The Gut/Lung Microbiome Axis in Obesity, Asthma and Bariatric Surgery: A literature review.

Abstract

Mounting evidence suggests that obesity, parameters of metabolic syndrome, and asthma are significantly associated. Interestingly, these conditions are also associated with microbiome dysbiosis, notably in the airway microbiome for patients with asthma and in the gut microbiome for patients with obesity and/or metabolic syndrome. In this review, since improvements in asthma control, lung function and airway hyperresponsiveness are often reported after bariatric surgery, we investigated the potential role of bacterial gut and airway microbiome changes after bariatric surgery in ameliorating asthma symptoms. Rapid and persistent gut microbiota alterations were reported post-surgery, some of which can be sustained for years. The gut microbiome is thought to modulate airway cellular responses via short-chain fatty acids and inflammatory mediators, such that increased propionate and butyrate levels following surgery may aid in reducing asthma symptoms. In addition, increased prevalence of Akkermansia muciniphila after Roux-en-Y gastric bypass and sleeve gastrectomy may confer protection against airway hyperreactivity and inflammation. Metabolic syndrome parameters also improved following bariatric surgery, and whether weight loss-independent metabolic changes affect airway processes and asthma pathobiology merits further research. Fulfilling knowledge gaps outlined in this review could facilitate the development of new therapeutic options for patients with obesity and asthma.

Introduction

Asthma is a heterogeneous disease characterized by bronchial inflammation, airway hyperresponsiveness (AHR) and airway remodeling resulting in dyspnea.¹ The observed heterogeneity has contributed to the current understanding that asthma treatments are most effective in specific subsets of patients based on asthma phenotype, and further research of asthma pathophysiology is needed in order to appropriately manage the multidimensionality of asthma. Multiple large cluster analyses of patients with asthma have identified various asthma endotypes with incidence being dependent on age of asthma onset, sex, body mass index (BMI), or inflammatory profiles, among others.^2–4 Of these clusters, patients with early-onset asthma—asthma that presents between 0 to 12 years of age —typically exhibit atopic symptoms with a male predominant population; however, post-puberty, the population is female predominant.¹

In addition to the early-onset atopic asthma endotype, cluster analyses identified a significant number of patients with late-onset asthma concurrent with obesity consisting predominantly of adult females.^2–4 This latter population of mostly female patients with late-onset asthma and obesity exhibited less evidence of atopic inflammation and reported more frequent and severe exacerbations than atopic patients with asthma.⁴ While evidence has shown that increasing BMI is associated with severe asthma,^5,6 the underlying mechanism is poorly understood, and few treatment options are available.

Interestingly, patients with obesity and asthma undergoing bariatric surgery experience a significant increase in lung function 12 months post-operation, with greater improvement in patients with late-onset non-atopic asthma and obesity.⁷ Such findings support the use of surgical intervention as a possible treatment for this asthma endotype.⁸ In addition, patients with normal serum immunoglobulin E (IgE) experienced a greater post-operative improvement in AHR following methacholine challenge when compared to their high IgE counterparts.⁷ These findings were supported by another study that reported patients with asthma who underwent bariatric surgery experienced an increase in small airway function and asthma control, but no improvement in the ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC), an indicator of airway obstruction.⁹ These studies suggested that obesity is associated with irreversible airway remodeling in asthma.

The prevalence of obesity is also associated with metabolic syndrome, and recent studies have identified a relationship between metabolic syndrome and asthma incidence.¹⁰ Although the definition of metabolic syndrome is debated, most clinicians follow the modified National Cholesterol Education Program (NCEP) Adults Treatment Panel III (ATP III) guidelines set forth by the American Heart Association and the National Heart, Lung and Blood Institute.¹¹ According to the modified NCEP ATP III, in order to be diagnosed with metabolic syndrome the patient must exhibit at least 3 of the 5 following criteria presented in Table 1,^11,12 all of which were found to be significantly associated with asthma incidence.^10,13–21 Such findings support the hypothesis that diagnosis of metabolic syndrome can be used to identify individuals at higher risk for developing asthma. By considering obesity and metabolic syndrome in patients with asthma, clinicians may be able to implement early prevention management strategies, such as improved nutrition education, dietary changes, exercise regimens and weight loss programs to slow the progression of airway remodeling.²²

Table 1.

