title: Intestinal bacteria modify lymphoma incidence and latency by affecting systemic inflammatory state, oxidative stress, and leukocyte genotoxicity.
abstract: Ataxia-telangiectasia is a genetic disorder associated with high incidence of B-cell lymphoma. Using an ataxia-telangiectasia mouse model, we compared lymphoma incidence in several isogenic mouse colonies harboring different bacterial communities, finding that intestinal microbiota are a major contributor to disease penetrance and latency, lifespan, molecular oxidative stress, and systemic leukocyte genotoxicity. High-throughput sequence analysis of rRNA genes identified mucosa-associated bacterial phylotypes that were colony-specific. Lactobacillus johnsonii, which was deficient in the more cancer-prone mouse colony, was causally tested for its capacity to confer reduced genotoxicity when restored by short-term oral transfer. This intervention decreased systemic genotoxicity, a response associated with reduced basal leukocytes and the cytokine-mediated inflammatory state, and mechanistically linked to the host cell biology of systemic genotoxicity. Our results suggest that intestinal microbiota are a potentially modifiable trait for translational intervention in individuals at risk for B-cell lymphoma, or for other diseases that are driven by genotoxicity or the molecular response to oxidative stress.
authors.affiliation: Department of Pathology and Lab Medicine, David Geffen School of Medicine, University of California, California, USA.
authors.forename: Mitsuko L
authors.initials: ML
authors.lastname: Yamamoto
authors.forename: Irene
authors.initials: I
authors.lastname: Maier
authors.forename: Angeline Tilly
authors.initials: AT
authors.lastname: Dang
authors.forename: David
authors.initials: D
authors.lastname: Berry
authors.forename: Jared
authors.initials: J
authors.lastname: Liu
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ruegger
authors.forename: Jiue-In
authors.initials: JI
authors.lastname: Yang
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Soto
authors.forename: Laura L
authors.initials: LL
authors.lastname: Presley
authors.forename: Ramune
authors.initials: R
authors.lastname: Reliene
authors.forename: Aya M
authors.initials: AM
authors.lastname: Westbrook
authors.forename: Bo
authors.initials: B
authors.lastname: Wei
authors.forename: Alexander
authors.initials: A
authors.lastname: Loy
authors.forename: Christopher
authors.initials: C
authors.lastname: Chang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Braun
authors.forename: James
authors.initials: J
authors.lastname: Borneman
authors.forename: Robert H
authors.initials: RH
authors.lastname: Schiestl
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000150:complications; D042822:Genomic Instability; D015994:Incidence; D007249:Inflammation / Q000382:microbiology*; D007422:Intestines / Q000382:microbiology*; D007778:Lactobacillus / Q000502:physiology*; D007962:Leukocytes / Q000382:microbiology*; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D064307:Microbiota; D018384:Oxidative Stress / Q000502:physiology