Vaccine Hyporesponse Induced by Individual Antibiotic Treatment in Mice and Non-Human Primates Is Diminished upon Recovery of the Gut Microbiome

Emerging evidence demonstrates a connection between microbiome composition and suboptimal response to vaccines (vaccine hyporesponse). Harnessing the interaction between microbes and the immune system could provide novel therapeutic strategies for improving vaccine response. Currently we do not fully understand the mechanisms and dynamics by which the microbiome influences vaccine response. Using both mouse and non-human primate models, we report that short-term oral treatment with a single antibiotic (vancomycin) results in the disruption of the gut microbiome and this correlates with a decrease in systemic levels of antigen-specific IgG upon subsequent parenteral vaccination. We further show that recovery of microbial diversity before vaccination prevents antibiotic-induced vaccine hyporesponse, and that the antigen specific IgG response correlates with the recovery of microbiome diversity. RNA sequencing analysis of small intestine, spleen, whole blood, and secondary lymphoid organs from antibiotic treated mice revealed a dramatic impact on the immune system, and a muted inflammatory signature is correlated with loss of bacteria from Lachnospiraceae, Ruminococcaceae, and Clostridiaceae. These results suggest that microbially modulated immune pathways may be leveraged to promote vaccine response and will inform future vaccine design and development strategies.

Download Full-text

Vaccine Hyporesponse Induced By Individual Antibiotic Treatment In Mice And Non-Human Primates Is Diminished Upon Recovery Of The Gut Microbiome

10.1101/2021.04.02.438241 ◽

2021 ◽

Author(s):

Gokul Swaminathan ◽

Michael Citron ◽

Jianying Xiao ◽

James E Norton ◽

Abigail L Reens ◽

...

Keyword(s):

Immune System ◽

Gut Microbiome ◽

Oral Treatment ◽

Sequencing Analysis ◽

Vaccine Response ◽

Microbiome Composition ◽

Microbiome Diversity ◽

Specific Igg ◽

Novel Therapeutic Strategies ◽

Secondary Lymphoid Organs

Emerging evidence demonstrates a connection between microbiome composition and suboptimal response to vaccines (vaccine hyporesponse). Harnessing the interaction between microbes and the immune system could provide novel therapeutic strategies for improving vaccine response. Currently we do not fully understand the mechanisms and dynamics by which the microbiome influences vaccine response. Using both mouse and non-human primate models, we report that short-term oral treatment with a single antibiotic (vancomycin) results in disruption of the gut microbiome and this correlates with a decrease in systemic levels of antigen-specific IgG upon subsequent parenteral vaccination. We further show that recovery of microbial diversity before vaccination prevents antibiotic-induced vaccine hyporesponse, and that the antigen specific IgG response correlates with the recovery of microbiome diversity. RNA-sequencing analysis of small intestine, spleen, whole blood, and secondary lymphoid organs from antibiotic treated mice revealed a dramatic impact on the immune system, and a muted inflammatory signature is correlated with loss of bacteria from Lachnospiraceae, Ruminococcaceae, and Clostridiaceae. These results suggest that microbially modulated immune pathways may be leveraged to promote vaccine response and will inform future vaccine design and development strategies.

Download Full-text

Quantifying the impact of Human Leukocyte Antigen on the human gut microbiome

10.1101/2020.01.14.907196 ◽

2020 ◽

Cited By ~ 2

Author(s):

Stijn P. Andeweg ◽

Can Keşmir ◽

Bas E. Dutilh

Keyword(s):

