Dynamic Colonization of Microbes and Their Functions after Fecal Microbiota Transplantation for Inflammatory Bowel Disease

Chu, Nathaniel D.; Crothers, Jessica W; Nguyen, Le T T; Kearney, Sean M.; Smith, Mark; Kassam, Zain; Collins, Cheryl; Xavier, Ramnik J.; Moses, Peter L.; Alm, Eric J.

doi:10.1128/mbio.00975-21

Cited by 31 publications

(39 citation statements)

References 67 publications

(95 reference statements)

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“…We find that, as has been shown in past studies 23 , the use of strain haplotypes inferred from SNP profiles 22 greatly improved the sensitivity of our transmission analysis. While this was expected given the large number of shared taxa at the species and 16S rRNA gene amplicon SNV levels, it is surprising that this improvement was possible without tuning hyper-parameters of the Strain Finder algorithm.…”

Section: Discussionsupporting

confidence: 72%

“…In fact, features of the microbiome, in either patients or their donors, that predict FMT efficacy have not been convincingly identified 19 – 21 . An important challenge for understanding the role of engraftment is in distinguishing taxa originating in donors’ or recipients’ microbiomes 22 , 23 . While statistical approaches like SourceTracker, which models samples as blends of taxa from multiple sources, have been effectively applied to both 16S rRNA gene 24 and metagenomic surveys 25 , most tools for taxonomic analysis of microbial communities cannot differentiate between donor and patient populations of the same species, due to limited taxonomic resolution 26 .…”

Section: Introductionmentioning

confidence: 99%

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Strain-resolved analysis in a randomized trial of antibiotic pretreatment and maintenance dose delivery mode with fecal microbiota transplant for ulcerative colitis

Smith

Piceno²,

Zydek

et al. 2022

Sci Rep

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Fecal microbiota transplant is a promising therapy for ulcerative colitis. Parameters maximizing effectiveness and tolerability are not yet clear, and it is not known how import the transmission of donor microbes to patients is. Here (clinicaltrails.gov: NCT03006809) we have tested the effects of antibiotic pretreatment and compared two modes of maintenance dose delivery, capsules versus enema, in a randomized, pilot, open-label, 2 × 2 factorial design with 22 patients analyzed with mild to moderate UC. Clinically, the treatment was well-tolerated with favorable safety profile. Of patients who received antibiotic pretreatment, 6 of 11 experienced remission after 6 weeks of treatment, versus 2 of 11 non-pretreated patients (log odds ratio: 1.69, 95% confidence interval: −0.25 to 3.62). No significant differences were found between maintenance dosing via capsules versus enema. In exploratory analyses, microbiome turnover at both the species and strain levels was extensive and significantly more pronounced in the pretreated patients. Associations were also revealed between taxonomic turnover and changes in the composition of primary and secondary bile acids. Together these findings suggest that antibiotic pretreatment contributes to microbiome engraftment and possibly clinical effectiveness, and validate longitudinal strain tracking as a powerful way to monitor the dynamics and impact of microbiota transfer.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Strain-resolved analysis in a randomized trial of antibiotic pretreatment and maintenance dose delivery mode with fecal microbiota transplant for ulcerative colitis

Smith

Piceno²,

Zydek

et al. 2022

Sci Rep

Self Cite

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“…Therefore, we will be able to develop precise therapeutic strategies for patients having similar individual disease spectrums to treat IBD. (Colman and Rubin, 2014;Costea et al, 2017;Nishida et al, 2017;Ishikawa et al, 2018;Goyal et al, 2018;Allegretti et al, 2019;Caruso et al, 2020;Ng et al, 2020;Chu et al, 2021;Saha et al, 2021) Anti-TNF Inhibiting the inflammation of TNF (Aden et al, 2019;Zhuang et al, 2020) Diet (EEN) Change the composition of the microbiota (Heerasing et al, 2017;Lewis and Abreu, 2017;Levine et al, 2018;Pigneur et al, 2019;Jongsma et al, 2020) Vedolizumab Inhibit the migration of lymphocytes from vascular endothelium to intestine (Stevens et al, 2017;Fleisher et al, 2018) Gut Target IL-12 and IL-23 (Feagan et al, 2016;Bradley, 2017) Tofacitinib, Filgotinib, and Upadacitinib Target Janus kinases (Hanauer et al, 2020;Feagan et al, 2021;Parigi et al, 2021) Tungstate inhibit the proliferation of Enterobacteriaceae (Zhu et al, 2018) FMT, fecal microbiota transplantation; Anti-TNF, anti-tumor necrosis factor; EEN. Exclusive enteral nutrition; HABN, Hyaluronic acid-coated bilirubin nanodrug.…”