Modified NCEP ATP III Values of Inclusion for Metabolic Syndrome, Adapted from Huang.¹²

Criteria	Criteria Definition	Association with Asthma
Abdominal Adiposity	Waist Circumference > 40 inches for Males (M) > 35 inches for Females (F)	Yes10,13,14
Dyslipidemia	Triglycerides ≥ 150 mg/dl or prescription for treatment	Yes15,16
Low Blood High Density Lipoprotein (HDL)	HDL < 40 mg/dl (M)    < 50 mg/dl (F) or prescription for treatment	Yes15–17
Insulin Resistance/Hyperglycemia	Fasting Glucose ≥ 100 mg/dl or prescription for treatment	Yes10,18,19
Hypertension	Systolic Pressure ≥ 130 mmHg Diastolic Pressure ≥ 85 mmHg or prescription for treatment	Yes20,21

To explore how bariatric surgery impacts obesity and asthma outcomes, this review investigates the potential role of postoperative microbiota alterations in modulating asthma and metabolic syndrome symptoms. The microbiota refers to the collection of microorganisms living within and on us. The genomes and genes in the microbiota are collectively termed the metagenome, as obtained from shotgun sequencing. The microbiota composition can also be estimated using next generation sequencing of marker genes such as 16S ribosomal ribonucleic acid gene for prokaryotes. The term microbiome refers to the microbiota, its metagenome, and the surrounding abiotic environmental conditions.²³ The reduction of cost in sequencing and the development of metagenomic analytical pipelines have increasingly allowed researchers to study the microbiome without the limitations of culture-dependent methodologies.

The role the gut microbiome plays in regulating human health has garnered researchers’ attention. The gut microbiota is incredibly diverse and distinct; in a global dataset (n = 3,948) of gut microbiomes, a total of 664 genera were discovered, of which only 14 were shared by more than 95% of individuals.²⁴ Most gut microbiota belong to phyla Firmicutes and Bacteroidetes, followed by Actinobacteria, Proteobacteria and Verrucomicrobia.²⁵ Gut microbiome dysbiosis, a phenomenon that occurs when the microbial community composition is altered to create an imbalance in the community, is associated with obesity (see Microbiomes in Obesity and Metabolic Syndrome Section), hypertension, diabetes, and cancer, among other diseases.²⁶ One known mechanism through which the gut microbiome affects human health is via the production of short-chain fatty acids (SCFAs). Microbes produce SCFAs such as butyrate, formate, acetate, and propionate through fermentation of complex carbohydrates. SCFAs can regulate inflammatory immune response and also partake in maintaining colonic epithelial integrity, appetite regulation, lipid metabolism amongst others.²⁷ The intricate relationships between the gut microbiome, asthma and/or obesity are further discussed later in this review.

For respiratory illnesses, the role of airway/lung microbiome has received particular interest. Contrary to traditional belief, the lungs are not sterile: Sze et al.²⁸ reported that approximately 20–1,252 bacterial cells exist for every 1,000 somatic cells in the lung. The most common bacterial phyla include Firmicutes and Proteobacteria, followed by Actinobacteria and Bacteroidetes.²⁹ In healthy individuals, the lung microbiome resembles the mouth microbiome, and lower and upper respiratory tract microbiomes are compositionally similar but the lower respiratory tract harbors less bacterial biomass.³⁰ Among other diseases, dysbiosis in the lung microbiome is associated with chronic obstructive pulmonary disease²⁸ and asthma (see Microbiomes and Asthma Section).

In this review, given the role of airway/lung and gut microbiomes on human health, we first explore how these microbiomes affect asthma as well as obesity and metabolic syndrome. Then we discuss the microbiota changes associated with bariatric surgery. Finally, we present the microbiome in patients with obesity and asthma in relation to previous sections to draw conclusions on whether bariatric surgery affects airway and gut microbiomes to reduce symptoms of asthma, obesity, and metabolic syndromes. An overview of mechanisms through which bariatric surgery may improve asthma pathobiology are presented in Figure 1.

Figure 1:

Mechanisms through which bariatric surgery may contribute to reduced asthma symptoms, including airway inflammation, remodeling and AHR, in addition to specific weight-loss effects. While postsurgical gut microbiome changes and possibly airway microbiome changes could impact metabolic syndrome and/or metabolic changes, more studies that explore their associations and possible causality are needed.

