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

doi:10.1016/j.chom.2018.09.009

. 2018 Oct 10;24(4):600-610.e4.

doi: 10.1016/j.chom.2018.09.009.

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

Melanie Schirmer¹, Lee Denson², Hera Vlamakis³, Eric A Franzosa¹, Sonia Thomas⁴, Nathan M Gotman⁵, Paul Rufo⁶, Susan S Baker⁷, Cary Sauer⁸, James Markowitz⁹, Marian Pfefferkorn¹⁰, Maria Oliva-Hemker¹¹, Joel Rosh¹², Anthony Otley¹³, Brendan Boyle¹⁴, David Mack¹⁵, Robert Baldassano¹⁶, David Keljo¹⁷, Neal LeLeiko¹⁸, Melvin Heyman¹⁹, Anne Griffiths²⁰, Ashish S Patel²¹, Joshua Noe²², Subra Kugathasan⁸, Thomas Walters²⁰, Curtis Huttenhower¹, Jeffrey Hyams²³, Ramnik J Xavier²⁴

Affiliations

¹ The Broad Institute of MIT and Harvard, Infectious Disease and Microbiome, Cambridge, MA 02142, USA; Harvard T.H. Chan School of Public Health, Biostatistics Department, Boston, MA 02115, USA.
² Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
³ The Broad Institute of MIT and Harvard, Infectious Disease and Microbiome, Cambridge, MA 02142, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁴ Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27516, USA; RTI International, Biostatistics and Epidemiology Division, Research Triangle Park, NC 27709, USA.
⁵ Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27516, USA.
⁶ Children's Hospital Boston, Boston, MA 02115, USA.
⁷ Women and Children's Hospital of Buffalo WCHOB, Buffalo, NY 14222, USA.
⁸ Emory Children's Center, Atlanta, GA 30322, USA.
⁹ Cohen Children's Medical Center, Pediatric Gastroenterology, New York, NY 11040, USA.
¹⁰ Riley Children's Hospital Indiana University, School of Medicine, Section of Gastroenterology/Hepatology/Nutrition, Indianapolis, IN 46202, USA.
¹¹ Johns Hopkins Children's Center, Department of Pediatrics, Baltimore, MD 21287, USA.
¹² Goryeb Children's Hospital/Atlantic Health, Pediatric Gastroenterology, Morristown, NJ 07960, USA.
¹³ IWK Health Centre, Division of Gastroenterology and Nutrition, Halifax, NS B3K 6R8, Canada.
¹⁴ Nationwide Children's Hospital, Pediatrics, Columbus, OH 43205, USA.
¹⁵ Children's Hospital of Eastern Ontario and University of Ottawa, Department of Pediatrics, Ottawa, ON K1H 8L1, Canada.
¹⁶ Children's Hospital of Philadelphia CHOP, Pediatric Gastroenterologist, Philadelphia, PA 19104, USA.
¹⁷ UPMC Children's Hospital of Pittsburgh, Department of Pediatrics, Pittsburgh, PA 15224, USA.
¹⁸ Hasbro Children's Hospital, Pediatric Gastroenterology, Providence, RI 02903, USA.
¹⁹ University of California at San Francisco, Pediatric Gastroenterology, San Francisco, CA 94158, USA.
²⁰ Sickkids Hospital, University of Toronto, Gastroenterology, Hepatology and Nutrition, Toronto, ON M5G 1X8, Canada.
²¹ UT Southwestern, Department of Pediatrics, Dallas, TX 75390, USA.
²² Medical College of Wisconsin, Gastroenterology, Milwaukee, WI 53226, USA.
²³ Connecticut Children's Medical Center, Division of Digestive Diseases, Hartford, CT 06106, USA.
²⁴ The Broad Institute of MIT and Harvard, Infectious Disease and Microbiome, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

PMID: 30308161
PMCID: PMC6277984
DOI: 10.1016/j.chom.2018.09.009

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

Melanie Schirmer et al. Cell Host Microbe. 2018.

