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Disruption of the early-life microbiota alters Peyer's patch development and germinal center formation in gastrointestinal-associated lymphoid tissue

Borbet, Timothy C; Pawline, Miranda B; Li, Jackie; Ho, Melody L; Yin, Yue Sandra; Zhang, Xiaozhou; Novikova, Ekaterina; Jackson, Katelyn; Mullins, Briana J; Ruiz, Victoria E; Hines, Marcus J; Zhang, Xue-Song; Müller, Anne; Koralov, Sergei B; Blaser, Martin J
During postnatal development, both the maturing microbiome and the host immune system are susceptible to environmental perturbations such as antibiotic use. The impact of timing in which antibiotic exposure occurs was investigated by treating mice from days 5-9 with amoxicillin or azithromycin, two of the most commonly prescribed medications in children. Both early-life antibiotic regimens disrupted Peyer's patch development and immune cell abundance, with a sustained decrease in germinal center formation and diminished intestinal immunoglobulin A (IgA) production. These effects were less pronounced in adult mice. Through comparative analysis of microbial taxa, Bifidobacterium longum abundance was found to be associated with germinal center frequency. When re-introduced to antibiotic-exposed mice, B. longum partially rescued the immunological deficits. These findings suggest that early-life antibiotic use affects the development of intestinal IgA-producing B cell functions and that probiotic strains could be used to restore normal development after antibiotic exposure.
PMCID:10206152
PMID: 37235047
ISSN: 2589-0042
CID: 5543952

Partial convergence of the human vaginal and rectal maternal microbiota in late gestation and early post-partum

Shin, Hakdong; Martinez, Keith A; Henderson, Nora; Jay, Melanie; Schweizer, William; Bogaert, Debby; Park, Gwoncheol; Bokulich, Nicholas A; Blaser, Martin J; Dominguez-Bello, Maria Gloria
The human vaginal and fecal microbiota change during pregnancy. Because of the proximity of these perineal sites and the evolutionarily conserved maternal-to-neonatal transmission of the microbiota, we hypothesized that the microbiota of these two sites (rectal and vaginal) converge during the last gestational trimester as part of the preparation for parturition. To test this hypothesis, we analyzed 16S rRNA sequences from vaginal introitus and rectal samples in 41 women at gestational ages 6 and 8 months, and at 2 months post-partum. The results show that the human vaginal and rectal bacterial microbiota converged during the last gestational trimester and into the 2nd month after birth, with a significant decrease in Lactobacillus species in both sites, as alpha diversity progressively increased in the vagina and decreased in the rectum. The microbiota convergence of the maternal vaginal-anal sites perinatally might hold significance for the inter-generational transmission of the maternal microbiota.
PMCID:10264455
PMID: 37311781
ISSN: 2055-5008
CID: 5541392

Joint modeling of zero-inflated longitudinal proportions and time-to-event data with application to a gut microbiome study

Hu, Jiyuan; Wang, Chan; Blaser, Martin J; Li, Huilin
Recent studies have suggested that the temporal dynamics of the human microbiome may have associations with human health and disease. An increasing number of longitudinal microbiome studies, which record time to disease onset, aim to identify candidate microbes as biomarkers for prognosis. Owing to the ultra-skewness and sparsity of microbiome proportion (relative abundance) data, directly applying traditional statistical methods may result in substantial power loss or spurious inferences. We propose a novel joint modeling framework [JointMM], which is comprised of two sub-models: a longitudinal sub-model called zero-inflated scaled-Beta generalized linear mixed-effects regression to depict the temporal structure of microbial proportions among subjects; and a survival sub-model to characterize the occurrence of an event and its relationship with the longitudinal microbiome proportions. JointMM is specifically designed to handle the zero-inflated and highly skewed longitudinal microbial proportion data and examine whether the temporal pattern of microbial presence and/or the non-zero microbial proportions are associated with differences in the time to an event. The longitudinal sub-model of JointMM also provides the capacity to investigate how the (time-varying) covariates are related to the temporal microbial presence/absence patterns and/or the changing trend in non-zero proportions. Comprehensive simulations and real data analyses are used to assess the statistical efficiency and interpretability of JointMM. This article is protected by copyright. All rights reserved.
PMID: 34213763
ISSN: 1541-0420
CID: 4950332

