IL-4, IL-5, and

IL-13 production in Th2 cells [23, 36]. Even more, leptin increases the expression of adhesion molecules in pulmonary epithelial cells and the
production of other inflammatory cytokines, including C-C motif chemokine-11 (CCL11) which is crucial for eosinophils' recruitment [37].

However, the eosinophil count in sputum in adult patients can be lower than expected, as these cells can accumulate in lung submucosa [38].

This discrepancy suggests the sub-diagnosis of T2high asthma in certain groups of obese subjects, which have been previously categorized as

non-eosinophilic.

3.2. Obesity in T2low asthma endotype associated with Th1 profile

Another modification of the early onset of asthma by obesity consists of the skewing of the classical T2high endotype towards a Th1

profile, with higher IFN- levels [39, 40], reduction of both atopy and eosinophilic inflammation [39, 41]. This would explain, in part, the

diminished response to immunobiological therapies targeting T2high endotype [42]. Usually elevated signature of Th1 immune response, as

increased levels of IFN-, TNF-, and interferon gamma-induced protein (IP)-10 are associated with severe forms of asthma, especially IFN-

, that aggravates AHR [42]. Experimental models of obesity-aggravated asthma in BALB/c mice also support this association, showing

reduced IgE levels and an increase of IFN- [25]. Interestingly, obese-asthmatic children share DNA methylation patterns associated with Th1

polarization, non-atopic inflammation, and macrophage activation, presenting a hypomethylated profile on CCL5, IL2RA, and TBX21 genes

[43].

Although leptin potentializes T2high asthma, it is also the culprit of several other inflammatory deviations associated with non-T2

responses: increasing Th1 cells and IFN- levels in obese asthmatics children [7, 23]; increasing IgG2a titers, in detriment of IgE (in

experimental model) [44]; inducing B cells senescence and affecting class switch [45]. These data support the role of obesity in non-atopic

asthma [39], however, there is still no consensus on the role of Th1/Th2 balance in obesity asthma association, as the current data is

conflicting, requiring further investigation.

3.3. Obesity in T2low asthma endotype associated with Th17 profile

Deviations from the classic asthma profile may not always be essentially linked to a Th1 profile, in some cases, a Th17/neutrophilic

response is observed and is not associated with a family history of allergy, and the symptoms usually appear in adulthood. Cluster analysis

from the Severe Asthma Research Program (SARP) associates obesity with a specific subgroup of asthmatics, particularly women [46]. These

patients present a late-onset Th2low asthma [47], with increased Th17 response and neutrophilic inflammation [48, 49], associated or not, with

higher eosinophilia [38, 50]. Another feature of this group is the reduced IgE titers [51] which are frequently associated with higher IgG titers

in experimental models [25, 44]. The effect of this humoral pattern is yet to be uncovered, however, IgG plays an important role in neutrophil-
mediated anaphylaxis [52].

The airway influx of neutrophils is a common factor associated with the severity of asthma, contributing to the unresponsiveness to

corticosteroid therapy [53]. Neutrophils in severe asthma can present a distinct profile, displaying a set of pro-inflammatory markers, increased

granules secretion, phagocytic activity, and neutrophils extracellular traps (NET) formation, however, their clearance capability is dampened

due to defective respiratory burst [54]. These cells are abundant in obese-asthmatics in comparison to lean-asthmatics and are associated with

elevated expression of adhesion molecules such as intercellular adhesion molecule (ICAM)-1, E-selectin, and P-selectin [55, 56]. Neutrophil

activation can also cause tissue damage due to metalloproteinase-9 (MMP)-9 release, leading to increased tissue remodeling [57]. In addition,

excessive release of NETs, may contribute to epithelial damage and lung tissue injury [58], while cytoplasts formed during this process can

induce Th17 differentiation, by acting over dendritic cells [59]. This Th17 profile is also sustained by the TLR2 stimulation by histones

present in the NETs extrusions, which lead to STAT3/ retineic acid receptor related orphan nuclear receptor (ROR)γT expression [60], in a

crosstalk between neutrophils and Th17 cells that is alike the macrophages type one (M1)-Th1 interaction.