. 2018 Oct 10;24(4):600-610.e4.

doi: 10.1016/j.chom.2018.09.009.

Authors

Affiliations

¹ The Broad Institute of MIT and Harvard, Infectious Disease and Microbiome, Cambridge, MA 02142, USA; Harvard T.H. Chan School of Public Health, Biostatistics Department, Boston, MA 02115, USA.
² Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
³ The Broad Institute of MIT and Harvard, Infectious Disease and Microbiome, Cambridge, MA 02142, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁴ Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27516, USA; RTI International, Biostatistics and Epidemiology Division, Research Triangle Park, NC 27709, USA.
⁵ Collaborative Studies Coordinating Center, Department of Biostatistics, University of North Carolina, Chapel Hill, NC 27516, USA.
⁶ Children's Hospital Boston, Boston, MA 02115, USA.
⁷ Women and Children's Hospital of Buffalo WCHOB, Buffalo, NY 14222, USA.
⁸ Emory Children's Center, Atlanta, GA 30322, USA.
⁹ Cohen Children's Medical Center, Pediatric Gastroenterology, New York, NY 11040, USA.
¹⁰ Riley Children's Hospital Indiana University, School of Medicine, Section of Gastroenterology/Hepatology/Nutrition, Indianapolis, IN 46202, USA.
¹¹ Johns Hopkins Children's Center, Department of Pediatrics, Baltimore, MD 21287, USA.
¹² Goryeb Children's Hospital/Atlantic Health, Pediatric Gastroenterology, Morristown, NJ 07960, USA.
¹³ IWK Health Centre, Division of Gastroenterology and Nutrition, Halifax, NS B3K 6R8, Canada.
¹⁴ Nationwide Children's Hospital, Pediatrics, Columbus, OH 43205, USA.
¹⁵ Children's Hospital of Eastern Ontario and University of Ottawa, Department of Pediatrics, Ottawa, ON K1H 8L1, Canada.
¹⁶ Children's Hospital of Philadelphia CHOP, Pediatric Gastroenterologist, Philadelphia, PA 19104, USA.
¹⁷ UPMC Children's Hospital of Pittsburgh, Department of Pediatrics, Pittsburgh, PA 15224, USA.
¹⁸ Hasbro Children's Hospital, Pediatric Gastroenterology, Providence, RI 02903, USA.
¹⁹ University of California at San Francisco, Pediatric Gastroenterology, San Francisco, CA 94158, USA.
²⁰ Sickkids Hospital, University of Toronto, Gastroenterology, Hepatology and Nutrition, Toronto, ON M5G 1X8, Canada.
²¹ UT Southwestern, Department of Pediatrics, Dallas, TX 75390, USA.
²² Medical College of Wisconsin, Gastroenterology, Milwaukee, WI 53226, USA.
²³ Connecticut Children's Medical Center, Division of Digestive Diseases, Hartford, CT 06106, USA.
²⁴ The Broad Institute of MIT and Harvard, Infectious Disease and Microbiome, Cambridge, MA 02142, USA; Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: xavier@molbio.mgh.harvard.edu.

PMID: 30308161
PMCID: PMC6277984
DOI: 10.1016/j.chom.2018.09.009

Abstract

Evaluating progression risk and determining optimal therapy for ulcerative colitis (UC) is challenging as many patients exhibit incomplete responses to treatment. As part of the PROTECT (Predicting Response to Standardized Colitis Therapy) Study, we evaluated the role of the gut microbiome in disease course for 405 pediatric, new-onset, treatment-naive UC patients. Patients were monitored for 1 year upon treatment initiation, and microbial taxonomic composition was analyzed from fecal samples and rectal biopsies. Depletion of core gut microbes and expansion of bacteria typical of the oral cavity were associated with baseline disease severity. Remission and refractory disease were linked to species-specific temporal changes that may be implicative of therapy efficacy, and a pronounced increase in microbiome variability was observed prior to colectomy. Finally, microbial associations with disease-associated serological markers suggest host-microbial interactions in UC. These insights will help improve existing treatments and develop therapeutic approaches guiding optimal medical care.