Immune System ◽

Gut Microbiome ◽

Human Leukocyte ◽

Human Gut ◽

Microbiome Composition ◽

Leukocyte Antigen ◽

Human Gut Microbiome ◽

Microbiome Diversity ◽

Human Immune ◽

Hla Molecules

AbstractObjectiveThe gut microbiome is affected by a number of factors, including the innate and adaptive immune system. The major histocompatibility complex (MHC), or the human leukocyte antigen (HLA) in humans, performs an essential role in vertebrate immunity, and is very polymorphic in different populations. HLA determines the specificity of T lymphocyte and natural killer (NK) cell responses, including against the commensal bacteria present in the human gut. Thus, it is likely that our HLA molecules and thereby the adaptive immune response, can shape the composition of our microbiome. Here, we investigated the effect of HLA haplotype on the microbiome composition.ResultsWe performed HLA typing and microbiota composition analyses on 3,002 public human gut microbiome datasets. We found that (i) individuals with functionally similar HLA molecules (i.e. presenting similar peptides) are also similar in their microbiota, and (ii) HLA homozygosity correlated with microbiome diversity, suggesting that diverse immune responses limit microbiome diversity.ConclusionOur results show a statistical association between host HLA haplotype and gut microbiome composition. Because the HLA haplotype is a readily measurable parameter of the human immune system, these results open the door to incorporating the immune system into predictive microbiome models.IMPORTANCEThe microorganisms that live in the digestive tracts of humans, known as the gut microbiome, are essential for hosts survival as they support crucial functions. For example, they support the host in facilitating the uptake of nutrients and give colonization resistance against pathogens. The composition of the gut microbiome varies among humans. Studies have proposed multiple factors driving the observed variation, including; diet, lifestyle, and health condition. Another major influence on the microbiome is the host’s genetic background. We hypothesized the immune system to be one of the most important genetic factors driving the differences observed between gut microbiomes. Therefore, we are interested in linking the polymorphic molecules that play a role in human immune responses to the composition of the microbiome. HLA molecules are the most polymorphic molecules in our genome and therefore makes an excellent candidate to test such an association/link. To our knowledge for the first time, our results indicate a significant impact of the HLA on the human gut microbiome composition.

Download Full-text

0135 Self-Reported Sleep and Gut Microbiome Composition and Diversity: Associations in Well-Functioning Older Adults

SLEEP ◽

10.1093/sleep/zsaa056.133 ◽

2020 ◽

Vol 43 (Supplement_1) ◽

pp. A53-A53

Author(s):

C Holingue ◽

N T Mueller ◽

T Tanaka ◽

M K Differding ◽

C W Chia ◽

...

Keyword(s):

Older Adults ◽

Sleep Duration ◽

Relative Abundance ◽

Gut Microbiome ◽

Rating Scale ◽

Self Report ◽

Microbiome Composition ◽

Microbiome Diversity ◽

Falling Asleep ◽

Insomnia Symptoms

Abstract Introduction The gut microbiome is believed to play an important role in health and disease, yet little is known about the link between sleep and the gut microbiome in humans. We investigated the association of self-reported sleep with gut microbiome composition and diversity in a cohort of well-functioning older adults. Methods We studied 791 participants (mean age = 71.5±12.0 years, 55% women) in the Baltimore Longitudinal Study of Aging with self-report sleep measures and whole-genome DNA sequencing of stool samples. Predictors (modeled as continuous variables) included insomnia symptoms from the Women’s Health Initiative Insomnia Rating Scale (WHIIRS), sleep duration (<5, 5–6, 6–7, >7 hours), and frequency of excessive daytime sleepiness (EDS). We tested their association with gut microbiome diversity (Shannon index) and relative abundance of individual taxa using Kendall Tau Correlation. Next, we assessed whether these sleep variables were associated with overall microbiome structure (Bray-Curtis), adjusting for age, sex, race, education, BMI, depressive symptoms, and number of comorbidities. Results Sleep duration was associated with overall microbiome composition (p<0.01), with longer sleep duration associated with lower biodiversity of microbes in the gut (p<0.05). In phylum-level analyses, higher WHIIRS total (i.e., more severe insomnia) was associated with lower relative abundance of Actinobacteria, while more frequent EDS was associated with lower relative abundance of Fusobacteria. More frequent trouble falling asleep, staying asleep, early waking, poorer sleep quality and higher WHIIRS total were associated with lower abundance of Synergistetes (all p<0.05). Conclusion In well-functioning older adults, self-reported sleep duration, symptoms of insomnia, and EDS were associated with microbiome diversity and composition. The phylum Synergistetes, which has been associated with protective humoral immune response in prior literature, may be an important correlate of insomnia symptoms in older adults. Future investigations are needed to examine the gut microbiome as a driver or mediator of sleep-health associations. Support This study was supported in part by National Institute on Aging (NIA) grant R01AG050507, the NIA Intramural Research Program (IRP), and Research and Development Contract HHSN-260-2004-00012C.