The development of the Th17/neutrophilic profile, typical of late-onset obese-asthma, can be associated with early disturbances in

innate immunity events. Mast cell accumulation is higher in the lungs of obese mice, being considered a powerful TNF- source, after asthma

induction, and is associated with intense mucus production [25, 61]. The increased TNF- levels, when combined with higher toll like

receptor (TLR)-4 activation, due to lipolysaccharide (LPS) or saturated fatty acids exposure, induce the nucleotide-binding oligomerization

domain-like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome activation [62]. These events could contribute to

macrophage polarization into pro-inflammatory M1 phenotype [63, 64], which presents higher NLRP-3 expression, associated with

neutrophilia in asthma [65], linked to increased disease severity [66]. Additionally, the IL-1β and TNF- production by M1 macrophages can

promote the expansion of ILC-3 [63, 67], which are constitutively present at the mucosal barrier, playing an essential role in immunity and

tissue homeostasis. However, their elevated frequency is found in bronchoalveolar lavage fluid of severe asthma patients [63] and peripheral

blood of obese asthmatic children [68], being an important source of IL-17A [63, 69]. Epigenetic alterations related to elevated BMI, such as

DNA methylation of TBC1D16, TBC1D8, RASA2, and SSH1 genes [70], can be linked to several inflammation paths, including the NLRP3-

IL1β-IL17 axis [71] supporting this deviated profile.

The setting of the presented profile is also accompanied by defective development of the initial allergic response that takes place in the

epithelia, as the TSLP production, essential for the Th2 response, is dampened in the deviated form [25], interestingly, obesity alone reduces
the production of this alarmin [72]. The lack of a consistent TSLP signaling to dendritic cells compromises the Th2 differentiation, favoring

the Th17 polarization [73], along with that, obesity affects dendritic cells progenitors differentiation, as well as activation and function of

mature cells [74, 75], what may explain in part the delayed response of obese mice [25, 76] (Figure 2). Although the innate immunity

components are decisive for the setting of the Th17 profile, both fatty acids and leptin can also skew the response toward a Th17 profile in the

lungs [77], acting as a ligand directly in RORC/RORT [78], while promoting a reduction of T regulatory cells (TRegs)

Foxp3+CD4+CD25+ proliferation and function [79]. Interestingly, obesity itself also promotes an increase of Th17 cells frequency in the

spleen [44] and peripheral circulation, regardless of the asthma status [80], indicating the systemic effect of obesity. In the lungs of obese

subjects, IL-17A levels precede asthma development being considered a risk factor for asthma and AHR [69].

4. Asthma and microbiota interaction

The original hygiene hypothesis was the first attempt to explain the link between exposure to microorganisms and decreased risk of

atopy and allergic diseases. This hypothesis advocates that reduced exposure to pathogens during childhood, due to a modern lifestyle,

including reduced family size, health care improvement, vaccination programs, use of antibiotics, and hygiene habits, favor Th2 polarization to

detriment of the Th1 profile [81, 82]. Evidence points towards a protective effect of early exposure to bacterial endotoxins against

sensitization and atopy development [83], an event mediated by TLRs signaling enhancement in dendritic cells, priming T cells polarization

towards Th1 and TReg profiles [81]. However, the hygiene hypothesis became insufficient to explain host-microorganism interaction in

asthma context, as respiratory viral infections, by Rhinovirus (RV) and Respiratory Syncytial Virus (RSV) are important risk factors and the

most common cause of asthma exacerbations [84, 85]. In addition, the role of non-pathogenic microbes was also neglected in this previous

theory. More recently, the hygiene hypothesis was adapted into ―the old friends hypothesis‖, to include specific commensal microorganisms

from the microbiota, which shape immune response soon after birth, protecting the host from the overreaction to potential ubiquitous antigens

[86].

Microbiota refers to the community of microorganisms including bacteria, archaea, fungi, viruses, and protozoa which colonize host

tissues. However, the majority of the amplified genes (up to 99%) in the gastrointestinal tract are from the bacterial community, reaching 1014

cells per gram of tissue, which are distributed in five main bacterial phyla. Bacteroidetes and Firmicutes are the main groups, representing

more than 90% of this community, followed by Proteobacteria, Actinobacteria, Fusobacteria, and Verrucomicrobia phyla [87, 88].
Commensal bacteria play several functions such as nutritional metabolism; stimuli for immune system maturation and immunity modulation;

defense against pathogens [88]. The imbalance in the composition of the microbial species, termed dysbiosis, is associated with alterations in

metabolic functions; break of immune tolerance; increased susceptibility to inflammatory diseases, such as obesity and asthma [89–91]. This

connection between microbiota and allergy is supported by the higher predisposition to a Th2-immune response in germ-free mice,

characterized by eosinophilia and elevated IgE titers [92].

