The Antibacterial Lectin RegIIIγ Promotes the Spatial Segregation of Microbiota and Host in the Intestine

Vaishnava, Shipra; Yamamoto, Misa; Severson, Kari M.; Ruhn, Kelly A.; Yu, Xiaofei; Koren, Omry; Ley, Ruth E.; Wakeland, Edward K.; Hooper, Lora V.

doi:10.1126/science.1209791

Cited by 1,178 publications

(1,021 citation statements)

References 24 publications

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“…To demonstrate its generalizability, we used microbe–phenotype triangulation to identify commensal bacteria that induce intestinal expression of Reg3γ, a critical antimicrobial peptide that maintains spatial segregation between the epithelial layer and the microbiota 16 . Although commensal microbes are known to be required for induction of Reg3γ expression 17 , few specific organisms have been defined.…”

Section: Main Textmentioning

confidence: 99%

Moving beyond microbiome-wide associations to causal microbe identification

Surana

Kasper

2017

Nature

203

149

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Microbiome-wide association studies have established that numerous diseases are associated with changes in the microbiota1,2. These studies typically generate a long list of commensals implicated as biomarkers of disease, with no clear relevance to disease pathogenesis1–5. If the field is to move beyond correlations and begin to address causation, an effective system is needed for refining this catalog of differentially abundant microbes and allow for subsequent mechanistic studies1,4. Herein, we demonstrate that triangulation of microbe–phenotype relationships is an effective method for reducing the noise inherent in microbiota studies and enabling identification of causal microbes. We found that gnotobiotic mice harboring different microbial communities exhibited differential survival in a colitis model. Co-housing of these mice generated animals that had hybrid microbiotas and displayed intermediate susceptibility to colitis. Mapping of microbe–phenotype relationships in parental mouse strains and in mice with hybrid microbiotas identified the bacterial family Lachnospiraceae as a correlate for protection from disease. Using directed microbial culture techniques, we discovered Clostridium immunis, a previously unknown bacterial species from this family, that—when administered to colitis-prone mice—protected them against colitis-associated death. To demonstrate the generalizability of our approach, we used it to identify several commensal organisms that induce intestinal expression of an antimicrobial peptide. Thus, we have used microbe–phenotype triangulation to move beyond the standard correlative microbiome study and identify causal microbes for two completely distinct phenotypes. Identification of disease-modulating commensals by microbe–phenotype triangulation may be more broadly applicable to human microbiome studies.

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Section: Main Textmentioning

confidence: 99%

Moving beyond microbiome-wide associations to causal microbe identification

Surana

Kasper

2017

Nature

203

149

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“…However, differences were observed between wild-type and TLR mutant colonies that had been maintained as separate lines from homozygous 3 homozygous crosses for many years. These results raise awareness about the importance of considering lineage or legacy effects in microbiome studies, and it should be noted that these effects were considered in several of the cited studies (Vaishnava et al 2011).…”

Section: Micementioning

confidence: 76%

“…Targeted intestinal epithelial deletion of MyD88 using Villin-Cre 3 MyD88-Flox mice has revealed that such mice have reduced levels of the polymeric immunoglobulin receptor mucin-2 and antibacterial peptides (Frantz et al 2012). MyD88 regulation of the expression of RegIIIg, an antibacterial lectin that lyses Gram-positive bacteria, is of special importance, as RegIIIg restricts the localization of bacteria and ensures its proper segregation from the inner mucus layer of the intestinal mucosa (Vaishnava et al 2011). …”

Section: Micementioning

confidence: 99%

Exploring host–microbiota interactions in animal models and humans

2013

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The animal and bacterial kingdoms have coevolved and coadapted in response to environmental selective pressures over hundreds of millions of years. The meta'omics revolution in both sequencing and its analytic pipelines is fostering an explosion of interest in how the gut microbiome impacts physiology and propensity to disease. Gut microbiome studies are inherently interdisciplinary, drawing on approaches and technical skill sets from the biomedical sciences, ecology, and computational biology. Central to unraveling the complex biology of environment, genetics, and microbiome interaction in human health and disease is a deeper understanding of the symbiosis between animals and bacteria. Experimental model systems, including mice, fish, insects, and the Hawaiian bobtail squid, continue to provide critical insight into how host-microbiota homeostasis is constructed and maintained. Here we consider how model systems are influencing current understanding of host-microbiota interactions and explore recent human microbiome studies.The distinctive body plans of animals offer many niches for members of the archaeal and bacterial kingdoms. While the lumen of the human distal gut is one of the most densely populated ecosystems on our planet, humans and other animals harbor several microbiomes on and within their body surfaces such as the respiratory and urogenital tracts and the skin. As the gut has evolved from the relatively simple tube of the ancient cyclostomatida to the more highly compartmentalized gastrointestinal tracts of mammalian species, the diversity and complexity of the microbial inhabitants of those spaces has increased as well (Fig.

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“…Within the intestine the microbiota stimulates epithelial production of antimicrobial peptides,44, 45, 46 in addition to promoting the antimicrobial activity of immune cells 47. These mechanisms of microbiota‐mediated protection against intestinal infection have been extensively reviewed elsewhere15, 38, 48 and will not be discussed in this article.…”

Section: Introductionmentioning

confidence: 99%

The regulation of host defences to infection by the microbiota

Brown

Clarke

2016

Immunology

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SummaryThe skin and mucosal epithelia of humans and other mammals are permanently colonized by large microbial communities (the microbiota). Due to this life‐long association with the microbiota, these microbes have an extensive influence over the physiology of their host organism. It is now becoming apparent that nearly all tissues and organ systems, whether in direct contact with the microbiota or in deeper host sites, are under microbial influence. The immune system is perhaps the most profoundly affected, with the microbiota programming both its innate and adaptive arms. The regulation of immunity by the microbiota helps to protect the host against intestinal and extra‐intestinal infection by many classes of pathogen. In this review, we will discuss the experimental evidence supporting a role for the microbiota in regulating host defences to extra‐intestinal infection, draw together common mechanistic themes, including the central role of pattern recognition receptors, and outline outstanding questions that need to be answered.

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The Antibacterial Lectin RegIIIγ Promotes the Spatial Segregation of Microbiota and Host in the Intestine

Cited by 1,178 publications

References 24 publications

Moving beyond microbiome-wide associations to causal microbe identification

Moving beyond microbiome-wide associations to causal microbe identification

Exploring host–microbiota interactions in animal models and humans

The regulation of host defences to infection by the microbiota

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