Exploring the Role of Human Gut Microbiota in Atopic Asthma - The Gut Lung Node
Vijayasri Hari and Deepa Parvathi V*
Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, India
Submission:May 02, 2022;Published:May 19, 2022
*Corresponding author:Deepa Parvathi Venkatachalam, Assistant Professor, Department of Biomedical Sciences, Sri Ramachandra Institute of Higher Education and Research, Porur, Chennai, India
How to cite this article: Vijayasri H, Deepa P V. Exploring the Role of Human Gut Microbiota in Atopic Asthma - The Gut Lung Node. Curr Trends Biomedical Eng & Biosci. 2022; 20(5): 556048. DOI:10.19080/CTBEB.2022.20.556048
Abstract
Atopic asthma is a hypersensitive reaction that occurs on exposure to allergens mediated by immunoglobulin E. Environmental, genetic and immunological factors concurrently influence the onset, development and severity of the disease characterized by wheezing, bronchospasm, cough and airway remodeling. Human gut microbiota is a complex, dynamic and diverse environment that regulates physiological mechanisms and prevents occurrence of disorders. The role of gut microbiota in atopic asthma has been established due to its effects at the immunological and histological levels. Composition of microbiota in the case of atopic asthma has been found to vary with age, health status, maternal effect, usage of antibiotics and method of delivery. Therapeutics that can modify the microbiota including probiotics, prebiotics and synbiotics are implicated in treatment of atopic asthma. Furthermore, traditional medicine-based interventions are also being explored among which curcumin has proven to be highly efficacious. This review provides a comprehensive view on factors, diagnosis, treatment, association of gut microbiome and remedies for asthma.
Keywords: Atopic asthma; Gut microbiota; Curcumin
Abbreviations: IgE: Immunoglobulin E; IL: Interleukin; Fc receptor: Fragment crystallizable receptor; Th17: T helper Cell 17; Th2: T helper Cell 2; SCIT: Subcutaneous Immunotherapy; SLIT: Sublingual Immunotherapy; TNF-β: Tumor Necrosis Factor Beta; IgA: Immunoglobulin A; IgG4: Immunoglobulin G4; Treg: Regulatory T cell; DC: Dendritic Cell; iNKT: invariant Natural Killer T cell; C-section: Caesarean section; MMP9: Matrix Metalloproteinase 9; eNO: Exhaled Nitric Oxide; Th1: T helper Cell 1; HLA-DR: Human Leukocyte Antigen-DR isotype; HMOs: Human Milk Oligosaccharides; TNF-α – Tumor Necrosis Factor α; NF-κB: Nuclear Factor kappa B; LPS: Lipopolysaccharide; RSV: Respiratory Syncytial Virus; eIF2α: Eukaryotic Translation Initiation Factor 2 Subunit 1; PKR: Protein Kinase R; AQP: Aquaporin; LGG: Lactobacillus rhamnosus GG; CCL17: Chemokine Ligand 17;
Introduction
Asthma is a pulmonary disorder associated with inflammation, bronchoconstriction and hyperactivity [1,2]. Approximately, 300 million people are affected by asthma worldwide with 8% in India alone [3]. There is a complex interplay between genetic, environmental and immunological factors throughout the progression of the disease. In recent times, the role of gut microbiome in asthma has been investigated providing insights into mechanism as well as treatment.
Types of Asthma
Asthma can be broadly classified as atopic and non-atopic asthma [4]. Atopic asthma is a type I hypersensitivity reaction occurring from infancy, triggered on exposure to allergens. On the other hand, non-atopic asthma is related to viral infections and certain allergens. Drugs and air pollutants have also been reported to induce asthmatic attacks [2,4].
Atopic Asthma
Atopic asthma, also known as allergic or extrinsic asthma, is initiated from childhood characterized by an exaggerated hyperresponsiveness to common aeroallergens. Individuals with a familial predisposition are susceptible and display this phenomenon mediated by IgE antibodies. It is accompanied by rhinitis, wheezing and eczema [4-6]. Diet, ozone, dust mites, pets, endotoxin, pollen [7-10], animal dander are few of the risk factors [4]. Pertaining to childhood asthma, tobacco, oxidative stress and method of delivery have been noted [11,12]. An increased consumption of fast food and polyunsaturated fatty acids (PUFAs) can precipitate while antioxidant sources including fruits, vegetables and omega-3 fatty acids containing fish constitute a protective action [13,14]. These effects arise from the influence on biogenesis of inflammatory mediators [15]. Interestingly, not all asthmatics with atopy develop atopic asthma [16].