Influence of the early-life gut microbiota on the immune responses to an inhaled allergen

Borbet, Timothy C; Pawline, Miranda B; Zhang, Xiaozhou; Wipperman, Matthew F; Reuter, Sebastian; Maher, Timothy; Li, Jackie; Iizumi, Tadasu; Gao, Zhan; Daniele, Megan; Taube, Christian; Koralov, Sergei B; Müller, Anne; Blaser, Martin J
Antibiotics, among the most used medications in children, affect gut microbiome communities and metabolic functions. These changes in microbiota structure can impact host immunity. We hypothesized that early-life microbiome alterations would lead to increased susceptibility to allergy and asthma. To test this, mouse pups between postnatal days 5-9 were orally exposed to water (control) or to therapeutic doses of azithromycin or amoxicillin. Later in life, these mice were sensitized and challenged with a model allergen, house dust mite (HDM), or saline. Mice with early-life azithromycin exposure that were challenged with HDM had increased IgE and IL-13 production by CD4+ T cells compared to unexposed mice; early-life amoxicillin exposure led to fewer abnormalities. To test that the microbiota contained the immunological cues to alter IgE and cytokine production after HDM challenge, germ-free mice were gavaged with fecal samples of the antibiotic-perturbed microbiota. Gavage of adult germ-free mice did not result in altered HDM responses, however, their offspring, which acquired the antibiotic-perturbed microbiota at birth showed elevated IgE levels and CD4+ cytokines in response to HDM, and altered airway reactivity. These studies indicate that early-life microbiota composition can heighten allergen-driven Th2/Th17 immune pathways and airway responses in an age-dependent manner.
PMID: 35842561
ISSN: 1935-3456
CID: 5280022

Oral and gastric microbiome in relation to gastric intestinal metaplasia

Wu, Fen; Yang, Liying; Hao, Yuhan; Zhou, Boyan; Hu, Jiyuan; Yang, Yaohua; Bedi, Sukhleen; Sanichar, Navin Ganesh; Cheng, Charley; Perez-Perez, Guillermo; Tseng, Wenche; Tseng, Wenzhi; Tseng, Mengkao; Francois, Fritz; Khan, Abraham R; Li, Yihong; Blaser, Martin J; Shu, Xiao-Ou; Long, Jirong; Li, Huilin; Pei, Zhiheng; Chen, Yu
Evidence suggests that Helicobacter pylori plays a role in gastric cancer (GC) initiation. However, epidemiologic studies on the specific role of other bacteria in the development of GC are lacking. We conducted a case-control study of 89 cases with gastric intestinal metaplasia (IM) and 89 matched controls who underwent upper gastrointestinal endoscopy at three sites affiliated with NYU Langone Health. We performed shotgun metagenomic sequencing using oral wash samples from 89 case-control pairs and antral mucosal brushing samples from 55 case-control pairs. We examined the associations of relative abundances of bacterial taxa and functional pathways with IM using conditional logistic regression with and without elastic-net penalty. Compared with controls, oral species Peptostreptococcus stomatis, Johnsonella ignava, Neisseria elongata and Neisseria flavescens were enriched in cases (odds ratios [ORs] = 1.29-1.50, P = .004-.01) while Lactobacillus gasseri, Streptococcus mutans, S parasanguinis and S sanguinis were under-represented (ORs = 0.66-0.76, P = .006-.042) in cases. Species J ignava and Filifactor alocis in the gastric microbiota were enriched (ORs = 3.27 and 1.43, P = .005 and .035, respectively), while S mutans, S parasanguinis and S sanguinis were under-represented (ORs = 0.61-0.75, P = .024-.046), in cases compared with controls. The lipopolysaccharide and ubiquinol biosynthesis pathways were more abundant in IM, while the sugar degradation pathways were under-represented in IM. The findings suggest potential roles of certain oral and gastric microbiota, which are correlated with regulation of pathways associated with inflammation, in the development of gastric precancerous lesions.
PMID: 34664721
ISSN: 1097-0215
CID: 5043202

