Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course

Schirmer, Melanie; Denson, Lee A.; Vlamakis, Hera; Franzosa, Eric A.; Thomas, Siep; Gotman, Nathan; Rufo, Paul A.; Baker, Susan S.; Sauer, Cary G.; Markowitz, James; Pfefferkorn, Marian D.; Oliva‐Hemker, Maria; Rosh, Joel R.; Otley, Anthony; Boyle, Brendan; Mack, David R.; Baldassano, Robert N.; Keljo, David J.; Leleiko, Neal S.; Heyman, Melvin B.; Griffiths, Anne M.; Patel, Ashish; Noe, Joshua D.; Kugathasan, Subra; Walters, Thomas D.; Huttenhower, Curtis; Hyams, Jeffrey S.; Xavier, Ramnik J.

doi:10.1016/j.chom.2018.09.009

Cited by 224 publications

(218 citation statements)

References 52 publications

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“…Crucially, intestinal inflammation is correlated with elevated or “pathological” cell shedding, which is also correlated with altered microbiota profiles 13-15 . Previous studies have indicated that antibiotic usage, and antibiotic‐induced microbiota perturbations, particularly in infancy, are linked to increased risk of developing inflammatory disorders in later life 16 . More recently, research, including our own, has shown important links between members of the intestinal microbiota and the cell shedding response in vivo, demonstrating that early life members of the gut microbial community (ie, Bifidobacterium ) can drive protection against pathological cell shedding in adult mice 17,18 …”

Section: Introductionmentioning

confidence: 99%

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

et al. 2020

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The early life gut microbiota plays a crucial role in regulating and maintaining the intestinal barrier, with disturbances in these communities linked to dysregulated renewal and replenishment of intestinal epithelial cells. Here we sought to determine pathological cell shedding outcomes throughout the postnatal developmental period, and which host and microbial factors mediate these responses. Surprisingly, neonatal mice (Day 14 and 21) were highly refractory to induction of cell shedding after intraperitoneal administration of liposaccharide (LPS), with Day 29 mice showing strong pathological responses, more similar to those observed in adult mice. These differential responses were not linked to defects in the cellular mechanisms and pathways known to regulate cell shedding responses. When we profiled microbiota and metabolites, we observed significant alterations. Neonatal mice had high relative abundances of Streptococcus, Escherichia, and Enterococcus and increased primary bile acids. In contrast, older mice were dominated by Candidatus Arthromitus, Alistipes, and Lachnoclostridium, and had increased concentrations of SCFAs and methyamines. Antibiotic treatment of neonates restored LPS-induced small intestinal cell shedding, whereas adult fecal microbiota transplant alone had no effect.Our findings further support the importance of the early life window for microbiotaepithelial interactions in the presence of inflammatory stimuli and highlights areas for further investigation. K E Y W O R D S antibiotics, cell shedding, early life, fecal microbiota transplant, inflammation, intestinal epithelium, metabolites, microbiota 7076 | HUGHES Et al.

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Section: Introductionmentioning

confidence: 99%

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

et al. 2020

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“…Crucially, intestinal inflammation is correlated with elevated or 'pathological' cell shedding, which is also correlated with altered microbiota profiles [12][13][14]. Previous studies have indicated that antibiotic usage, and antibiotic-induced microbiota perturbations, particularly in infancy, are linked to increased risk of developing inflammatory disorders in later life [15]. More recently, research, including our own, has shown important links between members of the intestinal microbiota and the cell shedding response in vivo, demonstrating that early life members of the gut microbial community (i.e.…”

