Customizing laboratory mice by modifying gut microbiota and host immunity in an early “window of opportunity”

Hansen, Camilla Hartmann Friis; Metzdorff, Stine Broeng; Hansen, Axel Kornerup

doi:10.4161/gmic.23999

Cited by 27 publications

(24 citation statements)

References 35 publications

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“…However, whether the accumulation of SFB or other specific bacteria taxa in class Clostridia alters epithelial cell turnover and barrier function-enhancing sensitivity to epithelial injury-awaits further investigation with singlespecies colonization of germ-free mice. It should be also noted that investigators should be cautious with the interpretation of the effects in germ-free mice as they are known to have abnormalities in intestinal development and mucosal immune system (71)(72)(73)(74).…”

Section: Discussionmentioning

confidence: 99%

Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model

Shi

Wang

et al. 2017

FASEB j.

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Exposure to microgravity leads to alterations in multiple systems, but microgravity-related changes in the gastrointestinal tract and its clinical significance have not been well studied. We used the hindlimb unloading (HU) mouse model to simulate a microgravity condition and investigated the changes in intestinal microbiota and colonic epithelial cells. Compared with ground-based controls (Ctrls), HU affected fecal microbiota composition with a profile that was characterized by the expansion of Firmicutes and decrease of Bacteroidetes. The colon epithelium of HU mice showed decreased goblet cell numbers, reduced epithelial cell turnover, and decreased expression of genes that are involved in defense and inflammatory responses. As a result, increased susceptibility to dextran sulfate sodium-induced epithelial injury was observed in HU mice. Cohousing of Ctrl mice with HU mice resulted in HUlike epithelial changes in Ctrl mice. Transplantation of feces from Ctrl to HU mice alleviated these epithelial changes in HU mice. Results indicate that HU changes intestinal microbiota, which leads to altered colonic epithelial cell homeostasis, impaired barrier function, and increased susceptibility to colitis. We further demonstrate that alteration in gastrointestinal motility may contribute to HU-associated dysbiosis. These animal results emphasize the necessity of evaluating astronauts' intestinal homeostasis during distant space travel.-Shi, J., Wang, Y., He, J., Li, P., Jin, R., Wang, K., Xu, X., Hao, J., Zhang, Y., Liu, H., Chen, X., Wu, H., Ge, Q. Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model. FASEB J. 31, 3695-3709 (2017 Exposure to microgravity leads to alterations, such as bone demineralization, muscle atrophy, cardiovascular deconditioning, and immune dysfunction, in multiple systems (1). Limited reports also suggest that spaceflight and microgravity affect the integrity of intestinal epithelium. For instance, reduced length of villi and depth of crypts was found in rats that were flown on 12-d Cosmos 2044 and Foton M3 missions (2, 3), and decreased mucin production of intestinal epithelial cells was shown in rats that were flown on the 19.5-d Cosmos 605 mission (4). Colonic TGF-b expression was altered in mice aboard the 13-d STS-135 or 91-d International Space Station missions (5, 6). Using a well-accepted, ground-based spaceflight analog, the hindlimb unloading (HU) mouse model (7) found that simulated microgravity resulted in a transient increase in intestinal permeability, which is characterized by the elevation of circulating LPS and the activation of the innate immune system. The clinical significance and mechanism of these epithelial changes are not clear; however, Chopra et al. (8) reported that HU mice that were infected with Salmonella enterica serovar typhimurium had a 100-fold decrease in LD 50 compared with normal-gravity control (Ctrl) mice. This indicates that microgravity-induced intestinal epithelial changes may exacerbate bacte...

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Section: Discussionmentioning

confidence: 99%

Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model

Shi

Wang

et al. 2017

FASEB j.

