Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice

Sharpton, Thomas J.; Lyalina, Svetlana; Luong, Julie; Pham, Joey; Deal, Emily M.; Armour, Courtney R.; Gaulke, Christopher A.; Sanjabi, Shomyseh; Pollard, Katherine S.

doi:10.1128/msystems.00036-17

Cited by 47 publications

(45 citation statements)

References 131 publications

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“…1a ) compared to treatment with vehicle control. To take advantage of the “within-subjects” analysis of longitudinal changes, we used a generalized linear mixed-effects model to evaluate longitudinal changes 22 , and found that Firmicutes were significantly increased (slope=0.038, p =0.005) and Bacteroidetes were decreased (slope=-0.049, p =0.057). Eleven bacterial genera were differentially abundant comparing high-dose treatment to vehicle control (4 decreased and 7 increased, DESeq p adj <0.01, day 4).…”

Section: Resultsmentioning

confidence: 99%

“…DESeq2 62 was used to determine differentially abundant taxa on raw count data. Significance testing of longitudinal trends was determined using generalized mixed effects models using the cplm package 22,63 (v. 0.7-7) on clr normalized values. For each sample, fastq files are available in NCBI’s Sequence Read Archive (SRA), accession number SRP5125967.…”

Section: Methodsmentioning

confidence: 99%

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Perturbation of the human gut microbiome by a non-antibiotic drug contributes to the resolution of autoimmune disease

Nayak

Alexander

Stapleton-Grey

et al. 2019

Preprint

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15The trillions of microorganisms (microbiota) found within the human gut play a critical role in 16 shaping the immune system, yet these complex microbial communities are also highly sensitive 17 to numerous environmental factors. While much of the focus to date has been on dietary intake, 18 emerging data has begun to suggest that the use of pharmaceutical drugs, even those that are not 19 considered to be antibiotics, can alter the human gut microbiota with unknown consequences for 20 treatment outcomes. Here, we use a combination of in vitro, in vivo, and ex vivo methods to 21 demonstrate that the first-line therapy for rheumatoid arthritis (RA), methotrexate (MTX), has 22 off-target effects on the human gut microbiota, resulting in a significant growth advantage for 23 drug-resistant Firmicutes over the Bacteroidetes, which tend to be more sensitive. Longitudinal 24 analyses of the gut microbiotas of RA patients revealed that MTX-induced shifts in bacterial 25 relative abundance are associated with improved drug response and transplant experiments in 26 gnotobiotic mice show that these shifts lead to reduced inflammation. Together, these results 27 suggest that the mechanism-of-action of non-antibiotic drugs may be due in part to off-target 28 effects on the gut microbiota, while providing a critical first step towards explaining long-29 standing differences in drug response between patients. 30

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Perturbation of the human gut microbiome by a non-antibiotic drug contributes to the resolution of autoimmune disease

Nayak

Alexander

Stapleton-Grey

et al. 2019

Preprint

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“…Generalized linear mixed models (GLMMs) (97) were used to determine significantly different temporal trends in abundance for microbial taxa. A Tweedie compound Poisson distribution was chosen for this model given that it best captures the nature of amplicon sequence datasets (e.g., overdispersion, zero-inflated datasets, and continuous values) (98). The ‘cpglmm’ function of the ‘cplm’ R package (99) was used for time-series analyses following the general procedure outlined in (98).…”

Section: Methodsmentioning

confidence: 99%

“…A Tweedie compound Poisson distribution was chosen for this model given that it best captures the nature of amplicon sequence datasets (e.g., overdispersion, zero-inflated datasets, and continuous values) (98). The ‘cpglmm’ function of the ‘cplm’ R package (99) was used for time-series analyses following the general procedure outlined in (98). Summarized sequence count tables of family-level taxonomic units were created and full GLMMs were fit relating counts to treatment, days post transplantation, the interaction of main effects, and random effects of each taxon.…”

Section: Methodsmentioning

confidence: 99%

Recovery and Community Succession of theZostera marinaRhizobiome After Transplantation