Microbiomes and Asthma

In recent years, exploring the role of the gut and lung microbiomes in asthma has gained traction. For reference, the taxonomy hierarchy of microbiota is as follows, from most inclusive to most specific: domain, kingdom, phylum, class, order, family, genus, and species. In the gut microbiome, children at risk of asthma had significantly lower relative abundances of genera Faecalibacterium, Lachnospira, Rothia, and Veillonella (FLVR) at 3 months of age. Supplementing germ-free mice with live FLVR significantly reduced proinflammatory cytokines interleukin (IL)-17A, IL-6, and tumor necrosis factor-alpha (TNFα) associated with severe asthma.³¹ Further, lower gut microbiome diversity at 1 month old³² and slower diversification of gut microbiota during infants’ first year³³ were related to asthma. For children with asthma at 5 years of age (n = 60), increased risk of asthma was associated with higher abundance of Veillonella and lower abundances of Roseburia, Alistipes and Flavonifractor at 1-year of age, though the association was only significant for children with asthmatic mothers.³⁴ The contradictory role of Veillonella may be due to the depth of sequencing analysis; identification at the species level may be needed to fully elucidate the role of genus Veillonella in asthma. Similarly, the genus Clostridium was shown to be protective of wheezing in infants³⁵ though colonization of the species Clostridium difficile in infancy (1 month) is associated with increased risk of wheezing and asthma at 6 to 7 years old.³⁶

In the airway microbiome, several studies reported the presence of Streptococcus pneumoniae, Haemophilus influenzae,³⁷ Moraxella catarrhalis^37,38 and Haemophilus spp.^38,39 in patients with asthma. Proteobacteria were associated with worsening Asthma Control Questionnaire scores [as defined by Juniper et al.⁴⁰] and increased expression of inflammation genes related to T-helper cell 17 (Th17)-directed pathways in patients with severe asthma.⁴¹ Moreover, Proteobacteria were enriched in airway³⁹ microbiota of patients with asthma, and Proteobacteria families (Pasteurellaceae, Enterobacteriaceae, Neisseriaceae, Burkholderiaceae, and Pseudomonadaceae) correlated with increased AHR in patients with sub-optimally controlled asthma.⁴² In particular, Gammaproteobacteria were more abundant in the sputum of individuals with asthma compared to healthy counterparts.⁴³ In comparison, Prevotella^39,44 and Veillonella⁴⁴ were less abundant in patients with asthma. Additionally, an increase in lower airway bacterial populations compared to healthy controls was observed in patients with sub-optimally controlled or severe asthma.^41,42

Airway microbiota trends varied based on sputum inflammatory cell profiles: neutrophilic asthma was associated with enriched Proteobacteria,⁴⁵ Moraxella, Haemophilus,⁴⁶ and H. influenzae.⁴⁵ Further, reduced sputum bacterial diversity characterized neutrophilic asthma as compared to other asthma phenotypes,^45,46 with lower prevalence of Streptococcus, Gemella, and Porphyromonas observed.⁴⁶ In comparison, patients with asthma and high sputum eosinophils had sputum enrichments of Tropheryma whipplei,⁴⁵ Granulicatella adiacens, Streptococcus parasanguinis, S. pneumoniae, Veillonella rogosae, Haemophilus parainfluenzae, and Neisseria perflava.⁴⁷

In the gut microbiome, diet can induce rapid microbiota changes. Thus, whether diet can influence lung and gut microbiomes and hence, airway pathobiology and asthma symptoms, was considered. One study reported that lifetime supplementation of vitamin D increased an Acinetobacter operational taxonomic unit (OTU) in female mice lungs. However, allergic airway disease induced via ovalbumin caused substantially greater alterations in the lung microbiota, signifying that the microbiota-modulating role of vitamin D may be limited.⁴⁸ Other studies involved the gut microbiome in explaining how diet affects asthma. In mice, a high-fiber diet led to protection against allergen-induced peribronchial inflammation, AHR and airway mucus production through increased SCFA levels in blood. In particular, propionate reduced Th2-related proinflammatory cytokines, IL-13, IL-4 and IL-5 and Th17-directed IL-17A in the lungs in a mechanism requiring signaling through the SCFA receptor, G-protein coupled receptor 41 (GPR41).⁴⁹ Also, Sun et al.⁵⁰ demonstrated in mice that SCFAs promoted Th1 cell production of an immunosuppressive cytokine, IL-10, by signaling through another SCFA receptor, GPR43. Finally, Zhang et al.⁵¹ correlated high fiber intake in mice with reduced allergic responses, lower serum IgE and IL-4 levels, and a higher IL-10 level, though higher proinflammatory interferon gamma (IFN-γ) levels were also observed.

Butyrate and propionate were shown to increase differentiation of regulatory T cells (T_regs).⁵² T_regs suppress Th2 cell functions via cell-to-cell contact or immunosuppressive cytokines IL-10 and transforming growth factor beta, thereby reducing allergic responses.⁵³ In mice, both in vivo and in vitro propionate treatments were shown to increase expression of IL10 and T_regs transcription factor Foxp3.⁵⁴ Taken together, diet, especially fiber and SCFA production, can ultimately affect airway inflammation in allergic asthma via reducing Th2- or Th17-related proinflammatory cytokines while increasing immunosuppressive T_regs and IL-10.

