Navigating inflammatory response and microbiome signatures: three case studies

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2026-09-08

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2024

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Abstract

The immune system constantly distinguishes the variegated microbiota harbored by the host as either commensals or pathogens. Inflammation is the body’s natural response to pathogens and injury to restore homeostasis. Yet today, diseases associated with chronic systematic inflammation that occurs in the absence of an infection are responsible for the majority of global deaths. Simultaneously, advanced sequencing technologies have underscored the systematic effects that the gut microbiome and its metabolites have on various organs and inflammatory diseases. Of particular interest are short chain fatty acids (SCFAs), which are bacterial metabolites with potent immunomodulatory properties. SCFAs can have systematic effects throughout the body by modulating the immune system and circulating to other organs. For instance, the interaction between the gut and lung microbiomes, and their metabolites such as SCFAs, is termed the gut-lung microbiome axis. Despite the booming interest in the microbiome field, the ability for precision microbiome engineering to improve human health is limited in part due to the complexity of interconnected systems. Many environmental factors and lifestyle choices influence both the microbiome and inflammation, and the bidirectional interactions between the microbes and the immune system are still being uncovered.In this dissertation, the overarching hypothesis that there exist microbial taxa whose prevalence is correlated with inflammatory markers was tested in three specific case studies: 1) obese asthma, 2) occupational exposure to hog farm dust, and 3) hematopoietic stem cell transplant (HSCT). Obesity and asthma are both inflammatory diseases that often co-occur: almost 40% of people with asthma also have concurrent obesity in the United States (US). However, the additive effects of obesity and asthma on the gut and lung microbiomes are understudied. Interestingly, individuals that received bariatric surgery report reduced asthma symptoms and for some, complete cessation of asthma medication. Bariatric surgery also alters the gut microbiome community and restores circulating levels of glucagon-like peptide-1 (GLP-1), a satiety and insulin-inducing hormone. Recent studies also suggest that GLP-1 is a gut microbiome regulator and may confer protection against lung inflammation. Thus, the microbiome of human bronchoalveolar lavage fluid (BALF) from individuals with different obesity, asthma, and bariatric surgery status was characterized. Furthermore, a murine loss-of-function and intervention model was utilized to untangle the role of GLP-1 receptor signaling in modulating the gut and lung microbiomes and host respiratory and inflammatory health following bariatric surgery. Results indicated that the percentage of eosinophils in BALF was negatively correlated with body mass index and positively correlated with the prevalence of Capnocytophaga and Flavobacteriaceae in human BALF, suggesting that these taxa may be of interest in type 2-high asthma. While GLP-1 receptor signaling deficiency did not lead to significantly altered host respiratory or inflammatory metrics herein, mice fed high fat diet had lower fecal prevalence of SCFA-associated taxa Bifidobacterium, Lachnospiraceae UCG-001, and Parasutterella. The prevalence of each taxon was positively correlated with serum GLP-1 levels and negatively with serum leptin levels, body weight, and glucose intolerance. The second case study focuses on dust inside hog concentrated animal feeding operations (CAFOs), as workers are exposed to this dust that induces respiratory inflammation in vitro and in vivo. North Carolina raises 10 million hogs annually, mostly in CAFOs, leading to an extremely high concentration of CAFOs in southeastern North Carolina counties. Despite studies from other continents discovering over 150 antibiotic resistant genes in hog farm dust, its equivalent in the United States remains mostly uncharacterized. Furthermore, studies that analyze the inflammatory and microbiome effects of hog farm dust exposure in tandem are scarce. As such, shotgun metagenomic sequencing was applied to two hog CAFO dust samples from North Carolina to characterize its microbiome and resistome. In addition, C57BL/6 mice were exposed to hog dust extract or saline via intranasal instillation for three weeks. Contrary to previous studies, exposure to hog dust extract did not lead to significant changes in host respiratory, inflammatory, and gut microbiome changes herein, and minimal effects on lung microbiome composition were reported. Potential confounding variables included cage effects and the dust originating from a relatively small farm. Although shotgun sequencing analyses were hindered by low sequencing depth, even at a shallow sequencing depth 23 antibiotic resistance genes and a total of 686 species were identified between the two dust samples. Lastly, the fecal microbiome of patients undergoing HSCT were analyzed in two intervention studies: pre-transplant high intensity interval training (HIIT) and home-based treatment after transplant. Since hematopoietic stem cells are the progenitors of all blood cells, HSCT is the only curative treatment for many hematologic malignancies. Unfortunately, 40-60% of HSCT recipients experience graft-versus-host-disease (GvHD), a potentially life-threatening inflammatory response wherein the engrafted donor immune system recognizes normal host cells as foreign and attacks them. Mounting research identifies the gut microbiome as a modulator of GvHD, however, its role has not been investigated in these two interventions with successful pilot trials. Pre-transplant HIIT intervention aims to improve cardiovascular health as poor cardiovascular fitness is associated with worsened treatment outcomes. On the other hand, receiving post-transplant care at home results in comparable treatment outcomes (as hospital care) while increasing patient comfort and reducing financial burden. For both interventions, fecal microbiome was compared between individuals receiving the intervention and their respective controls matched for age, sex, disease, and conditioning regimen. In line with previous studies, a markedly lower fecal microbiome diversity evidenced by the domination of a single phylum was observed in people undergoing HSCT. Across all patients, patients that developed chronic GvHD had lower fecal prevalence of Streptococcus and Anaerostipes hadrus compared to those that did not. Furthermore, individuals that underwent HIIT intervention had higher fecal alpha diversity metrics and lower prevalence of Roseburia inulinivorans and Enterococcus faecium as compared to matched controls. While no fecal taxa were identified as being differentially abundant based on post-transplant care environment, the potential role of microbiome of the built environment on patient microbiome and health merits further attention. As taxa of interest reported here, namely A. hardus and R. inulinivorans, are both SCFA producers, future studies should further investigate the gut-SCFA axis in people with hematologic malignancies. Altogether, this dissertation emphasizes the importance of SCFA-producing taxa across a wide range of inflammatory states and identifies taxa of interest to be validated in larger cohorts for future mechanistic studies. The interdisciplinary studies herein provide methods and a framework for analyzing the gut microbiome, the low biomass murine lung tissue microbiome, and host health metrics in tandem with practical suggestions for future studies. Continuing to fill the research gaps regarding the complex interplay between environmental exposure, microbiomes, and inflammation will lead to precision microbiome engineering strategies. These strategies may be of broad interest due to their ability to be applied to different inflammatory conditions that are often studied separately.

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Kim, Yeon Ji (2024). Navigating inflammatory response and microbiome signatures: three case studies. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/31951.

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