Pathogenesis of Atopic Asthma
Cellular and humoral mediated immune responses together contribute to pathogenesis of asthma. This occurs in two phases: early and late. Early phase is largely resolvable whereas late phase progressively leads to irreversible damage [1]. When an allergen enters the airway, it is endocytosed and processed by antigenpresenting cells (APCs), predominantly dendritic cells. It is then presented to T-cells stimulating their maturation. T-helper-2 and T-helper-17 cells (Th2, Th17) are the two major subtypes involved in pathogenesis of asthma. Upon binding to the antigen via cell surface receptors, they produce interleukins IL-4, IL-13, IL-5 and IL-17 respectively. IL-4 and IL-13 induce B-lymphocytes, which then secrete IgE antibodies. IgE antibodies interact with mast cells and basophils via Fc receptors. It remains in circulation as well as bound to the surfaces. On subsequent contact with the same allergen, an antigen-antibody (immune) complex is formed on their surfaces and causes degranulation. Degranulation results in release of cytokines such as histamine, prostaglandins, leukotrienes that promote vasodilation, inflammation and smooth muscle contraction. In addition, they increase the permeability of vessels and synthesis of mucus. Because of chemotaxis, eosinophils, T-lymphocytes and neutrophils are recruited to the site, which establish a sustained inflammatory reaction. IL-5 from Th2 cells enhances eosinophils, which also emit inflammatory mediators. Th-17 support Th-2 mediated response through IL-17 [17]. Consequences of this cascade are epithelial injury, obstruction, bronchospasm, oedema and airway remodeling [18,19] . These pathophysiological changes manifest as wheezing, dyspnea and cough [1]. At the histological level; hyperplasia, hypertrophy, fibrosis, accumulation of mucus, denudation of epithelium, infiltration of cells, thickening of basement membrane and presence of goblet cells have been observed [1,20].
Factors
Factors responsible for asthma can be attributed to the individual (host) and environment (causal or precipitating). Host factors refer to variations within the individual such as genetic mutations, inherited vulnerability and atopy [4]. ORMDL3, GSDMB [21], ZPBP2 [22] on 17q21 locus; IL33 [21,22], CYBRD1 [23], RAD50, IL2RB, IL1RL1, DENND1BI [22], TNFSF15 [23], ADAM33 [24], ABI3BP, MICA, NAF1 [21], IL-4 , IL-10, SCYA11, PHF11, iNOS, CD14 FcεRIβ [24] and HLA-DQB1 [22] are demonstrated to be associated with asthma. In addition to allergens, diet, tobacco, rhinoviral and respiratory syncytial viral infections above mentioned [25-27]; obesity [28], exercise [2], usage of nonsteroidal anti-inflammatory (NSAIDs) [2], indoor and outdoor air pollutants [11], climate changes, fetal health [29-30] and chemical irritants are categorized as causal factors [11].
Diagnosis
Diagnosis of asthma begins with description and occurrence of symptoms, exposure to potential allergens, familial atopy and consolidation of case history. Expiration tests and evaluation of nasal cavity is performed routinely. Since atopic asthma is an allergic response, allergy testing either in-vitro or in-vivo is recommended. Skin prick test, an in-vivo technique, utilizes a panel of allergens and controls to identify hypersensitivity responses of the individual. It is crucial that the test is based on regulated reagents to produce valid, reliable and safe results. Panel of allergens to be included will be determined by the case history. Skin prick test is conducted at regular intervals to identify new allergic reactions. Measurement of IgE in serum is done in-vitro depending on the nature and severity of the response [31].
Treatment
Treatment is based on pharmacotherapy and immunotherapy.
Pharmacotherapy
Objective of pharmacotherapy is to alleviate the symptoms, reduce the exaggerated responses with minimal side effects. The design depends upon severity of attacks, effectiveness of drugs and phenotype [31]. Some of commonly used drugs for treatment of asthma are given in Table 1.
Based on stage of management of asthma, different regimes varying in number, type, route of administration and dosage of drugs should be followed as given in Table 2.