Download Full-text

Lessons on dietary biomarkers from twin studies

Proceedings of The Nutrition Society ◽

10.1017/s0029665116002810 ◽

2017 ◽

Vol 76 (3) ◽

pp. 303-307 ◽

Cited By ~ 1

Author(s):

Cristina Menni

Keyword(s):

Gut Microbiome ◽

Twin Studies ◽

Dietary Interventions ◽

Twin Design ◽

Dietary Biomarkers ◽

Microbiome Composition ◽

Twin Model ◽

Nutrition Research ◽

Gene Environment ◽

Microbiome Diversity

Metabolomic and microbiome profiling are promising tools to identify biomarkers of food intake and health status. The individual's genetic makeup plays a significant role on health, metabolism, gut microbes and diet and twin studies provide unique opportunities to untangle gene–environment effects on complex phenotypes. This brief review discusses the value of twin studies in nutrition research with a particular focus on metabolomics and the gut microbiome. Although, the twin model is a powerful tool to segregate the genetic component, to date, very few studies combine the twin design and metabolomics/microbiome in nutritional sciences. Moreover, since the individual's diet has a strong influence on the microbiome composition and the gut microbiome is modifiable (60 % of microbiome diversity is due to the environment), future studies should target the microbiome via dietary interventions.

Download Full-text

Aging and serum MCP-1 are associated with gut microbiome composition in a murine model

10.7287/peerj.preprints.1754v1 ◽

2016 ◽

Author(s):

Melissa N. Conley ◽

Carmen P. Wong ◽

Kyle M. Duyck ◽

Norman Hord ◽

Emily Ho ◽

...

Keyword(s):

Immune System ◽

Murine Model ◽

Gut Microbiome ◽

Inflammatory Marker ◽

Low Grade ◽

Host Immune System ◽

Cancer Type ◽

Microbiome Composition ◽

Aged Mice ◽

Age Related

Introduction Age is the primary risk factor for major human chronic diseases, including cardiovascular disorders, cancer, type 2 diabetes, and neurodegenerative diseases. Chronic, low-grade, systemic inflammation is associated with aging and the progression of immunosenescence. Immunosenescence may play an important role in the development of age-related chronic disease and the widely observed phenomenon of increased production of inflammatory mediators that accompany this process, referred to as “inflammaging”. While it has been demonstrated that the gut microbiome and immune system interact, the relationship between the gut microbiome and age remains to be clearly defined, particularly in the context of inflammation. The aim of the study was to clarify the associations between age, the gut microbiome, and pro-inflammatory marker serum MCP-1 in a C57BL/6 murine model. Results We used 16S rRNA gene sequencing to profile the composition of fecal microbiota associated with young and aged mice. Our analysis identified an association between microbiome structure and mouse age, and revealed specific groups of taxa whose abundances stratify young and aged mice. This includes the Ruminococcaceae, Clostridiaceae, and Enterobacteriaceae. We also profiled pro-inflammatory serum MCP-1 levels of each mouse and found that aged mice exhibited elevated serum MCP-1, a phenotype consistent with inflammaging. Robust correlation tests identified several taxa whose abundance in the microbiome associates with serum MCP-1 status, indicating that they may interact with the mouse immune system. We find that taxonomically similar organisms can exhibit differing, even opposite, patterns of association with the host immune system. We also find that many of the OTUs that associate with serum MCP-1 also stratify individuals by age. Discussion Our results demonstrate that gut microbiome composition is associated with age and the pro-inflammatory marker, serum MCP-1. The correlation between age, relative abundance of specific taxa in the gut microbiome, and serum MCP-1 status in mice indicates that the gut microbiome may play a modulating role in age-related inflammatory processes. These findings warrant further investigation of taxa associated with the inflammaging phenotype and the role of gut microbiome in the health status and immune function of aged individuals.