Wang

English

Tomàs

et al. 2020

Preprint

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18Seagrasses can form mutualisms with their microbiomes that facilitate the exchange of 19 energy sources, nutrients, and hormones, and ultimately impact plant stress resistance. Little is 20 known about community succession within the belowground seagrass microbiome after 21 disturbance and its potential role in the plant's recovery after transplantation. We transplanted 22 Zostera marina shoots with and without an intact rhizosphere and cultivated plants for four 23 weeks while characterizing microbiome recovery and effects on plant traits. Rhizosphere and 24 root microbiomes were compositionally distinct, likely representing discrete microbial niches. 25 Furthermore, microbiomes of washed transplants were initially different from those of sod 26 transplants, and recovered to resemble an undisturbed state within fourteen days. Conspicuously, 27 changes in microbial communities of washed transplants corresponded with changes in 28 rhizosphere sediment mass and root biomass, highlighting the strength and responsive nature of 29 the relationship between plants, their microbiome, and the environment. Potential mutualistic 30 microbes that were enriched over time include those that function in the cycling and turnover of 31 sulfur, nitrogen, and plant-derived carbon in the rhizosphere environment. These findings 32 highlight the importance and resiliency of the seagrass microbiome after disturbance. 33 Consideration of the microbiome will have meaningful implications on habitat restoration 34 practices. 35Importance 37 Seagrasses are important coastal species that are declining globally, and transplantation 38 can be used to combat these declines. However, the bacterial communities associated with 39 seagrass rhizospheres and roots (the microbiome) are often disturbed or removed completely 40 prior to transplantation. The seagrass microbiome benefits seagrasses through metabolite, 41 nutrient, and phytohormone exchange, and contributes to the ecosystem services of seagrass 42 meadows by cycling sulfur, nitrogen, and carbon. This experiment aimed to characterize the 43 importance and resilience of the seagrass belowground microbiome by transplanting Zostera 44 marina with and without intact rhizospheres and tracking microbiome and plant morphological 45 recovery over four weeks. We found the seagrass microbiome to be resilient to transplantation 46 disturbance, recovering after fourteen days. Additionally, microbiome recovery was linked with 47 seagrass morphology, coinciding with increases in rhizosphere sediment mass and root biomass. 48Results of this study can be used to include microbiome responses in informing future restoration 49 work. 52The rhizobiome has long been recognized to have important impacts on plant growth and 53 health (1). The microbes of the rhizobiome, which directly interact with and are influenced by 54 the roots (2), can benefit their plant hosts through recycling and producing bioavailable nutrients 55 (3-5), increasing disease resistance through competition with or in...

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“…We included in each regression model the same demographic and gut-related terms to account for their variance as well. The regression method used was a compound Poisson generalized linear model (CPGLM; (73)), which uses a distribution that has a point mass over zero, allowing it to better handle the sparseness of functional and taxonomic community data (74). After all pairwise regressions, we adjusted the p-values using the False Discovery Rate (FDR) with a cutoff of q = 0.05.…”

Section: Methodsmentioning

confidence: 99%

Gut feelings begin in childhood: how the gut metagenome links to early environment, caregiving, and behavior

Flannery

Stagaman

Burns

et al. 2019

Preprint

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32Psychosocial environments impact normative behavioral development in children, increasing the 33 risk of problem behaviors and psychiatric disorders across the lifespan. Converging evidence 34 demonstrates early normative development is affected by the gut microbiome, which itself can be 35 altered by early psychosocial environments. Nevertheless, these relationships are poorly 36 understood in childhood, particularly beyond peri-and postnatal microbial colonization. To 37 determine the gut microbiome's role in the associations between childhood adversity and 38 behavioral development, we conducted a metagenomic investigation among cross-sectional 39 sample of early school-aged children with a range of adverse experiences and caregiver stressors 40 and relationships. Our results indicate that the taxonomic and functional composition of the gut 41 microbiome links to behavioral dysregulation during a critical period of child development. 42Furthermore, our analysis reveals that both socioeconomic risk exposure and child behaviors 43 associate with the relative abundances of specific taxa (e.g., Bacteroides and Bifidobacterium 44 species) as well as functional modules encoded in their genomes (e.g., monoamine metabolism) 45that have been linked to cognition and health. We also identified heretofore novel linkages 46 between gut microbiota, their functions, and behavior. These findings hold important 47 translational implications for developmental psychology and microbiome sciences alike, as they 48suggest that caregiver behavior might mitigate the impact of socioeconomic risk on the 49 microbiome and modify the relationship between subclinical symptoms of behavioral 50 dysregulation and the gut microbiome in early school-aged children. 51 52

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Development of Inflammatory Bowel Disease Is Linked to a Longitudinal Restructuring of the Gut Metagenome in Mice

Cited by 47 publications

References 131 publications

Perturbation of the human gut microbiome by a non-antibiotic drug contributes to the resolution of autoimmune disease

Perturbation of the human gut microbiome by a non-antibiotic drug contributes to the resolution of autoimmune disease

Recovery and Community Succession of theZostera marinaRhizobiome After Transplantation

Gut feelings begin in childhood: how the gut metagenome links to early environment, caregiving, and behavior

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