Fecal IgA Levels Are Determined by Strain-Level Differences in Bacteroides ovatus and Are Modifiable by Gut Microbiota Manipulation

Yang, Chao; Mogno, Ilaria; Contijoch, Eduardo J.; Borgerding, Joshua N.; Aggarwala, Varun; Li, Zhihua; Siu, Sophia; Grasset, E.; Helmus, Drew; Dubinsky, Marla; Mehandru, Saurabh; Cerutti, Andrea; Faith, Jeremiah J.

doi:10.1016/j.chom.2020.01.016

Cited by 157 publications

(157 citation statements)

References 59 publications

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“…Germ-free mice and colonization with cultured bacteria: The mice experiments were performed as a part of other published studies for understanding the strain-level differences and their role in fecal-IgA levels 7,67,68 , as well as the impact of the IBD and non-IBD microbiome on baseline immune tone and colitis. These data were used to evaluate the performance of our Strainer algorithm in defined communities of bacterial strains in germ-free mice.…”

Section: Methodsmentioning

confidence: 99%

“…Several studies have demonstrated that gut microbiota strain variation impacts health [1][2][3][4][5][6][7] through mechanisms including altered immune function 8,9 and drug metabolism 10,11 .…”

Section: Introductionmentioning

confidence: 99%

“…Manipulation of gut microbiota strain composition therefore provides a potential route to influence health 7,[12][13][14][15] . Clinically, the dominant therapeutic application of gut microbiota additive engineering is Fecal Microbiota Transplantation 16 (FMT) for recurrent Clostridioides difficile infection (rCDI), which has success rates of over 90% across a variety of administration routes [17][18][19][20][21] with documented but much lower efficacy for ulcerative colitis [22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

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Quantification of discrete gut bacterial strains following fecal transplantation for recurrentClostridioides difficileinfection demonstrates long-term stable engraftment in non-relapsing recipients

Aggarwala

Mogno

et al. 2020

Preprint

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Fecal Microbiota Transplantation (FMT), while successful for the treatment of recurrent Clostridioides difficile (rCDI) infection, lacks a quantitative identification of the discrete bacterial strains that transmit and stably engraft in recipients, and their association with clinical outcomes. Using >1,000 unique bacterial strains isolated and sequenced from a combination of 22 FMT donors and recipients, we develop a statistical approach Strainer to detect and track sequenced bacterial strains from low depth metagenomic sequencing data. On application to 14 FMT interventions, we detect stable and high engraftment of ∼71% of gut microbiota strains in recipients at even 5-years post-transplant, a remarkably durable therapeutic from a single administration. We found differential transmission and engraftment efficacy across bacterial taxonomic groups over short and long-time scales. Although ∼80% of the original pre-FMT recipient strains were eliminated by the FMT, those strains that remain persist even 5 years later, along with newer strains acquired from the environment. The precise quantification of donor bacterial strains in recipients independently explained the clinical outcomes of early and late relapse. Our framework identifies the consistently engrafting discrete bacterial strains for use in Live Biotherapeutic Products (LBP) as a safer, scalable alternative to FMT and enables systematic evaluation of different FMT and LBP study designs.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Quantification of discrete gut bacterial strains following fecal transplantation for recurrentClostridioides difficileinfection demonstrates long-term stable engraftment in non-relapsing recipients

Aggarwala

Mogno

et al. 2020

Preprint

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“…Given the potential of gut microbiota alterations to modify immune activity [14,18,37], we investigated if a defined microbiota transplant would render tumors in mN1 mice susceptible to PD-L1 blockade.…”

Section: Microbial Transplant Enhances the Effector Cd8 + T Cell Phenmentioning

confidence: 99%

“…Moreover, the bacterial taxa associated with PD-1 responding patients have varied between studies, likely owing to differences in study design and patient populations [16]. Regulation of host immunity by the microbiota often occurs at the strain level [17,18], detail not captured by 16S sequencing, which has been used to find associations between gut microbiome composition and checkpoint response in human studies [12,13,15]. five defined microbiota (mR1-mR5) responded similarly to germ-free, antibiotic, and SPF mice (figs.…”

Section: Introductionmentioning

confidence: 99%

Human Microbial Transplant Restores T Cell Cytotoxicity and Anti-Tumor Response to PD-L1 Blockade in Gnotobiotic Mice

Borgerding

Shang

Britton

et al. 2020

Preprint

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Recent studies demonstrate that gut microbiota regulate tumor response to immune checkpoint blockade. Still, the mechanisms by which microbiota control tumor response to immunotherapy remain unclear. We colonized germ-free mice with cultured human-derived microbiota prior to tumor inoculation. While no human donor microbiota altered tumor growth, two distinct gut microbiota inhibited tumor response to anti-PD-L1. Colonization with non-responder microbiota led to reduced tumor immune cell infiltration and modified antigen presenting cell phenotype. RNA sequencing of tumor-infiltrating CD8+ T cells revealed enrichment for stem cell-like genes in non-responders and reduced effector-like expression conferring cytotoxic potential. Antibiotic depletion and microbiota transplant restored anti-PD-L1 response in non-responders, with expansion of effector cells and cytotoxicity. Concomitant blockade of TNFα similarly improved response to anti-PD-L1 and increased cytotoxicity. These results demonstrate inhibitory roles for the microbiota in checkpoint blockade and reveal the potential for microbiota transplant and TNF blockade to overcome microbiota-mediated resistance.

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Strain‐level immunomodulatory variation of gut bacteria

Hajjo

Geva‐Zatorsky

2021

FEBS Letters

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The gut microbiota and the immune system have co‐evolved to interact and cooperate in many ways. A recent study characterizing the immunomodulatory effects of over 60 different human‐derived gut microbes across phyla showed that bacteria‐induced immunomodulations are not dictated by the bacterial phylogeny. Yet, it remains unclear whether strains from the same species induce the same immunomodulatory effects on the host. We analyzed the strain‐level data from this recent study and found that strains from the same species can induce distinct and sometimes even opposing immunophenotypes. Hence, we suggest that the immunomodulatory capabilities of gut bacteria can be strain‐specific.

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Fecal IgA Levels Are Determined by Strain-Level Differences in Bacteroides ovatus and Are Modifiable by Gut Microbiota Manipulation

Abstract: Highlights d Bacteroides ovatus strain variation drives either high or low fecal IgA d CD4 + T cells are critical in B. ovatus-mediated gut IgA production d Cocktails of IgA high B. ovatus strains convert mice from lowto high-IgA producers

Cited by 157 publications

References 59 publications

Quantification of discrete gut bacterial strains following fecal transplantation for recurrentClostridioides difficileinfection demonstrates long-term stable engraftment in non-relapsing recipients

Quantification of discrete gut bacterial strains following fecal transplantation for recurrentClostridioides difficileinfection demonstrates long-term stable engraftment in non-relapsing recipients

Human Microbial Transplant Restores T Cell Cytotoxicity and Anti-Tumor Response to PD-L1 Blockade in Gnotobiotic Mice

Strain‐level immunomodulatory variation of gut bacteria

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