4.1. Microbiota and gut-lung axis

Gastrointestinal tract (GIT) microbiota composition impacts immune response in distal organs, specifically the lungs. The ―crosstalk‖

between gut and lung, also known as gut-lung axis, is mediated by active metabolites derived from dietary fiber fermentation, produced mainly

by members of Bacteroidetes phylum, in the gut [93]. Short-chain fatty acids (SCFAs), such as butyrate, acetate, and propionate, are the main

representatives of these metabolites. They can act locally, and also enter the bloodstream, exerting regulatory effects on distal organs and

tissues, including the lungs. These functions are mediated by G-protein coupled receptors (GPCRs) signaling in airway epithelial and immune

cells, and by epigenetic alterations, providing protective effects against asthma development [91]. For instance, the interference in histone

acetylation seems to be a mechanism by which SCFAs regulate immune responses. In that regard, butyrate, acetate, and propionate lead to

histone deacetylase (HDAC) inhibition, supporting FOXP3 promoter region acetylation, therefore favoring the peripheral TRegs generation

[94, 95]. Butyrate can also indirectly contribute to Tregs formation by reducing DCs activation and promoting HDAC inhibition in ILC2s,

ensuring a diminished Th2 differentiation [96, 97]. Butyrate also inhibits mast cell activation, as well as basophil’s IL-4 production, by

inducing epigenetic alterations in the promoter regions of important tyrosine kinases downstream FCRI signaling [98]. In addition, butyrate

also acts over eosinophils from allergic patients inducing apoptosis, migration reduction, and endothelial adhesion [99]. Propionate and

acetate administration affect DCs and macrophage precursors, in the bone marrow, reducing their ability to induce a Th2 response, in the

lungs, while maintaining their phagocytic capacity [91, 100]. Moreover, the presence of higher levels of butyrate and propionate in children’s

feces was associated with reduced atopy [91, 101]. On the other hand, reduced acetate levels, associated with decreased abundance of genera

such as Lachnospira, Rothia, Faecalibacterium, and Veillonella, are associated with increased risk of asthma development in childhood and in

experimental model [91, 102].

 Compelling evidence indicates intestinal dysbiosis is linked to obesity and asthma pathophysiology [103], in that sense changes in the

microbiota are highly dependent on the diet [104]. It has been demonstrated that westernized diets, rich in carbohydrates, saturated fat, and

poor in fibers, can cause an imbalance in the GIT bacterial community [105], prior to obesity development. This obesogenic diet reduces the

Bacteroidetes population [106], hence impacting an important source of SCFAs [107]. At the same time, the increase of Firmicutes taxa

contributes to endotoxemia and systemic low-grade inflammation [108]. Interestingly, more intense systemic/airway inflammation and

intestinal dysbiosis in obese asthmatic patients emphasize the additive effects of both diseases [103]. On the other hand, a diet based on plant

proteins increases the population of Bifidobacterium and Lactobacillus, while decreasing Bacteroides fragilis and Clostridium perfrigens,

promoting fortification of the gut barrier, increasing TRegs population, and reducing inflammation via augmentation of SCFAs levels [109]. In

the same way, a Mediterranean diet is associated with increased Bifidobacterium, Lactobacilli, Eubacteria, Bacteroides, and Prevotella

populations, as well as with reduced risk of obesity, diabetes mellitus 2, inflammation, and cardiovascular diseases [110].

4.2. Lung Microbiota

Beyond the influence of the gut-lung axis, the human lower respiratory tract (LRT) has a resident microbiome, with a highly diverse

microbiota population [111]. Compared to the gut, the lung bacterial community harbors a lower density ranging 103-105 microorganisms per

gram of tissue, established by the constant balance between migration from the upper respiratory tract and mouth, and the elimination in the

lungs [112]. This microbiome is shaped by peculiar characteristics inherent to the lower airway microenvironment such as pH, oxygen

availability, temperature, surfactant proteins, and mucociliary movement [113]. In addition, the diversity of lung microbiota can diverge due to

concentrations of local inflammatory cytokines, such as IL-1 and IL-4 [114]. The stable healthy lung bacterial composition is characterized

by a high prevalence of commensal Prevotella (Bacteroidetes), Corynebacterium spp (Actinobacteria), Streptococcus spp, Veillonella spp

(Firmicutes), and Acinetobacter (Proteobacteria) [111].