Drugs can be administered in different ways depending upon the type, physical properties, dosage, intended bioavailability, duration and site of action which can be oral or inhalation routes [31]. For inhalation route, inhaler devices are commonly used. Types of inhalers include metered-dose inhaler and dry powder inhaler. Nebulisers are rarely used [4].
Immunotherapy
Immunotherapy is a therapeutic intervention that administers allergens based on sensitisation profile in periodic and progressive concentrations in order to develop immunological tolerance in the individual. The modes of immunotherapy can be subcutaneous (SCIT) or sublingual (SLIT) [47]. SCIT has better efficacy. However, it relies upon injections containing aqueous extracts that can be only delivered in healthcare facilities with increased risk for immune reactions [48]. SLIT is suitable for self-management formulated as tablets or drops [48,49] . Immunotherapy modifies action of both the innate and adaptive components, producing antiinflammatory actions. Upon immunotherapy, regulatory T and B cells are activated which prevent Th2 mediated actions, inhibitory cytokines (IL-10, TNF-beta, IL-35) secreted, IgE-related effects suppressed along with presence of IgA and IgG4 in serum [48].
Extracts derived from Phleum pratense and Dermatophagoides pteronyssinus are used for preparations. Immunotherapy is indicated for atopic and controlled asthmatics elder than 5 years [49]. Since immunotherapy directly targets the immunological mechanisms involved in asthma, it can alter the advancement of the disease and thus is significant [48]. Other remedial measures include Th2 targeted strategies such as usage of Th2 cytokine inhibitor Suplatast tosilate in atopic asthma and inhibition of memory cells [50-52], incorporation of statins (Atorvastatin) for enhancing anti-inflammatory action, administration of cytokines in low concentrations, promising monoclonal antibodies against mediators like TNF (Infliximab) [53-55], Temperature controlled laminar airflow (TLA) decreasing allergen exposure beneficial in extrinsic asthma and adjunction of medications with acupuncture capable of regulating immune responses [56,57].
Overview of Gut Microbiome
Gut microbiome comprises of a plethora of diverse microorganisms ranging from bacteria, viruses, protozoa and fungi that interact with the gastrointestinal system establishing a dynamic environment [58,59]. As embryogenesis occurs, the microbiota is also gradually organised within the foetus. During neonatal development, there is a period defined as critical window which is when the infants respond more sensitively to microbiotadriven immunoregulatory mechanisms [60]. If the microbiota is altered in this period, it can underly atopic disorders [61]. Factors such as mode of delivery, formula-based feeding [61-64], vitamin D, breast feeding [58], nutrition [62], usage of antibiotics [58,61,62], ambient air pollution, environmental exposure, absence of pets and having siblings are implicated in maturation of gut microbiota. Canine associated households have a unique particulate microbial community with L. johnsonii being the focal bacterium [62,64]. It has been accounted to minimise respiratory syncytial viral (RSV) infection and overall atopy. Increase in Treg cells, production of fatty acid metabolites and a decrease in interleukins 4,5, 17 and DCs were responsible for the effects [64].
The environment within the gut is characterized by an interdependent, symbiotic relationship between the human and microorganisms. Essentiality of this association is implied in maintenance of physiological activities involving immunological,neural, metabolic and epithelial systems along with homeostasis. Microbes within the gut are sensitive to cues from the internal as well as the external milieu, producing different responses [59]. These responses may result in establishment of inflammatory bowel disease (IBD), obesity, autoimmune disorders, cancer, diabetes mellitus, autistic spectrum disorder, cardiovascular disorders and atopic asthma [64]. Distribution and abundance of microbes in the gut is influenced by host and co-existing microbial competition. Due to these variations, individuals are classified based on enterotypes. Enterotypes are defined as communities of microbes inhabiting within the individual. A metagenomic study conducted with samples from four different countries revealed variations arising from three dominant enterotypes belonging to Bacteroides, Prevotella and Ruminococcus genera, with microbial genes as potential biomarkers [65].