Current research data suggest an interplay between diet, gut microbiome, and airway inflammation through SCFAs and pro- or anti-inflammatory cytokines, but more studies that directly compare changes in the lung microbiome with altered diet could elucidate whether reduced allergic or asthma symptoms are due solely to gut microbiota changes. Moreover, since observational human studies are associative, murine models focusing on causal links between microbiome dysbiosis and airway pathobiology would aid in developing potential prebiotic or probiotic treatments. In addition, since gut microbiome studies on asthma have hitherto emphasized gut microbiome dysbiosis in infancy, studying whether adult patients with different asthma endotypes have specific gut microbiome dysbiosis could provide valuable information in developing targeted pre- or probiotic treatments.

Microbiomes in Obesity and Metabolic Syndrome

Microbiota alterations in the gut are associated with obesity. At the phylum level, some studies suggested that obesity is associated with increased Firmicutes/Bacteroidetes (F/B) ratio in humans.^55,56 However, conflicting evidence exists,⁵⁷ including a meta-analysis that did not find any statistically significant correlation between F/B ratio and BMI.⁵⁸ Studies vary greatly on which microbes are most affected by obesity. Microbiota dysbiosis in patients with obesity includes greater presence of Prevotellaceae, Veillonellaceae,⁵⁵ Lachnospiraceae,⁵⁹ Lactobacillus spp., Bacteroides fragilis,⁶⁰ Roseburia sp., Faecalibacterium sp.,⁵⁹ Megamonas spp., and a Prevotella spp.-dominated enterotype.⁶¹ Obesity was also associated with lower gene richness,⁶² lower microbiota diversity, and reduced presence of Odoribacteraceae, Clostridaceae,⁵⁵ Oscillospiraceae,⁶¹ Succinivibrio sp., and Oscillospira sp.⁵⁹ Bifidobacterium spp. were inversely correlated with BMI, whereas B. fragilis and Lactobacillus spp. were positively correlated.⁶⁰ Patients with obesity also had higher serum concentrations of proinflammatory cytokines IL-6 and TNFα⁶² and increased gut permeability than lean subjects.⁵⁵

SCFAs are identified as modulators of asthma-related cytokines (Microbiomes and Asthma Section). Their role in obesity is more complicated due to their contradictory effects: SCFAs provide an extra energy source, and thus, may promote obesity, but simultaneously stimulate appetite and satiety regulating hormones to help prevent obesity. In humans, higher fecal acetate, butyrate,⁵⁶ propionate,⁵⁷ and total SCFAs^56,57 were observed with obesity, and levels of SCFAs are correlated with hypertension, obesity, and gut microbiota dysbiosis.⁶³ Conversely, a study reported reduced fecal propionic and butyric acids concentrations in children with obesity⁵⁹ and in another, inulin-propionate ester supplementation increased satiety hormones peptide YY and glucagon like peptide-1 to achieve reduced weight gain as compared to inulin controls.⁶⁴ In murine studies, supplementation of acetate, propionate, butyrate or their mixture conferred protection against diet-induced obesity,^65,66 insulin resistance,⁶⁶ and reduced increases in triglycerides and IL-6.⁶⁵ Thus, the complex interplay between gut microbiota, SCFA production, obesity and metabolic syndrome merits further research if SCFAs or their microbial producers are to be considered for obesity and/or asthma therapies.

Several human cohort studies identified significant associations between gut microbiota dysbiosis and changes in parameters of metabolic syndrome. Fu et al.⁶⁷ noted, after correcting for age and sex, that gut bacterial richness was negatively correlated with both BMI and serum levels of triglycerides and positively correlated with serum HDL levels. This study estimated that as high as 6% of the variation in blood lipid levels may be attributed to gut microbiota composition, independent of age, sex and genetic factors. Similarly, Le Roy et al.⁶⁸ demonstrated that, in older females, gut biodiversity impacted visceral fat mass accumulation, either independently of, or in synergy with, diet, suggesting that a complex mechanism influenced by gut microbiota composition governs the development of abdominal adiposity. Gut microbiota dysbiosis was further associated with the pathogenesis of hypertension⁶⁹ and insulin resistance.⁷⁰ Palmu et al.,⁶⁹ among others, identified an increased risk of hypertension in individuals with poor gut microbial diversity stemming from changes in dietary intake. Furthermore, Kayser et al.⁷⁰ associated lower microbial gene richness with insulin resistance through ceramide accumulation. Taken together, current literature suggests an association between the parameters of metabolic syndrome and gut microbiome composition; however, further research is needed to better understand gut microbial diversities influence on metabolic syndrome development. While a correlation exists between the gut microbiome, obesity, and parameters of metabolic syndrome, the same cannot be said for the lung microbiome. Aside from sections of studies that explore the airway/lung microbiomes of patients with obesity and asthma (in Bariatric Surgery, Microbiome Alterations, and Asthma Concurrent with Obesity Section), all research studies identified through our literature search focused exclusively on gut microbiome alterations in relation to obesity. A large knowledge gap exists as to whether obesity, unassociated with asthma, alters the airway/lung microbiome, and if the change in microbiota composition leads to increased susceptibility to asthma. Furthermore, there is a dearth of literature correlating metabolic syndrome parameters and alterations in the airway microbiome. Given the associations between metabolic syndrome parameters and asthma (Table 1), this merits further attention to enhance our understanding of the multifaceted modulators of airway microbiome and asthma severity.