Pulmonary dysbiosis is observed in asthma patients, as the inflammatory environment provides adequate niches to specific bacteria, in

the lung. In that sense, studies demonstrated Gammaproteobacteria, an enhanced group in asthmatic lungs [115], benefit from nitrogen reactive

species, from the inflammatory environment, to survive [116]. Furthermore, asthmatic lungs are enriched with pathogenic Proteobacteria to

detriment of Firmicutes and Bacteroidetes phylum, this shift is associated with reduced diversity and corticosteroid resistance [111]. In fact,

distinct microbial profiles are associated with diverse immunological patterns, ranging from mild-moderate to severe asthma. Members of
Proteobacteria phyla such as Moraxella and Haemophilus are associated with epithelial expression of Th17-related genes, higher neutrophil

count [117, 118], and severe wheeze [119]. While Th2 severe asthma showed reduced bacterial load, with the prevalence of

Streptococcus/Staphylococcus (Firmicutes) [120]. Additionally, in children, the disturbance of nasal microbiota and persistence of Moraxella

catarrhalis induces epithelial damage with IL-33 and IL-8 production, associated with eosinophil activation and episodes of asthma

exacerbation [121]. Pathogenic bacteria are likely to be important in shaping the innate and acquired lung immune responses through their

interactions with innate receptors. Bacterial products as RNAs; cell wall components, such as LPS from gram-negative bacteria; and

lipoteichoic acid (LTA) from gram-positive bacteria, are potent stimuli to TLRs/NLRP3-inflammasome receptors, leading to the production of

IL-8, IL-1 and TNF- [122, 123], which are associated with Th17-neutrophil pathway. Interestingly, Haemophilus and Moraxella affect pro-

inflammatory cytokines production by DCs differently from commensal bacteria such as Prevotella spp., driving higher production of IL-23

and IL-12p70, in the lungs [124].

Although studies on the effect of diet or obesity on lung microbiota are still incipient, evidence shows an altered composition with

reduction of Enterococcaceae, Aeromonadaceae, Paraprevotella, Phascolarctobacterium e Megasphaera [103] or increased Prevotellaceae,

Mycoplasmataceae, Lachnospiraceae e Spirochaetaceae [117]. An early experimental study of our group demonstrated that obesity itself

affects the pulmonary microbiome, by increasing Proteobacteria. While, after asthma is induced in obese mice, there is an increase in

Firmicutes and Actinobacteria, and a reduction of Proteobacteria, however with a predominance of Moraxella catarrhalis [125]. Interestingly,

this species is associated with airway Th17 immune response and neutrophilic asthma [118, 126]. Another study identified a marked

predominance of Firmicutes in the lung of obese mice [127]. A possible explanation for the sudden specific pathogenic bacteria in the lung

could be the defective phagocytosis by macrophages and neutrophils, observed in severe asthma form [54], which could be induced by obesity.

Although papers associate obesity with impaired efferocytosis in the lung, and with phagocytosis on monocytes and adipose macrophage,

there is no study demonstrating the effect of obesity on the capacity of phagocytosis and microbial clearance in alveolar macrophage [128,

129].

5. Maternal asthma during pregnancy Effect of maternal obesity on asthma

Beyond the direct effects of obesity on asthma, indirect effects can occur in the offspring, triggered by maternal obesity. The

mechanisms are diverse and include the establishment of an early dysbiotic microbiota, the modification of epigenetic factors, and exposure to
inflammatory markers during development [130, 131]. In that sense, recent studies corroborate Barker’s theory of the developmental origin of

health and diseases, where he postulates that environmental exposures in early life can affect later health and risk for diseases [132]. With the

increased incidence of obesity among women, it is inevitable that the number of obese pregnant women increases as well, and, not only

obesity is programmed into the offspring, known as the intergeneration cycle of obesity, but also can increase the risk for other diseases, like

attention deficit hyperactivity disorder, cardiovascular diseases, diabetes and asthma [133, 134].