Section: Future Directionmentioning

confidence: 99%

“…To date, several clinical trials have shown that intensive dose and multi-donor FMT could induce clinical and endoscopic remission ( Moayyedi et al., 2015 ). However, one study found that the transferred microbes in the recipient who underwent FMT 10 weeks later were far from the donor bacteria, which provide a critical issue that the colonization dynamics of gut microbiota should be tracked and manipulated in the recipient of FMT ( Chu et al., 2021 ). In addition, FMT is currently being investigated in registration and ethical clinical research, and it has not been approved for clinical application.…”

Section: Microbiota-targeted Treatment In Ibdmentioning

confidence: 99%

The Gut Microbiota in Inflammatory Bowel Disease

Qiu

Ishimoto

et al. 2022

Front. Cell. Infect. Microbiol.

168

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Epidemiological surveys indicate that the incidence of inflammatory bowel disease (IBD) is increasing rapidly with the continuous growth of the economy. A large number of studies have investigated the relationship between the genetic factors related to the susceptibility to IBD and the gut microbiota of patients by using high-throughput sequencing. IBD is considered the outcome of the interaction between host and microorganisms, including intestinal microbial factors, abnormal immune response, and a damaged intestinal mucosal barrier. The imbalance of microbial homeostasis leads to the colonization and invasion of opportunistic pathogens in the gut, which increases the risk of the host immune response and promotes the development of IBD. It is critical to identify the specific pathogens related to the pathogenesis of IBD. An in-depth understanding of various pathogenic factors is of great significance for the early detection of IBD. This review highlights the role of gut microbiota in the pathogenesis of IBD and provides a theoretical basis for the personalized approaches that modulate the gut microbiota to treat IBD.

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“…Several tools have been developed that take this approach, including Lineage (O’Brien et al, 2014), Strain Finder (Smillie et al, 2018), DESMAN (Quince et al, 2017), and ConStrains (Luo et al, 2015). These methods have been used to track the transmission of inferred strains from donors’ to recipients’ microbiomes after fecal microbiota transplantation (FMT) (Smillie et al, 2018; Chu et al, 2021; Watson et al, 2021; Smith et al, 2022). The application of strain deconvolution has been limited, however, by the computational demands of existing methods, where runtimes scale poorly with increasing numbers of samples, latent strains, and SNPs considered.…”

Section: Introductionmentioning

confidence: 99%

Scalable microbial strain inference in metagenomic data using StrainFacts

Smith

Li²,

Shi

et al. 2022

Preprint

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While genome databases are nearing a complete catalog of species commonly inhabiting the human gut, their representation of intraspecific diversity is lacking for all but the most abundant and frequently studied taxa. Statistical deconvolution of allele frequencies from shotgun metagenomic data into strain genotypes and relative abundances is a promising approach, but existing methods are limited by computational scalability. Here we introduce StrainFacts, a method for strain deconvolution that enables inference across tens of thousands of metagenomes. We harness a "fuzzy" genotype approximation that makes the underlying graphical model fully differentiable, unlike existing methods. This allows parameter estimates to be optimized with gradient-based methods, speeding up model fitting by two orders of magnitude. A graphical processing unit implementation provides additional scalability. Extensive simulations show that StrainFacts can perform strain inference on thousands of metagenomes and has comparable accuracy to more computationally intensive tools. We further validate our strain inferences using single-cell genomic sequencing from a human stool sample. Applying StrainFacts to a collection of more than 10,000 publicly available human stool metagenomes, we quantify patterns of strain diversity, biogeography, and linkage-disequilibrium that agree with and expand on what is known based on existing reference genomes. StrainFacts paves the way for large-scale biogeography and population genetic studies of microbiomes using metagenomic data.

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Dynamic Colonization of Microbes and Their Functions after Fecal Microbiota Transplantation for Inflammatory Bowel Disease

Cited by 31 publications

References 67 publications

Strain-resolved analysis in a randomized trial of antibiotic pretreatment and maintenance dose delivery mode with fecal microbiota transplant for ulcerative colitis

Strain-resolved analysis in a randomized trial of antibiotic pretreatment and maintenance dose delivery mode with fecal microbiota transplant for ulcerative colitis

The Gut Microbiota in Inflammatory Bowel Disease

Scalable microbial strain inference in metagenomic data using StrainFacts

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