Microbiomes and Bariatric Surgery

In addition to reduced caloric intake, a potential explanation for weight reduction following bariatric surgery is through gut microbiota alterations. The two most common bariatric surgery procedures are Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG); both physically restrict stomach size, and RYGB is also malabsorptive.⁷¹ From literature review, taxa that exhibited statistically significant change in two or more human studies as compared to pre-RYGB and/or SG operation conditions are summarized below (Table 2). Both surgery types induce changes in the microbiome, but RYGB induces greater microbiota alterations as compared to laparoscopic adjustable gastric banding⁷² and to SG.⁷³ Gut microbiota alterations were observed as early as 1 month after surgery.⁷⁴ Significant shifts were observed at 3 months^73,75–79 and at 6 months.^77,80 Interestingly, at 3 months, two studies reported an increase in microbiota commonly found in oral cavity explained by an increase of gastrointestinal pH after RYGB.^73,77 This increase was a transient change attenuated by 6 months,⁷⁷ whereas other microbiota changes were sustained through 12 months.^75,76,80 These findings suggest that bariatric surgery induces rapid changes in gut microbiota, some of which are persistent.

Table 2.

Bariatric Surgery-Induced Gut Microbiota Changes in Humans Compared to Preoperative Conditions

	Increase	Decrease
RYGB	Bacteroidetes71 Firmicutes81 Fusobacteria73,75 Proteobacteria73,75,78 Akkermansia79,80 Alistipes82 Bacteroides82 Citrobacter78,80 Fusobacterium73 Granulicatella73,80 Klebsiella79,80 Streptococcus76,79,80,83 Veillonella73,76,78,80 Alistipes shahii75,79 Streptococcus parasanguinis75,79 Streptococcus salivarius75 Streptococcus thermophilus75,79 Veillonella dispar75,78 Veillonella parvula75,78	Bacteroidetes81 Firmicutes78 Bifidobacteriaceae73 Anaerostipes78 Bacteroides79 Bifidobacterium73,82 Blautia76,80,82 Faecalibacterium78,83 Coprococcus comes78 Faecalibacterium prausnitzii75,78 Streptococcus salivarius83
SG	Bacteroidetes81 Fusobacteria74 Akkermansia73,79 Alistipes83 Fusobacterium74 Klebsiella79 Streptococcus79,83 Alistipes shahii79 Faecalibacterium prausnitzii84 Streptococcus parasanguinis79 Streptococcus salivarius83 Streptococcus thermophilus79	Firmicutes74 Bifidobacteriaceae73,74 Anaerostipes73 Bacteroides79 Bifidobacterium73 Coprococcus comes84

Additional studies demonstrate that alterations to gut microbiota remain after 1 year⁸¹ to and even up to a decade⁸⁵ after bariatric surgery. The following studies compared gut microbiota of non-operated controls to patients who had undergone RYGB, and thus are limited by inter-individual differences such as diet, lifestyle, and genetic differences. Fouladi et al.⁸⁶ demonstrated that 2-5 years after RYGB, subjects that received surgery had increased Micrococcales, Lactobacillales, Rothia and Streptococcus. Similarly, Tremaroli et al.⁸⁷ reported increases in Proteobacteria genera Escherichia, Klebsiella, and Pseudomonas that were observed 9 years after surgery. Furthermore, 10.6 years after RYGB, those in the surgery group had more Verrucomicrobiaceae and Streptococcaceae, but less Bacteroidaceae.⁸⁵ Overall, these studies suggest that RYGB may induce a varied and persistent microbiota change.