The influence of nutritional status and obesity on asthma starts in utero (Figure 3). Strong evidence points to the impact of maternal

obesity, overweight and gestational weight gain on the risk of childhood asthma [130, 135, 136]. Directly, maternal obesity impairs lung

development by dampening fetal glucocorticoid production, which is pivotal for lung maturation and alveoli structure, an effect observed until

adulthood, in experimental model [133, 137]. Further, data from newborns of obese mothers show elevated leptin and high-sensitivity C-

reactive protein levels in cord blood and associate it with increased asthma risk and dysanapsis [16, 138]. Maternal obesity also impacts the

offspring's immune system, reducing the number of splenic lymphocytes, increasing IgE levels to detriment of IgG isotype [139]. These

individuals are also more susceptible to respiratory infections, due to the reduced number of CD4 T cells, and their impaired functions

correlating with epigenetic alterations [140], as well as lower responsiveness of dendritic cells and monocytes to TLR ligands, such as LPS

[141, 142].

The microbiome establishes very early in life, immediately after birth, and newborns acquire their microbiome when exposed to

maternal microbiota. Moreover, the presence of bacterial DNA in aspirates of preterm newborns suggests colonization as early as the prenatal

stage [143]. Maternal microbiota affects the early postnatal development, providing stimulus to innate immune system maturation, increasing

intestinal ILC3 and F4/80+CD11c+ mononuclear cells [144]. In addition, neonate exposition to commensal bacteria promotes IL-22+ILC3-

CCR4 traffic to the lungs, inducing a protector effect to mucosal barrier homeostasis and against infections [145]. On the other hand, gut

dysbiosis early in life was associated with a marked increase in the IL-17-producing ILC3s, dependent on the Firmicutes rate [146]. However,

the mechanisms by which obesity may affect this traffic are currently unknown. Remarkably, a high-fat diet and obesity will modify the

maternal microbiome, implicating in a shift of microbial metabolites passed to the offspring. In addition, changes in gut microbiome

composition can persist throughout the life of the offspring [147, 148]. In contrast, a healthy maternal diet with higher fiber and

polyunsaturated fatty acids (PUFAs) content, could protect against allergies by regulating the progeny microbiome [149]. Likewise, a fiber-
rich diet, which increases acetate serum levels, during pregnancy, increases TReg activity in the offspring, in an HDAC9 inhibition-dependent

manner, decreasing the risk of asthma [95].

Similarly to the gut microbiome, airway bacterial colonization is dynamic and strongly influenced by gestational age, delivery mode,

breastfeeding, maternal diet, and neonatal use of antibiotics [150]. The lung microbiome reaches higher diversity and relative stability in the

first years of life, being maintained into adulthood [151]. However, during a neonatal stage, a ―window of opportunity‖ is established, in

which the transient bacterial rate is critical to long-term outcomes, and may predispose the individual to atopy and asthma later in childhood.

For example, higher airway relative abundance of Gram-negative bacteria species such as Veillonella and Prevotella up to one month of life is

associated with childhood asthma until 6 years old, after this period this association was not observed [152]. Another study reported airway

colonization of neonates with Moraxella catarrhalis, Haemophilus influenza, and Streptococcus pneumoniae to be associated with higher

eosinophil counts in blood and elevated total IgE serum levels [153]. Whereas, Følsgaard and colleagues, detected a mix of Th1/Th2 and

Th17, with higher levels of IL-1 in airway fluids of asymptomatic neonates colonized with the same bacteria [154].

Is noteworthy that pulmonary microbiota exerts effects that go beyond the promotion of susceptibility or resistance to certain diseases.

In the neonatal period, the immune system and lung tissue are not completely mature, and recent experimental evidence demonstrates that

basal Th2 immune response contributes to lung morphology and microbiota composition [155, 156]. Conversely, the lungs require a higher

microenvironmental tolerance to avoid potential exaggerated immune response to environmental stimuli and to maintain local homeostasis,

and the microbiota can act to promote this effect [157]. In this context, murine neonate lung microbiota promotes the expression of the

inhibitory molecule programmed cell death ligand (PDL-1) in DCs, leading to TRegs differentiation [158]. However, the effect of the maternal

diet/obesity on lung microbiota is yet to be determined.