ARZIMM: A Novel Analytic Platform for the Inference of Microbial Interactions and Community Stability from Longitudinal Microbiome Study

He, Linchen; Wang, Chan; Hu, Jiyuan; Gao, Zhan; Falcone, Emilia; Holland, Steven M; Blaser, Martin J; Li, Huilin
Dynamic changes of microbiome communities may play important roles in human health and diseases. The recent rise in longitudinal microbiome studies calls for statistical methods that can model the temporal dynamic patterns and simultaneously quantify the microbial interactions and community stability. Here, we propose a novel autoregressive zero-inflated mixed-effects model (ARZIMM) to capture the sparse microbial interactions and estimate the community stability. ARZIMM employs a zero-inflated Poisson autoregressive model to model the excessive zero abundances and the non-zero abundances separately, a random effect to investigate the underlining dynamic pattern shared within the group, and a Lasso-type penalty to capture and estimate the sparse microbial interactions. Based on the estimated microbial interaction matrix, we further derive the estimate of community stability, and identify the core dynamic patterns through network inference. Through extensive simulation studies and real data analyses we evaluate ARZIMM in comparison with the other methods.
PMCID:8914110
PMID: 35281829
ISSN: 1664-8021
CID: 5184622

Microbial trend analysis for common dynamic trend, group comparison, and classification in longitudinal microbiome study

Wang, Chan; Hu, Jiyuan; Blaser, Martin J; Li, Huilin
BACKGROUND:The human microbiome is inherently dynamic and its dynamic nature plays a critical role in maintaining health and driving disease. With an increasing number of longitudinal microbiome studies, scientists are eager to learn the comprehensive characterization of microbial dynamics and their implications to the health and disease-related phenotypes. However, due to the challenging structure of longitudinal microbiome data, few analytic methods are available to characterize the microbial dynamics over time. RESULTS:We propose a microbial trend analysis (MTA) framework for the high-dimensional and phylogenetically-based longitudinal microbiome data. In particular, MTA can perform three tasks: 1) capture the common microbial dynamic trends for a group of subjects at the community level and identify the dominant taxa; 2) examine whether or not the microbial overall dynamic trends are significantly different between groups; 3) classify an individual subject based on its longitudinal microbial profiling. Our extensive simulations demonstrate that the proposed MTA framework is robust and powerful in hypothesis testing, taxon identification, and subject classification. Our real data analyses further illustrate the utility of MTA through a longitudinal study in mice. CONCLUSIONS:The proposed MTA framework is an attractive and effective tool in investigating dynamic microbial pattern from longitudinal microbiome studies.
PMCID:8442444
PMID: 34525957
ISSN: 1471-2164
CID: 5012392

Effect of antibiotic treatment on Oxalobacter formigenes colonization of the gut microbiome and urinary oxalate excretion