In order to reduce confounding variables, rodent models were used to study the effects of bariatric surgery. In mice, SG increased relative abundance of Bacteroidetes and reduced Firmicutes, which was observed even after co-housing with sham-operated mice.⁸⁸ Haange et al.⁸⁹ compared post-RYGB rats to sham-operated, body weight matched rats and reported RYGB-induced increases in Proteobacteria and Actinobacteria and a decrease in Firmicutes independent of weight loss. While these increases agree with human studies in Table 2, they also observed an increase of Bifidobacteriaceae,⁸⁹ contradicting human studies.^73,74 Murine models were also used to verify functional changes in gut microbiota. Colonization of mice with feces from post-RYGB human subjects (9.4 years post-surgery) attenuated body fat gain as compared to mice colonized with fecal samples from post-vertical banded gastroplasty subjects or from subjects with obesity.⁸⁷ Furthermore, mice colonized with feces from post-RYGB subjects (2-5 years post-surgery) who successfully lost weight (% excess weight loss (EWL) > 50%) gained less weight compared to mice colonized with feces from post-RYGB subjects that did not lose weight. Since the two human cohorts’ gut microbiota composition did not differ significantly, this difference suggests that long-term gut microbiota functionality changes may also affect weight loss after bariatric surgery.⁸⁶

Some patients who have undergone bariatric surgery also reported improvements in metabolic syndrome parameters including reduced waist circumference,^{62,71,73,76,84} reduced triglycerides,^73,76,84 reduced fasting glucose,^62,75 increased HDL,⁷⁶ and reduced blood pressure.^62,73,84 Interestingly, some of the microbiota changes were also associated with metabolic syndrome parameters. Veillonella increase after RYGB^73,76,78,80 is inversely correlated with waist circumference⁷³ and positively with percent EWL.⁷² Escherichia, Akkermansia, Enterococcus and Carnobacterium were also positively correlated with percent EWL, whereas Bifidobacterium and Sutterella were negatively correlated.⁷² Following SG, reduction in waist circumference correlated negatively with Proteobacteria.⁷¹ Verrucomicrobia, particularly Akkermansia, tended to correlate positively with HDL cholesterol.⁷³ Nonetheless, whether the microbiota changes are directly responsible for metabolic syndrome improvements remain unclear. This highlights a need for studies that elucidate mechanistic pathways through which gut microbiota may modulate metabolic syndrome.

Finally, whether bariatric surgery-induced microbiota changes differed from diet-induced changes were explored. Unlike bariatric surgery, medical weight loss (diet and physical activity) did not induce major changes in microbiota.^71,90 Increased prevalence of Roseburia⁹⁰ and Akkermansia were reported in association with medical weight loss.⁹¹ While transient changes were observed at 3 months after medical weight loss, the gut microbiota composition had a tendency to return to baseline composition after 1 year (except for an increase in Akkermansia), which differs from long-term changes observed with bariatric surgery.⁹¹ One study reported more significant diet-induced changes including increased F/B ratio.⁸⁴ Another explored the effect of crash diet prior to RYGB or SG, which resulted in reduced Shannon diversity [a measure of species diversity in a community that takes into account both the abundance and evenness of a particular species in the overall community⁹²], Streptococcaceae and Ruminococcaceae relative abundance, and increased Rikenellaceae prevalence. Following bariatric surgery, Shannon diversity was restored to baseline levels.⁹³ Since a restrictive diet is often recommended before bariatric surgery, this observation raises the question of whether the comparison to a baseline after a restrictive diet in studies analyzing postoperative microbiota changes is appropriate.

Evidence currently suggests that bariatric surgery induces human gut microbiota alterations which may last for years after surgery. However, because studies discerning long-term effects of bariatric surgery compared microbiota to non-operated controls,^85,87 similar studies that compare the same cohort to pre-bariatric surgery baselines are recommended to reduce inter-individual differences. Human studies are also limited by low sample size, some with less than 10 patients who underwent bariatric surgery.^{74,78,80,84,90} There is a clear need for more studies that consider the effect of a restrictive diet before surgery if one was employed. Finally, despite growing evidence that bariatric surgery could be beneficial for patients with asthma,^7,9,94,95 to the best of our knowledge no study has explored whether the airway/lung microbiome changes after bariatric surgery.

Bariatric Surgery, Microbiome Alterations, and Asthma Concurrent with Obesity

Bariatric surgery is associated with improvements in asthma control^7,95,96 and in AHR,⁷ though this protective effect was not observed in patients with metabolic syndrome.⁹⁶ Provided the relationships between the airway and gut microbiomes with obesity, asthma and bariatric surgery as presented in Figure 2, we questioned if the microbiomes contribute to bariatric surgery-associated protection against asthma. However, only a few studies could be identified that analyze microbiomes of patients with obesity and asthma, rendering a comparison between pre- and post-surgery microbiomes difficult.