6. Conclusion

Asthma is a multifactorial syndrome, and, despite of the strong hereditary component, the environment plays a critical role in the

establishment of this condition. In that sense, it has been demonstrated that microbiota can deeply affect the immune responses in the lung,

therefore being decisive for asthma onset. Hence, conditions that can disturb healthy colonization of the gut and lungs will contribute to both

asthma predisposition and severity. In that scenario, the widely known effect of obesity on disturbing the gut microbiome, and less known
effect on lung microbiota can interfere in asthma risk and aggravation. However, isolating the inflammatory and dysbiotic components of

obesity is challenging, and, most likely, they act in synergy. Additionally, the dysbiosis prompted by maternal obesity affects offspring

colonization and can have a long-term effect, especially by potentially shaping lung microbiota and building a favorable environment for

asthma development. Understanding the different levels of influence of obesity on asthma is pivotal to create new interventions, to better treat

or prevent the disease.

Author contribution

Menegati, L. M.; Oliveira, E. E.; Silva, F. M. C.; Initiated concept, writing original draft, review, and edition. Macedo, G. C.; Oliveira, B. C.;

participated in the review and edition of the manuscript. All authors participated in proofreading and revising the final manuscript.

Declaration of Competing Interest

The authors declare no conflict of interest.

Acknowledgments

This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq,Coordenação de

Aperfeiçoamento de Pessoal de Nível Superior-CAPES. Programa Pós-Graduação em Saúde (PPGS) - Universidade Federal de Juiz de Fora.

Juiz de Fora-MG, Brasil; Universidade do Estado do Rio de Janeiro, Rio de Janeiro-RJ, Brasil; Fundação de Amparo à Pesquisa do Estado do

Rio de Janeiro - FAPERJ

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Figure 1- Mechanisms in T2high asthma: Asthma patients frequently present lung dysbiosis, with an increased population of Streptococcus

spp, and also an intrinsic TRegs dysfunction making them more susceptible to innocuous antigen reactions. Allergens seep through the

epithelial barrier of the lungs or are captured by DCs in the lumen. Alarmins released by epithelial cells (TSLP, IL-25, IL-33) activate DCs
and ILC2. DCs migrate to secondary lymphoid organs and activate naïve T cells into Th2, and Tfh cells. The latter migrate to the germinal

center, activating B cells and promoting antibody class switch from IgM to IgE (in subsequent contacts) that in turn sensitize mast cells that

degranulate promoting an increase of vascular permeability, smooth muscle contraction, and mucus hypersecretion. The increased vascular

permeability facilitates eosinophil migration, which degranulates when exposed to IL-5; IL-9 increases mast cell activation, and together with

IL-13 increases mucus production. The eosinophil degranulation leads to further tissue damage, leading to remodeling of airway tissue and

loss of lung function (Created with BioRender.com).

Figure 2- T2low asthma response. Factors related to obesity lead to lung dysbiosis. An increase in Haemophilus and Moraxella populations is

associated with Th2-low asthma. The pro-inflammatory microenvironment with low levels of SCFAs and high levels of TNF-α IL-6 and IL-

1β, LPS, leptin, and fatty acids, promotes TLR-4 and NLRP3-IL1β pathway activation in macrophages and DCs, increasing ILC3 and mast

cells population, also causing TRegs functions impairment. Contact with allergen and increased epithelial damage leads to allergen infiltration

in lung tissue, followed by alarmins production in epithelial cells; low production of TSLP impairs DC activation; this distinct DC profile

migrates to secondary lymphoid organs, activating naïve T cells, which differentiate in Th17 cells. Additionally, the follicular T cells promote

antibody class switch from IgM to IgE, in lower levels when compared to T2high asthma, but still enough to sensitize mast cells, its

inflammatory mediators are released increasing vascular permeability, bronchial muscle contraction, and mucus production. IL-17 produced

by Th17 cells or ILC3 increases the recruitment of neutrophils, that in turn degranulate releasing ROS, NETs, and enzymes, increasing

inflammation and tissue damage, leading to extensive remodeling and loss of lung compliance (Created with BioRender.com).
Figure 3- Effect of maternal obesity and gut microbiome in offspring. Maternal obesity before or during gestation can dysregulate

offspring's immune system and increase predisposition to asthma. Maternal inflammation can impair lung development by dampening fetal

glucocorticoid production. Meanwhile, the maternal microbiome can affect host-microbial interactions in newborns, together with epigenetic

alterations. Environmental factors create a ―window of opportunity‖ for asthma and obesity development and aggravation, in childhood

presenting either a T2high response, with high eosinophilia, or a T2low response with increased Th1 response (Created with BioRender.com).