Download Full-text

Exploring the Triple Interaction between the Host Genome, the Epigenome, and the Gut Microbiome in Type 1 Diabetes

International Journal of Molecular Sciences ◽

10.3390/ijms22010125 ◽

2020 ◽

Vol 22 (1) ◽

pp. 125

Author(s):

Duaa Ahmed Elhag ◽

Manoj Kumar ◽

Souhaila Al Khodor

Keyword(s):

Type 1 Diabetes ◽

Immune System ◽

Environmental Factors ◽

Gut Microbiome ◽

Association Studies ◽

Host Immune System ◽

Genome Wide Association Studies ◽

Immune Disorder ◽

Microbiome Composition

Type 1 diabetes (T1D) is an auto-immune disorder characterized by a complex interaction between the host immune system and various environmental factors in genetically susceptible individuals. Genome-wide association studies (GWAS) identified different T1D risk and protection alleles, however, little is known about the environmental factors that can be linked to these alleles. Recent evidence indicated that, among those environmental factors, dysbiosis (imbalance) in the gut microbiota may play a role in the pathogenesis of T1D, affecting the integrity of the gut and leading to systemic inflammation and auto-destruction of the pancreatic β cells. Several studies have identified changes in the gut microbiome composition in humans and animal models comparing T1D subjects with controls. Those changes were characterized by a higher abundance of Bacteroides and a lower abundance of the butyrate-producing bacteria such as Clostridium clusters IV and XIVa. The mechanisms by which the dysbiotic bacteria and/or their metabolites interact with the genome and/or the epigenome of the host leading to destructive autoimmunity is still not clear. As T1D is a multifactorial disease, understanding the interaction between different environmental factors such as the gut microbiome, the genetic and the epigenetic determinants that are linked with the early appearance of autoantibodies can expand our knowledge about the disease pathogenesis. This review aims to provide insights into the interaction between the gut microbiome, susceptibility genes, epigenetic factors, and the immune system in the pathogenesis of T1D.

Download Full-text

Differences in Gut Microbiome Composition Between Sympatric Wild and Allopatric Laboratory Populations of Omnivorous Cockroaches

Frontiers in Microbiology ◽

10.3389/fmicb.2021.703785 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kara A. Tinker ◽

Elizabeth A. Ottesen

Keyword(s):

Microbial Community ◽

Gut Microbiome ◽

Periplaneta Americana ◽

Laboratory Environment ◽

Microbiome Composition ◽

Relative Contribution ◽

Microbiome Diversity ◽

Before And After ◽

Laboratory Populations ◽

Gut Microbial Community

Gut microbiome composition is determined by a complex interplay of host genetics, founder’s effects, and host environment. We are using omnivorous cockroaches as a model to disentangle the relative contribution of these factors. Cockroaches are a useful model for host–gut microbiome interactions due to their rich hindgut microbial community, omnivorous diet, and gregarious lifestyle. In this study, we used 16S rRNA sequencing to compare the gut microbial community of allopatric laboratory populations of Periplaneta americana as well as sympatric, wild-caught populations of P. americana and Periplaneta fuliginosa, before and after a 14 day period of acclimatization to a common laboratory environment. Our results showed that the gut microbiome of cockroaches differed by both species and rearing environment. The gut microbiome from the sympatric population of wild-captured cockroaches showed strong separation based on host species. Laboratory-reared and wild-captured cockroaches from the same species also exhibited distinct gut microbiome profiles. Each group of cockroaches had a unique signature of differentially abundant uncharacterized taxa still present after laboratory cultivation. Transition to the laboratory environment resulted in decreased microbiome diversity for both species of wild-caught insects. Interestingly, although laboratory cultivation resulted in similar losses of microbial diversity for both species, it did not cause the gut microbiome of those species to become substantially more similar. These results demonstrate how competing factors impact the gut microbiome and highlight the need for a greater understanding of host–microbiome interactions.