Nazzal, Lama; Francois, Fritz; Henderson, Nora; Liu, Menghan; Li, Huilin; Koh, Hyunwook; Wang, Chan; Gao, Zhan; Perez, Guillermo Perez; Asplin, John R; Goldfarb, David S; Blaser, Martin J
The incidence of kidney stones is increasing in the US population. Oxalate, a major factor for stone formation, is degraded by gut bacteria reducing its intestinal absorption. Intestinal O. formigenes colonization has been associated with a lower risk for recurrent kidney stones in humans. In the current study, we used a clinical trial of the eradication of Helicobacter pylori to assess the effects of an antibiotic course on O. formigenes colonization, urine electrolytes, and the composition of the intestinal microbiome. Of 69 healthy adult subjects recruited, 19 received antibiotics for H. pylori eradication, while 46 were followed as controls. Serial fecal samples were examined for O. formigenes presence and microbiota characteristics. Urine, collected serially fasting and following a standard meal, was tested for oxalate and electrolyte concentrations. O. formigenes prevalence was 50%. Colonization was significantly and persistently suppressed in antibiotic-exposed subjects but remained stable in controls. Urinary pH increased after antibiotics, but urinary oxalate did not differ between the control and treatment groups. In subjects not on antibiotics, the O. formigenes-positive samples had higher alpha-diversity and significantly differed in Beta-diversity from the O. formigenes-negative samples. Specific taxa varied in abundance in relation to urinary oxalate levels. These studies identified significant antibiotic effects on O. formigenes colonization and urinary electrolytes and showed that overall microbiome structure differed in subjects according to O. formigenes presence. Identifying a consortium of bacterial taxa associated with urinary oxalate may provide clues for the primary prevention of kidney stones in healthy adults.
PMCID:8361114
PMID: 34385560
ISSN: 2045-2322
CID: 5004452

Maternal cecal microbiota transfer rescues early-life antibiotic-induced enhancement of type 1 diabetes in mice

Zhang, Xue-Song; Yin, Yue Sandra; Wang, Jincheng; Battaglia, Thomas; Krautkramer, Kimberly; Li, Wei Vivian; Li, Jackie; Brown, Mark; Zhang, Meifan; Badri, Michelle H; Armstrong, Abigail J S; Strauch, Christopher M; Wang, Zeneng; Nemet, Ina; Altomare, Nicole; Devlin, Joseph C; He, Linchen; Morton, Jamie T; Chalk, John Alex; Needles, Kelly; Liao, Viviane; Mount, Julia; Li, Huilin; Ruggles, Kelly V; Bonneau, Richard A; Dominguez-Bello, Maria Gloria; Bäckhed, Fredrik; Hazen, Stanley L; Blaser, Martin J
Early-life antibiotic exposure perturbs the intestinal microbiota and accelerates type 1 diabetes (T1D) development in the NOD mouse model. Here, we found that maternal cecal microbiota transfer (CMT) to NOD mice after early-life antibiotic perturbation largely rescued the induced T1D enhancement. Restoration of the intestinal microbiome was significant and persistent, remediating the antibiotic-depleted diversity, relative abundance of particular taxa, and metabolic pathways. CMT also protected against perturbed metabolites and normalized innate and adaptive immune effectors. CMT restored major patterns of ileal microRNA and histone regulation of gene expression. Further experiments suggest a gut-microbiota-regulated T1D protection mechanism centered on Reg3γ, in an innate intestinal immune network involving CD44, TLR2, and Reg3γ. This regulation affects downstream immunological tone, which may lead to protection against tissue-specific T1D injury.
PMID: 34289377
ISSN: 1934-6069
CID: 4948332

Effects of early-life penicillin exposure on the gut microbiome and frontal cortex and amygdala gene expression

Volkova, Angelina; Ruggles, Kelly; Schulfer, Anjelique; Gao, Zhan; Ginsberg, Stephen D; Blaser, Martin J
We have established experimental systems to assess the effects of early-life exposures to antibiotics on the intestinal microbiota and gene expression in the brain. This model system is highly relevant to human exposure and may be developed into a preclinical model of neurodevelopmental disorders in which the gut-brain axis is perturbed, leading to organizational effects that permanently alter the structure and function of the brain. Exposing newborn mice to low-dose penicillin led to substantial changes in intestinal microbiota population structure and composition. Transcriptomic alterations implicate pathways perturbed in neurodevelopmental and neuropsychiatric disorders. There also were substantial effects on frontal cortex and amygdala gene expression by bioinformatic interrogation, affecting multiple pathways underlying neurodevelopment. Informatic analyses established linkages between specific intestinal microbial populations and the early-life expression of particular affected genes. These studies provide translational models to explore intestinal microbiome roles in the normal and abnormal maturation of the vulnerable central nervous system.
PMCID:8324854
PMID: 34355145
ISSN: 2589-0042
CID: 4966052