Section: Introductionmentioning

confidence: 99%

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

Hughes

Schofield

Dalby

et al. 2019

Preprint

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AbstractThe gut microbiota plays a crucial role in regulating and maintaining the epithelial barrier, particularly during early life. Notably, patients with chronic intestinal inflammation have a dysregulated process of renewal and replenishment of the intestinal epithelial cell (IEC) barrier, which is linked to disturbances in the gut microbiota. To date, there are no studies focussed on understanding the impact of inflammatory cell shedding events during the early life developmental window, and which host and microbial factors mediate these responses. Here we sought to determine pathological cell shedding outcomes throughout the postnatal developmental period (day 14, 21, 29 and week 8). Surprisingly neonatal mice (day 14 and 21) were highly refractory to induction of cell shedding after intraperitoneal administration of LPS, with day 29 mice showing strong pathological responses, more similar to those observed in adult mice. These differential responses were not linked to defects in the cellular mechanisms and pathways known to regulate cell shedding responses, although we did observe that neonatal mice had elevated anti-inflammatory (IL-10) responses. Notably, when we profiled microbiota and metabolites from these mice, we observed significant alterations. Neonatal mice had high relative abundances of Streptococcus, Escherichia and Enterococcus and increased primary bile acids. In contrast, older mice were dominated by Candidatus Arthromitus, Alistipes and Lachnoclostridium, and had increased concentrations of SCFAs and methyamines. Faecal microbiota transplant (FMT) and antibiotic studies confirmed the importance of early life gut microbiota in cell shedding responses. In these studies, neonates treated with antibiotics restored LPS-induced small intestinal cell shedding, whereas adult FMT alone had no effect. Our findings further support the importance of the early life window for microbiota-epithelial interactions in the presence of inflammatory stimuli and highlight areas for further investigation to probe underlying mechanisms to drive therapeutic development within the context of chronic inflammatory intestinal diseases.

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“…30 Widespread changes in the gut microbiota, including lower diversity and decreased abundance of putatively beneficial bacteria, such as Lachnospiraceae, have been demonstrated in both UC and CDI. 31, 32 Lachnospiraceae is a primary producer of butyrate, which is known to inhibit C. difficile in vitro 33 and enhances intestinal epithelial barrier function. 34 Furthermore, both C. difficile and Lachnospiraceae are taxonomically classified within the Clostridiales order.…”

Section: Discussionmentioning

confidence: 99%

Temporal Gut Microbial Changes Predict RecurrentClostridium difficilein Patients with and without Ulcerative Colitis

Lee

Limsrivilai

et al. 2019

Preprint

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BackgroundUlcerative colitis (UC) carries an increased risk of primary and recurrent Clostridium difficile infection (rCDI) and CDI is associated with UC flares. We hypothesized that specific fecal microbial changes associate with UC flare and rCDI.MethodsWe conducted a prospective observational cohort study of 57 patients with UC and CDI, CDI only, and UC flare only. Stool samples were collected at baseline, at the end of antibiotic therapy, and after reconstitution for 16S rRNA sequencing. The primary outcomes were recurrent UC flare and rCDI. Logistic regression and Lasso models were constructed for analysis.ResultsThere were 21 (45.7%) patients with rCDI, while 11 (34.4%) developed UC flare. Patients with rCDI demonstrated significant inter-individual (P=.008) and intra-individual differences (P=.004 relative to baseline samples) in community structure by Jensen-Shannon distance (JSD) compared with non-rCDI. Two cross-validated models identified by Lasso regression predicted risk of rCDI: a baseline model with female gender, hospitalization for UC in the past year, increased Ruminococcaceae and Verrucomicrobia, and decreased Eubacteriaceae, Enterobacteriaceae, Lachnospiraceae, and Veillonellaceae (AuROC=0.94); and a model 14 days after completion of antibiotics with female gender, increased Shannon diversity, Ruminococcaceae and Enterobacteriaceae, and decreased community richness and Faecalibacterium (AuROC=0.9). Adding JSD between baseline and post-treatment samples to the latter model improved fit (AuROC=0.94). A baseline model including UC hospitalization in the past year and increased Bacteroidetes showed good fit characteristics for predicting increased risk of UC flare (AuROC=0.88).ConclusionFecal microbial features at baseline and following therapy predict rCDI risk in patients with and without UC. These results may help risk stratify patients to guide management.

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Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course

Cited by 224 publications

References 52 publications

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

Temporal Gut Microbial Changes Predict RecurrentClostridium difficilein Patients with and without Ulcerative Colitis

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