Download Full-text

A Comprehensive Assessment of Demographic, Environmental and Host Genetic Associations with Gut Microbiome Diversity in Healthy Individuals

10.1101/557124 ◽

2019 ◽

Author(s):

Petar Scepanovic ◽

Flavia Hodel ◽

Stanislas Mondot ◽

Valentin Partula ◽

Allyson Byrd ◽

...

Keyword(s):

Environmental Factors ◽

Gut Microbiome ◽

Genetic Factors ◽

European Ancestry ◽

Healthy Individuals ◽

Fecal Microbiome ◽

Microbiome Composition ◽

Microbiome Diversity ◽

Α Diversity ◽

Host Genetic

ABSTRACTBackgroundThe gut microbiome is an important determinant of human health. Its composition has been shown to be influenced by multiple environmental factors and likely by host genetic variation. In the framework of the Milieu Intérieur Consortium, a total of 1,000 healthy individuals of western European ancestry, with a 1:1 sex ratio and evenly stratified across five decades of life (age 20 – 69), were recruited. We generated 16S ribosomal RNA profiles from stool samples for 858 participants. We investigated genetic and non-genetic factors that contribute to individual differences in fecal microbiome composition.ResultsAmong 110 demographic, clinical and environmental factors, 11 were identified as significantly correlated with α-diversity, ß-diversity or abundance of specific microbial communities in multivariable models. Age and blood alanine aminotransferase levels showed the strongest associations with microbiome diversity. In total, all non-genetic factors explained 16.4% of the variance. We then searched for associations between >5 million single nucleotide polymorphisms and the same indicators of fecal microbiome diversity, including the significant non-genetic factors as covariates. No genome-wide significant associations were identified after correction for multiple testing. A small fraction of previously reported associations between human genetic variants and specific taxa could be replicated in our cohort, while no replication was observed for any of the diversity metrics.ConclusionIn a well-characterized cohort of healthy individuals, we identified several non-genetic variables associated with fecal microbiome diversity. In contrast, host genetics only had a negligible influence. Demographic and environmental factors are thus the main contributors to fecal microbiome composition in healthy individuals.

Download Full-text

Aging and serum MCP-1 are associated with gut microbiome composition in a murine model

PeerJ ◽

10.7717/peerj.1854 ◽

2016 ◽

Vol 4 ◽

pp. e1854 ◽

Cited By ~ 47

Author(s):

Melissa N. Conley ◽

Carmen P. Wong ◽

Kyle M. Duyck ◽

Norman Hord ◽

Emily Ho ◽

...

Keyword(s):