Keywords: 5ASA; colectomy; corticosteroids; disease course; gut microbiome; host-microbial interactions; pediatric ulcerative colitis; response to therapy; serological markers; treatment-naive.

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Figures

**Figure 1:. Microbial and serological changes in relation to disease severity and treatment efficacy.**
(A) Patients with a baseline (week 0) and at least one follow-up sample were included (week 0: n_severe=90, n_moderate=139, n_mild=75). Ordination analysis (PCoA on Bray-Curtis distance) over all samples revealed marked stratification by disease severity (B) and fecal calprotectin level (C), which were significantly associated (D; sequential Wilcoxon tests, all p<0.01). Stratification closely followed the longitudinal sequence of samples within patients, consistent with improvement over time (E). (F) Microbial profiles significantly changed (Bray-Curtis) over time within individuals (Wilcoxon; all p<0.05 except for changes from week 0-4 to week 0-12). (G) Network of significant associations between microbial clades in baseline samples (gray nodes) and serological markers (yellow nodes) determined by linear model coefficients (MaAsLin). Edges summarize the association strength by Spearman correlation (red, positive; blue, negative; heavier edge weight implies greater strength). See also Fig. S1 and Tables S1+S6.

**Figure 2:. Factors associated with variation in microbial community composition.**
**(A)** Comparison of paired microbial profiles in biopsies and stool samples from treatment-naive patients (n=132, week 0). OTUs were required to occur in ≥20 biopsy or stool samples with mean abundance >10⁻⁵. Error bars specify SEM, color indicates Spearman correlation coefficient for each OTU across all samples. The 15 OTUs with the largest difference between sample types (outliers from the x=y line) and the 5 most abundant OTUs (top right) are labeled. (B) Intra-patient correlation of biopsy versus stool samples at week 0, stratified by disease severity (min. abundance: 10⁻⁴). Correlation coefficients decreased with increasing disease severity (median Spearman r_mild=0.28, r_moderate=0.28, r_severe=0.17), however, this trend was not statistically significant. (C) Microbial taxonomic variation explained by various factors (y-axis) for all or only baseline samples (permANOVA, nperm=1,999). Percentages indicate variance explained by each variable in single-variable models. Total variation explained by all variables is indicated in the final row. See also Fig. S2.

**Figure 3:. Microbial associations with disease severity, colectomy, and remission.**
**(A)** Significant (FDR<0.05) associations between microbial abundance and disease severity in treatment-naive (week 0) stool samples and biopsies (n_mild=123, n_moderate=215, n_severe=137). Any OTU significantly altered in moderate or severe disease compared to mild was included (see also Table S5). Associations are summarized by fold change in mean OTU abundance for mild vs. moderate (orange) and mild vs. severe (red) disease. Black diamonds/circles indicate OTUs associated with antibiotics. **(B)** *V. dispar* was the most depleted species in mild disease (Wilcoxon, mild-moderate: p=0.003, moderate-severe: p=0.0005). **(C)** Significant (FDR<0.2) associations between microbial abundance in baseline samples and refractory disease requiring colectomy. Associations are summarized by fold change in mean OTU abundances in the colectomy group (n=19) vs. patients not requiring colectomy (n=304). Significant (FDR<0.2) associations between microbial abundance and CS-free remission at week (D) 12 and (E) 52. See also Fig. S3 and Tables S2 and S5.