Figure 2:

Microbiome dysbiosis in patients with obesity or asthma compared to healthy counterparts and postsurgical changes following bariatric surgery. Microbial taxa were chosen because they were amongst the most reported changes in literature. Full taxa changes are available in the Microbiomes and Asthma Section for asthma and in Table 2 for bariatric surgery. Short chain fatty acids (SCFAs) and inflammatory mediators such as interleukins (IL), regulatory T cells (T_regs) and tumor necrosis factor alpha (TNFα) are key signaling features of the gut/lung axis, and knowledge gaps are marked with a question mark.

Huang et al.⁴¹ reported that patients with obesity and severe asthma had increased prevalence of taxa belonging to Prevotellaceae, Mycoplasmataceae, Lachnospiraceae (Clostridium), and Spirochaetaceae (Treponema). Furthermore, a quantitative polymerase chain reaction analysis positively correlated Prevotella spp. with increased BMI. Similarly, taxa in Bacteroidetes and Firmicutes could be significantly correlated with BMI.⁴¹ Michalovich et al.⁹⁷ compared gut and airway microbiomes between patients with obesity, patients with both obesity and asthma, patients with asthma and healthy controls. In the lower respiratory tract, decreases of Enterococcaceae, Aeromonadaceae, Paraprevotella, Phascolarctobacterium, and Megasphaera were reported that were unique to patients with obesity and asthma, and a decrease of Parabacteroides and Coriobacteriaceae in both patients with obesity and all patients with asthma compared to healthy counterparts. Unfortunately, to the best of our knowledge, no study has reported lung or airway microbiome changes after bariatric surgery; thus, future research is needed to elucidate whether relative abundances of taxa associated with patients with obesity and asthma are altered following surgery.

In a murine model, administration of antibiotics to db/db mice with genetic obesity reduced ozone-induced AHR. Furthermore, fecal transplantation from db/db mice to lean germ-free mice resulted in ozone-induced AHR. Since ozone is a common non-atopic asthma trigger, this suggests that the gut microbiota associated with obesity may contribute to augmented AHR in nonatopic asthma.⁹⁸ In gut microbiota of patients with obesity and asthma, Michalovich et al.⁹⁷ reported an increased prevalence of Tissierellaceae (genus 1-68) and decreased Serratia compared to healthy counterparts; further, a reduction in Clostridiales was observed as with other patients with obesity. However, over 70% of the patients with asthma (with and without obesity) in this study had allergy. Thus, analyses of gut microbiome in patients with asthma and obesity that are stratified by atopic status or Th2 inflammatory gene signatures may reveal important differences in the influence of gut microbiome on clinical outcomes in specific asthma phenotypes.

Current data on bacterial gut microbiota changes following bariatric surgery and their relationships to asthma are insufficient, although one species shows promise. In a single study, fecal A. muciniphila levels were negatively correlated with asthma severity independent of BMI, and both acute and chronic murine models suggested that A. muciniphila conferred protection against airway hyperreactivity and inflammation.⁹⁷ A. muciniphila’s role in airway health merits attention as this species was reported to increase after RYGB and SG.^75,77,79 Lower abundances of Alistipes,³⁴ Veillonella, and Faecalibacterium³¹ were associated with increased risk of asthma in infants. Of these, Alistipes^82,83 and Veillonella^73,76,78,80 were reported to increase following bariatric surgery; in comparison, decreases in Faecalibacterium were reported.^78,83 Given the physiological differences between an infant and an adult, and the conflicting evidence that Veillonella is positively correlated with increased risk of asthma,³⁴ whether any gut microbiota changes following bariatric surgery is associated with altered airway pathobiology and improved clinical outcomes in asthma remains a knowledge gap aside from possible beneficial effects of increased presence of A. muciniphila.

A possible link between gut microbiota alterations and improved asthma symptoms includes increased production of SCFAs, particularly butyrate and propionate. Following RYGB, increases of propionate/acetate and butyrate/acetate ratios were reported in humans,^72,80 though another study reported a postsurgical tendency of SCFAs to decrease after RYGB.⁸⁷ While SCFAs have a conflicting role in obesity, butyrate^50,52 and propionate^49,50,52,54 were associated with reduced proinflammatory cytokines and/or increased immunosuppressive cytokines which could in turn modulate the pathobiology of asthma concurrent with obesity. Thus, the role of increased propionate and butyrate levels and their impact on asthma-related cytokines is another knowledge gap. This is particularly important because postsurgical improvements in AHR paradoxically coincided with increases of proinflammatory TNFα and IL-6 cytokines, among others, both in humans⁷ and in mice.⁹⁹ Hence, another question remains about which beneficial effects, if any, of SCFA-related cytokines could mitigate harmful effects of increased proinflammatory cytokines.