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“…Second, preclinical studies relevant to osteoporosis concentrate on the adult skeletal phenotype, which requires older animals. Transfer of gut microbiota is not as effective in older animals (93,94) and the adult phenotype can be quite sensitive to the timing of microbial exposure (95) , making it difficult to study changes in gut flora after skeletal maturity. Lastly, methods of manipulating the gut flora as a form of treatment remain poorly understood.…”

Section: Future Directionsmentioning

confidence: 99%

Links Between the Microbiome and Bone

Hernandez

Guss

Luna

et al. 2016

Journal of Bone and Mineral Research

162

136

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The human microbiome has been shown to influence a number of chronic conditions associated with impaired bone mass and bone quality including obesity, diabetes and inflammatory bowel disease. The connection between the microbiome and bone health, however, has not been well studied. The few studies available demonstrate that the microbiome can have a large effect on bone remodeling and bone mass. The gut microbiome is the largest reservoir of microbial organisms in the body and consists of over a thousand different species interacting with one another in a stable dynamic equilibrium. How the microbiome can affect organs distant from the gut is not well understood, but is believed to occur through regulation of nutrition, regulation of the immune system and/or translocation of bacterial products across the gut endothelial barrier. Here we review each of these mechanisms and discuss their potential effect on bone remodeling and bone mass. We review how preclinical studies of bone-microbiome interactions are challenging because the microbiome is sensitive to genetic background, housing environment, and vendor source. Additionally, although the microbiome exhibits a robust response to external stimuli, it rapidly returns to its original steady state after a disturbance, making it difficult to sustain controlled changes in the microbiome over time periods required to detect alterations in bone remodeling, mass or structure. Despite these challenges, an understanding of the mechanisms by which the gut microbiome affects bone has the potential to provide insights into the dissociation between fracture risk and bone mineral density in patients including those with obesity, diabetes or inflammatory bowel disease. In addition, alteration of the gut microbiome has the potential to serve as a biomarker of bone metabolic activity as well as a target for therapies to improve bone structure and quality using pharmaceutical agents or pre- or probiotics.

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“…The major potential effects of the host microbiome on diverse immune responses in mice have been extensively reviewed (Gagliani, Hu, Huber, Elinav, & Flavell, 2014; Hansen, Metzdorff, & Hansen, 2013; Honda & Littman, 2012). While the extent to which host microbiome-related differences might contribute to the divergent results obtained by different groups studying the roles of MCs in individual models of disease or host defense is not clear, this possibility needs to be considered.…”

Section: Using Mast Cell-deficient or Mast Cell-associated Proteasmentioning

confidence: 99%

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

Galli

Tsai

Marichal

et al. 2015

Advances in Immunology

101

110

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The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions seems unassailable, studies employing various mice deficient in mast cells or mast cell-associated proteases have yielded divergent conclusions about the roles of mast cells or their proteases in certain other immunological responses. Such “controversial” results call into question the relative utility of various older versus newer approaches to ascertain the roles of mast cells and mast cell proteases in vivo. This review discusses how both older and more recent mouse models have been used to investigate the functions of mast cells and their proteases in health and disease. We particularly focus on settings in which divergent conclusions about the importance of mast cells and their proteases have been supported by studies that employed different models of mast cell or mast cell protease deficiency. We think that two major conclusions can be drawn from such findings: (1) no matter which models of mast cell or mast cell protease deficiency one employs, the conclusions drawn from the experiments always should take into account the potential limitations of the models (particularly abnormalities affecting cell types other than mast cells) and (2) even when analyzing a biological response using a single model of mast cell or mast cell protease deficiency, details of experimental design are critical in efforts to define those conditions under which important contributions of mast cells or their proteases can be identified.

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Customizing laboratory mice by modifying gut microbiota and host immunity in an early “window of opportunity”

Cited by 27 publications

References 35 publications

Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model

Intestinal microbiota contributes to colonic epithelial changes in simulated microgravity mouse model

Links Between the Microbiome and Bone

Approaches for Analyzing the Roles of Mast Cells and Their Proteases In Vivo

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