**Figure 4:. Temporal variation in microbial profiles linked to treatment efficacy and disease progression.**
**(A)** Microbial changes between week 0 and 4 were associated with initial treatment efficacy within each treatment group (CS and 5ASA). Asterisks indicate patient groups for which the association was significant (FDR<0.05). **(B)** Microbial associations with disease severity in biopsies and stool samples from all time points (n_inactive=447, n_mild=337, n_moderate=275, n_severe=152). Mean abundances of each disease severity group for the 30 most significant OTUs (FDR<10⁻¹⁰). **(C)** *H. parainfluenzae* (OTU 865469) levels showed opposing temporal trends in connection with CS-free remission at week 52. Patients with initially mild disease that failed to achieve remission (dotted grey line) displayed consistent levels, while patients with initially severe disease that achieved remission (blue line) showed a substantial reduction in *H. parainfluenzae.* **(D)** Intra-patient stability was significantly lower (Wilcoxon, p=0.02) in the colectomy group. We compared intra-patient similarity of microbial community composition (Bray-Curtis; fecal samples only) from the first 3 time points. Dotted lines indicate group medians. See also Fig. S4 and Tables S3+S4.

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References

1. Ananthakrishnan AN, Luo C, Yajnik V, Khalili H, Garber JJ, Stevens BW, Cleland T & Xavier RJ (2017). Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases. Cell Host Microbe, 21, 603–610 e3. - PMC - PubMed
1. Atarashi K, Suda W, Luo C, Kawaguchi T, Motoo I, Narushima S, Kiguchi Y, Yasuma K, Watanabe E, Tanoue T, et al. (2017). Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science, 358, 359–365. - PMC - PubMed
1. Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, et al. (2013). Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature, 500, 232–6. - PubMed
1. Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, Griffiths AM, Jevon GP, Higuchi LM, Hyams JS, et al. (2007). Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America. J Pediatr Gastroenterol Nutr, 44, 653–74. - PubMed
1. Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, Owens SM, Betley J, Fraser L, Bauer M, et al. (2012). Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. Isme j, 6, 1621–4. - PMC - PubMed

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[1] Ananthakrishnan AN, Luo C, Yajnik V, Khalili H, Garber JJ, Stevens BW, Cleland T & Xavier RJ (2017). Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases. Cell Host Microbe, 21, 603–610 e3. - PMC - PubMed

[2] Ananthakrishnan AN, Luo C, Yajnik V, Khalili H, Garber JJ, Stevens BW, Cleland T & Xavier RJ (2017). Gut Microbiome Function Predicts Response to Anti-integrin Biologic Therapy in Inflammatory Bowel Diseases. Cell Host Microbe, 21, 603–610 e3. - PMC - PubMed

[3] Atarashi K, Suda W, Luo C, Kawaguchi T, Motoo I, Narushima S, Kiguchi Y, Yasuma K, Watanabe E, Tanoue T, et al. (2017). Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science, 358, 359–365. - PMC - PubMed

[4] Atarashi K, Suda W, Luo C, Kawaguchi T, Motoo I, Narushima S, Kiguchi Y, Yasuma K, Watanabe E, Tanoue T, et al. (2017). Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science, 358, 359–365. - PMC - PubMed

[5] Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, et al. (2013). Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature, 500, 232–6. - PubMed

[6] Atarashi K, Tanoue T, Oshima K, Suda W, Nagano Y, Nishikawa H, Fukuda S, Saito T, Narushima S, Hase K, et al. (2013). Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature, 500, 232–6. - PubMed

[7] Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, Griffiths AM, Jevon GP, Higuchi LM, Hyams JS, et al. (2007). Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America. J Pediatr Gastroenterol Nutr, 44, 653–74. - PubMed

[8] Bousvaros A, Antonioli DA, Colletti RB, Dubinsky MC, Glickman JN, Gold BD, Griffiths AM, Jevon GP, Higuchi LM, Hyams JS, et al. (2007). Differentiating ulcerative colitis from Crohn disease in children and young adults: report of a working group of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the Crohn's and Colitis Foundation of America. J Pediatr Gastroenterol Nutr, 44, 653–74. - PubMed

[9] Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, Owens SM, Betley J, Fraser L, Bauer M, et al. (2012). Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. Isme j, 6, 1621–4. - PMC - PubMed

[10] Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, Owens SM, Betley J, Fraser L, Bauer M, et al. (2012). Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. Isme j, 6, 1621–4. - PMC - PubMed

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

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

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