Immune System ◽

Murine Model ◽

Gut Microbiome ◽

Inflammatory Marker ◽

Low Grade ◽

Host Immune System ◽

Cancer Type ◽

Microbiome Composition ◽

Aged Mice ◽

Age Related

Introduction.Age is the primary risk factor for major human chronic diseases, including cardiovascular disorders, cancer, type 2 diabetes, and neurodegenerative diseases. Chronic, low-grade, systemic inflammation is associated with aging and the progression of immunosenescence. Immunosenescence may play an important role in the development of age-related chronic disease and the widely observed phenomenon of increased production of inflammatory mediators that accompany this process, referred to as “inflammaging.” While it has been demonstrated that the gut microbiome and immune system interact, the relationship between the gut microbiome and age remains to be clearly defined, particularly in the context of inflammation. The aim of our study was to clarify the associations between age, the gut microbiome, and pro-inflammatory marker serum MCP-1 in a C57BL/6 murine model.Results.We used 16S rRNA gene sequencing to profile the composition of fecal microbiota associated with young and aged mice. Our analysis identified an association between microbiome structure and mouse age and revealed specific groups of taxa whose abundances stratify young and aged mice. This includes the Ruminococcaceae, Clostridiaceae, and Enterobacteriaceae. We also profiled pro-inflammatory serum MCP-1 levels of each mouse and found that aged mice exhibited elevated serum MCP-1, a phenotype consistent with inflammaging. Robust correlation tests identified several taxa whose abundance in the microbiome associates with serum MCP-1 status, indicating that they may interact with the mouse immune system. We find that taxonomically similar organisms can exhibit differing, even opposite, patterns of association with the host immune system. We also find that many of the OTUs that associate with serum MCP-1 stratify individuals by age.Discussion.Our results demonstrate that gut microbiome composition is associated with age and the pro-inflammatory marker, serum MCP-1. The correlation between age, relative abundance of specific taxa in the gut microbiome, and serum MCP-1 status in mice indicates that the gut microbiome may play a modulating role in age-related inflammatory processes. These findings warrant further investigation of taxa associated with the inflammaging phenotype and the role of gut microbiome in the health status and immune function of aged individuals.

Download Full-text

Abstract 029: Menopause Alters The Gut Microbiome In Hispanic/Latina Women Of The Hispanic Community Health Study/Study Of Latinos (HCHS/SOL), With Implications For Metabolic Syndrome

Circulation ◽

10.1161/circ.143.suppl_1.029 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Brandilyn Peters-samuelson ◽

Juan Lin ◽

Qibin Qi ◽

Carmen R Isasi ◽

Yasmin Mossavar-Rahmani ◽

...

Keyword(s):

Gut Microbiome ◽

Cardiometabolic Risk ◽

Disease Risk ◽

Self Report ◽

Microbiome Composition ◽

Microbiome Diversity ◽

Menopausal Women ◽

Younger Men ◽

Post Menopause ◽

Post Menopausal

Introduction: During menopause, women experience an increase in cardiometabolic risk factors, thought to relate to aging and loss of endogenous estrogen. Menopause may also influence the gut microbiome, which plays a role in cardiometabolic risk. However, the menopause-microbiome relationship has not been examined in a large study and implications for disease are unknown. Hypothesis: Menopause alters gut microbiome composition, which may affect post-menopausal disease risk. Methods: Menopause was defined by self report of 12 months of amenorrhea, not due to surgery or other non-natural causes. Shotgun sequencing was used on stool from 2370 participants (301 pre-menopausal women; 1072 post-menopausal women; 997 men). Between pre- and post-menopausal women and age-matched men, we compared microbiome diversity, composition, and taxa. Results: Pre-menopausal women had higher gut microbiome diversity than post-menopausal women and men (all p<0.05, Figure 1a). Post-menopausal women also differed in overall microbiome composition from pre-menopausal women (p=0.005), while older and younger men did not differ from each other (p=0.70) (Figure 1b). We identified differentially abundant taxa between post- and pre-menopausal women, including class Betaproteobacteria and its genus Sutterella (enriched in post-menopause), and genera Shigella and Escherichia (depleted in post-menopause); associations were similar in comparisons of men vs. women, though the taxa did not differ between older and younger men (Figure 1c). In post-menopausal women, higher abundance of Shigella and Escherichia was associated with impaired fasting glucose (≥100 mg/dL or diabetes treatment) (Figure 1d). Conclusions: Menopause is associated with a gut microbiome more similar to that of men, perhaps related to the common condition of a low estrogen state. In HCHS/SOL, menopause was associated with depletion of gut pathogens, which were related to increased diabetes risk. These findings require confirmation in other racial/ethnic groups.

Download Full-text