Association Between Gut Microbiome and Atopic Asthma
Experimental data have ascertained that gut microbiome can regulate and modify behaviour of innate and adaptive immune system components by influencing the secretion of cytokines. Enhancing the synthesis of IL-10 and suppressing release of Chemokine ligand (CCL5), TNF, IL-12 and nuclear factor kappa B (NF-κB) constitutes an anti-inflammatory state. By expressing ligands for CXC chemokine receptor 2 (CXCR2) presents on surface of mast cells, epithelial cells home mast cells to the intestine, managing the functioning of the immune system. The maturation and differentiation of CD4+ cells and Treg cells are impacted by gut microbiome. Recruitment of pili-like protein stimulates Treg cells which in turn switch off Th2 cells. It is also responsible for maintaining the epithelial integrity through short chain fatty acid (SCFA) synthesis along with promotion of IgA class switching [58].
It is evident that role of gut microbiome is critical in protecting and preventing the host from disorders. Dysbiosis arises due to a disproportion in constitution and abundance of microbiota. Increase in infectious and decrease in beneficial microbial population can contribute to dysbiosis. An important consequence of dysbiosis is the loss of epithelial integrity. Without the presence of a functional barrier, intestinal permeability is distorted, allowing entry of foreign antigens which trigger an immune response. This lack of epithelial integrity is involved in many disorders including asthma. Activation of self-reactive immune cells, enzymatic production of epitopes, resistance of bacteria to their own inflammatory processes and alteration in production of antibodies are results of dysbiosis. Modifications in gut microbiome enhance the levels of IgE, activation of invariant Natural Killer T (iNKT) cells synthesising IL-4 and IL-13 which independently cause isotype switching of IgE to IgA, accompanied by profusion of circulating basophils and mast cells. Exposure to gut microbiota reducing the levels of iNKT in mice have been observed. Likelihood of an adult developing asthma later in life increases with dysbiosis during infancy [58]. Affluence of various microbial families in asthma has been described in table 3. Among these, a low distribution of Bifidobacterium, Lactobacilli, Akkermansia and Faecalibacterium can amplify the probability of child developing asthma [66].
Table 4 elucidates the immunological impact of microbes and microbial families. In asthmatics, Escherichia coli, Lactobacillus vaginalis, and Morganella morganii were shown to release histamine which may play a role in sustaining the allergic responses [68]. Composition of microflora varies with different stages of childhood. Its association with asthma in turn differs as given in table 5. Interestingly, occurrence of Clostridium difficile in children correlated with hospitals deliveries and C-sections with increased chances of acquiring asthma as well eczema when born to atopic individuals [58]. Culture samples were distinct between C-sections and normal delivery with former having lower counts of Bifidobacterium, Bacteroides and relatively higher in Staphylococcus, Streptococccus [62]. It is noted that diversity of microbial colonisation can have different effects at different periods of infancy. When microbial profile was compared between healthy adults and five-year-old asthmatic children, there was a paradigm shift in nature and abundance of composition. This has been depicted in table 6.
Asthmatic mothers can impact the composition of gut microbiota of the offspring in a gender-specific manner. The research conducted by Koleva PT et al. identified a higher occurrence of Bacteriodaceae and lower occurrence of Lactobacillus in female and male infants respectively, at 4 months of age. The alterations could be a susceptibility factor for acquiring asthma. Microbial remnants from elder siblings, on the other hand, could be beneficial in conferring an immunoprotective state against asthma [71]. Early-life exposure to antibiotics such as Vancomycin and Streptomycin can transform the microbiota constituents with a reduction in Clostridium and Bacteriodaceae in addition to depletion of regulatory cells [72].
Microbiota-based Remedies
Objective of microbiota-based remedies is to lessen overgrowth of certain microbes thus reinstituting the flora. Probiotics, prebiotics, and synbiotics represent the means for microbiota modulation [62,73].
Probiotics
Probiotics are live, active microorganism cultures that can be prescribed to improve and maintain the intestinal biota [73]. The quantity and schedule of prescription in addition to existing microbial population determine the usefulness of probiotics 62]. A well-documented bacterium in designing probiotic is Lactobacillus rhamnosus GG (LGG) that has proven to inhibit MMP9 [74,75], prevent intrusion of immune cells, reduce levels of eNO in children and Ovalbumin sensitised responses in mice [76]. Similarly, Lactobacillus rhamnosus reduced hyperresponsiveness, cytokines and strengthened gut microbiota [77]. Bifidobacterium lactis has been shown to decrease IgE levels, eosinophils and trigger of Treg cells in a mice model [74]. Bifidobacterium breve M-16V has been demonstrated to inhibit Th2 responses and regulate Th1/Th2 balance [73].