To advance the field, the baseline lung and gut microbiota composition of individuals with asthma and obesity before surgery needs to be established, and secondly, how microbiome changes affect postsurgical improvements in asthma symptoms should be evaluated. In particular, we have identified that studying the relationship between improvements in asthma symptoms based on asthma phenotypes and microbiota changes may aid in developing personalized pre- or probiotic treatment. In addition, there is a dearth of information on whether weight-independent metabolic changes following bariatric surgery result in remediation of asthma symptoms. At present, some postsurgical changes in the gut microbiome are correlated with parameters of metabolic syndrome. Furthermore, reduced asthma medication usage⁹⁵ and gut microbiome alterations were reported as early as 30 days post-surgery,⁷⁴ which is likely too soon for weight loss to have a large impact. Thus, a central question is whether this improvement in asthma control is due to metabolic changes and whether these changes are caused by microbiome alterations. Given the association between metabolic syndrome parameters and asthma (Table 1), if changes in gut microbiome can be strongly associated with improvement of asthma outcomes through metabolic syndrome remission, new microbiome-based therapeutics may be devised for patients with obesity and asthma.

Conclusion

Microbiome dysbiosis is a contributing factor in metabolic syndrome, obesity and asthma. Herein, we considered the role of bariatric surgery and subsequent microbiota changes for patients with obesity and asthma. We did not review the impact of viruses, archaea, and fungi on asthma. We also did not examine antibiotic treatment for asthma, though azithromycin appears to reduce severe asthma exacerbations while improving quality of life for patients with persistent symptomatic asthma.¹⁰⁰ All these factors will affect post-surgical outcomes and should ultimately be considered.

Bariatric surgery results in long-term bacterial gut microbiota changes that may influence airway inflammation, AHR and lung function through improvements in metabolic syndrome parameters and SCFA production. By studying changes in the lung/airway microbiomes following bariatric surgery, researchers can further untangle the complex interplay between obesity, asthma, and the microbiome. Advancing research will help determine whether bariatric surgery converts the airway and/or gut microbiome of patients with asthma to the same state as lean patients with asthma or as lean subjects without asthma, and elucidate how the altered microbiomes affect asthma pathobiology in patients with obesity. By filling the knowledge gaps highlighted in this review, we are hopeful that new therapeutic options will become available to patients with obesity and asthma.

Study Importance Questions.

What is already known about this subject?

• Parameters of metabolic syndrome and increasing body mass index (BMI) are significantly associated with asthma.

• The gut microbiome not only influences obesity and metabolic syndrome but also affects airway inflammation via short chain fatty acid production and modulation of cytokine levels.

• Significant improvements in asthma control and airway hyperresponsiveness are reported following bariatric surgery.

What are the new findings in your manuscript?

• Bariatric surgery induces rapid yet persistent changes in gut microbiota composition that may influence asthma pathobiology through increased prevalence of Akkermansia muciniphila and altered short chain fatty acid production.

• Major knowledge gaps include lung microbiome composition of adult patients with asthma before and after bariatric surgery and the impact of weight-independent metabolic changes following bariatric surgery on asthma pathobiology.

How might your results change the direction of research or the focus of clinical practice?

• For patients with obesity and asthma, bariatric surgery could become a promising treatment for symptoms of asthma and underlying airway inflammation.

• Fulfilling knowledge gaps outlined in this review can help develop new therapeutic options for patients with asthma and obesity by targeting the gut and/or the lung microbiome.

Abbreviations

AHR

Airway hyperresponsiveness

BMI

Body mass index

IgE

Immunoglobulin E

FEV₁

Forced expiratory volume in 1 second

FVC

Forced vital capacity

NCEP

National Cholesterol Education Program

ATP III

Adults Treatment Panel III

HDL

High density lipoprotein

SCFA

Short-chain fatty acids

FLVR

Faecalibacterium, Lachnospira, Rothia, and Veillonella

IL

Interleukin

TNFα

Tumor necrosis factor alpha

Th

T-helper cell

OTU

Operational taxonomic unit

GPR

G-protein coupled receptor

IFN-γ

Interferon gamma

T_reg

regulatory T cell

F/B ratio

Firmicutes/Bacteroidetes ratio

RYGB

Roux-en-Y gastric bypass

SG

Sleeve gastrectomy

EWL

Excess weight loss