Dispense of atopic asthmatic children with Trilac (1.6 × 109 lactic acid bacteria cells: Lactobacillus acidophilus - 37.5%, Bifidobacterium bifidum - 37.5% and Lactobacillus delbrueckii subsp. bulgaricus - 25%) resulted in fewer attacks, better pulmonary ability, higher monocytic HLA-DR and lower CD8/ CD45RA+ cells [78]. A randomized trial employed the use of Bifidobacterium lactis (Probio-M8 powder) as an additive to Budesonide/formoterol (Symbicort Turbuhaler) to evaluate the effects on asthmatics. Reduction in nitric oxide and increase in relative abundance of Bifidobacterium, Prevotella species and their associated metabolites indicate a promising therapeutic intervention [79]. Bacterial derivatives such as flagellin and endotoxin repress asthma in experimental models by recruiting Treg cells or ubiquitin-modifying enzyme A20 [62].
Prebiotics
Prebiotics are specific substances that are metabolised by microbes [73]. Galacto-oligosaccharide (GOS) and fructooligosaccharide (FOS) containing prebiotics offered protection against asthma in infants. However, data related to benefits of prebiotics in asthma is limited [62]. Human breast milk is enriched with nutrients, human milk oligosaccharides (HMOs), microbes and hormones. Once ingested, HMOs can act as prebiotics that can affect the immune system. HMOs get distributed to different organs and create a cross-talk between different immunological barriers. When this cross-talk occurs between the pulmonary barrier, HMOs could potentially guide the mucosa to confer immunity [80].
Synbiotics
Synbiotics is a mixture of prebiotic substrates and probiotic cultures. A combination of Bifidobacterium breve and galacto/ fructooligosaccharide alleviated asthmatic symptoms in children with atopic dermatitis [81]. Hydrolysed casein together with L. rhamnosus GG enhanced the endurance of the infant gut microbiome in response to bovine milk allergy [62]. The period of administration (prenatal or postnatal) might be an important factor for efficiency of biotics [62].
Curcumin in Treatment of Asthma
Curcumin or diferuloylmethane is a phytocompound rich in polyphenols, oils, saccharides and proteins obtained from the rhizome of Curcuma longa. It is a renowned medication in regions of Asia indicated in cancer, asthma, arthritis, cardiovascular and gastrointestinal diseases. Curcumin exhibits antioxidant, anti-tumoral, antimicrobial and anti-inflammatory effects [82- 84]. As a pharmacologic agent, it has spasmolytic properties via hypothesised blockage of calcium ion channels in addition to a differentiable range of vasoconstriction and vasodilation properties [85]. The bioavailability of curcumin is considerably low which disrupts its distribution and consequently therapeutic actions. Construction of nanoparticle-based curcumin could be a novel approach in improving pharmacodynamics and thus its efficacy [86]. At the molecular level, it suppresses the release of cytokines TNF-α, IL-6, IL-12, IL-1 and NF-κB. It also inhibits the synthesis of monocyte chemotactic proteins 1,3 and eotaxin from bronchial muscles [83]. It interferes with angiotensin converting enzyme (ACE), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon gamma (IFN-γ). Contrastingly, it enhances production of IL-10 whose dysfunction is implicated in neurodegenerative, allergic and autoimmune disorders [87].
Curcumin, at the microbiota, induces proliferation of beneficial microbes Bifidobacteria, Lactobacilli while inhibiting that of Prevotellaceae, Coriobacterales, Enterobacteria, and Rikenellaceae thus varying the microbial ratio of beneficial to harmful microbes promoting a healthy microflora. Furthermore, it regulates epithelial integrity counteracting IL-1β [84]. Microbiota can release lipopolysaccharide (LPS) into circulation upon disorganisation of intestinal barrier which has been associated with several disorders. Curcumin decreases the amount of LPS thus ameliorating the inflammatory condition [88]. Curcumin has a remarkable antiviral activity against RSV via proteosome, NF-κB inhibition and phosphorylation of eIF2α and PKR, which might be beneficial in prevention of virus-induced asthma [82,89].
In an ovalbumin sensitized murine model, curcumin demonstrated to reduce IL-4,5, eotaxin, TNF and heat shock protein 70 and enhance aquaporins AQP 1,5 resolving inflammation and oedema [90]. Another investigation with the same model analysed the efficacy of tetrahydrocurcumin, a metabolite of curcumin, in reversal of airway inflammation through exerting influence on intestinal microbiota by faecal microbiota transplantation technique. Results denoted a decrease in Proteobacteria, Ruminococcaceae, Intestinimonas and Lachnospiraceae and Th2 induced actions [91]. Additionally, tetrahydrocurcumin in combination with dexamethasone synergistically relived asthmatic symptoms along with reduction in Th2, Th17 counts as well as IL-4,5 [92]. The usage of LGG and turmeric extract as a synbiotic in house dust mite (HDM) allergised mice model revealed a decrease in Th2, Th17, eosinophils, IL-5, IL-13, CCL17 and an increase in Treg [93].
Conclusion
Atopic asthma is a multifactorial disorder which occurs as an exaggerated response of the immune system to aeroallergens. Components of cellular and humoral immune systems trigger a cascade of events resulting in bronchospasm, oedema, epithelial damage and airway remodelling. This hypersensitive reaction is initiated by intrinsic (genetic mutations, familial predisposition, obesity) and extrinsic (pollutants, allergens, irritants) causes. Diagnosis is based on allergy and physiological testing, radiological examination, haematological analysis, spirometry, expiratory methods and biomarkers. Currently available therapeutic intervention includes pharmacotherapy and immunotherapy. Pharmacotherapy aims for symptomatic relief employing different classes of drugs such as short-acting beta 2 agonists, long-acting beta 2 agonists, corticosteroids, leukotriene receptor antagonists, methylxanthines, anticholinergics, mast cell stabilizer and monoclonal antibodies. A regimen depending upon the stage of the disease has been prescribed to incorporate one or more therapeutics at a specific concentration and route of administration. Immunotherapy, on the other hand, delivers allergens subcutaneously or sublingually according to sensitivity profile of the individual. It thus alters the immune responses in vivo and subsequently the severity of the asthmatic attack. Human gut microbiota is defined as the microbial flora existing in the gastrointestinal tract. As embryogenesis occurs, the microbiota also undergoes development. Any variations during this period can bring about atopic disorders. Mode of delivery, formulabased feeding, having siblings; exposure to antibiotics, vitamin D, absence of pets and pollutants influence the differentiation of the microbiota. Host and microbial population thrive together in a mutually dependent relationship. This is substantiated by the role of microbiome in maintenance of physiological mechanisms and instigation of several diseases like inflammatory bowel disease, atopic asthma, diabetes, autism spectrum disorder, obesity and autoimmune diseases. Due to host and co-existing microbeimposed changes, the abundance and diversity of gut flora varies accounting for enterotypes. Role of gut microbiome in causation of atopic asthma stems from evidential data indicating that the microbiota modifies nature of immune responses and affects integrity of respiratory epithelium. Additionally, dysbiosis can impact epithelial permeability, aid self-reactive cells and modify antibody synthesis. Microbial profiling has revealed differences in microbial population between healthy individuals and asthmatics, abundance in various stages of asthma, affluence in asthma and influence on immunological system. Furthermore, composition of microbiota was found to differ with mode of delivery, asthmatic status of mothers, presence of elder siblings and exposure to antibiotics. In order to establish an equilibrium between beneficial and harmful microbes hence abetting occurrence and severity of atopic asthma, microbiota-based remedies like probiotics, prebiotics and synbiotics are recommended. Examples include Lactobacillus rhamnosus GG, oligosaccharides and Trilac. Apart from the conventional treatment modalities, traditional medicine is being extensively explored as a safe and effective alternative. Curcumin, a phytochemical obtained from the rhizome of Curcuma longa, shows anti-inflammatory, antimicrobial and antioxidant properties. It interferes with the actions of cytokines and increases abundance of beneficial microbes in the gut. Curcumin can also be incorporated with pharmacological agents or probiotics to synergistically improve efficacy. From this study, it is evident that natural products capable of interacting with and modifying the gut microbiota might be promising agents for treatment of atopic asthma. Future directions must focus on discovery and validation of traditional medicine compounds that resolve the condition from the level of microbiota.
Conflict of Interest
Authors declare that they have no conflict of interest.
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