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Title: Effects of ingested nanocellulose on intestinal microbiota and homeostasis in Wistar Han rats

Abstract

Micron scale crystalline and fibrillar cellulose materials are “generally regarded as safe” (GRAS) as binders and thickeners in food products. Yet, partly due to a lack of relevant toxicological data, nanocellulose (NC) materials, which have unique properties that can be exploited to improve food quality and safety, have yet to receive FDA approval as food ingredients. Results of in vitro and in vivo toxicological studies of ingested NC, detailed in a recent companion report, revealed minimal acute in vitro cytotoxicity, and no toxicity in a subacute rat gavage model, suggesting that NC materials are non-hazardous. However, ingested materials may also modulate gut microbial populations, or alter aspects of intestinal function not evaluated in standard totoxicity testing, which could have important health implications. Here, we report the results of studies of the effects of ingested cellulose nanofibrils (CNF) on the fecal microbiome and metabolome, intestinal (ileal) epithelial cell mRNA expression of cell junction genes, and ileal cytokine production. Feces, plasma, and ileum samples were collected from Wistar Han rats before and after five weeks of biweekly gavages of water or cream, with or without 1% w/w CNF. Analysis of fecal microbial populations revealed that CNF caused changes in both genus andmore » species diversity, with specific effects on species that produce short chain fatty acids, and that have been associated with increased IgA production and elevation of insulin levels. Fecal metabolomic analysis revealed relatively few effects of CNF, with significant changes in the levels of only ten metabolites out of 366 measured. Exposure to CNF also caused differential regulation of mRNA expression of several genes involved in epithelial cell junctions, and increased production of cytokines that both promote and inhibit proliferation of CD8 T cells. These perturbations in intestinal homeostasis contrast somewhat with the absence of in vitro and in vivo toxicity observed previously but would appear to represent minor effects. Additionally, the gut microbiome is highly sensitive to ingested substances, and such disturbances of the intestinal microbial ecosystem do not necessarily represent or predict meaningful pathology. Further studies, including chronic feeding studies, are needed to assess the real health implications, if any, of these changes.« less

Authors:
 [1];  [2];  [2];  [1];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [3];  [2];  [2]
  1. US Food & Drug Administration, Jefferson, AR (United States)
  2. Harvard T. H. Chan School of Public Health, Boston, MA (United States)
  3. Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1607654
Report Number(s):
PNNL-SA-149247
Journal ID: ISSN 2452-0748
Grant/Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
NanoImpact
Additional Journal Information:
Journal Volume: 18; Journal Issue: C; Journal ID: ISSN 2452-0748
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Nanocellulose; Microbiome; Metabolome; Ingested nanomaterial; In vivo; Rat; Intestinal permeability; Risk assessment

Citation Formats

Khare, Sangeeta, DeLoid, Glen M., Molina, Ramon M., Gokulan, Kuppan, Couvillion, Sneha P., Bloodsworth, Kent J., Eder, Elizabeth K., Wong, Allison R., Hoyt, David W., Bramer, Lisa M., Metz, Thomas O., Thrall, Brian D., Brain, Joseph D., and Demokritou, Philip. Effects of ingested nanocellulose on intestinal microbiota and homeostasis in Wistar Han rats. United States: N. p., 2020. Web. doi:10.1016/j.impact.2020.100216.
Khare, Sangeeta, DeLoid, Glen M., Molina, Ramon M., Gokulan, Kuppan, Couvillion, Sneha P., Bloodsworth, Kent J., Eder, Elizabeth K., Wong, Allison R., Hoyt, David W., Bramer, Lisa M., Metz, Thomas O., Thrall, Brian D., Brain, Joseph D., & Demokritou, Philip. Effects of ingested nanocellulose on intestinal microbiota and homeostasis in Wistar Han rats. United States. https://doi.org/10.1016/j.impact.2020.100216
Khare, Sangeeta, DeLoid, Glen M., Molina, Ramon M., Gokulan, Kuppan, Couvillion, Sneha P., Bloodsworth, Kent J., Eder, Elizabeth K., Wong, Allison R., Hoyt, David W., Bramer, Lisa M., Metz, Thomas O., Thrall, Brian D., Brain, Joseph D., and Demokritou, Philip. Fri . "Effects of ingested nanocellulose on intestinal microbiota and homeostasis in Wistar Han rats". United States. https://doi.org/10.1016/j.impact.2020.100216.
@article{osti_1607654,
title = {Effects of ingested nanocellulose on intestinal microbiota and homeostasis in Wistar Han rats},
author = {Khare, Sangeeta and DeLoid, Glen M. and Molina, Ramon M. and Gokulan, Kuppan and Couvillion, Sneha P. and Bloodsworth, Kent J. and Eder, Elizabeth K. and Wong, Allison R. and Hoyt, David W. and Bramer, Lisa M. and Metz, Thomas O. and Thrall, Brian D. and Brain, Joseph D. and Demokritou, Philip},
abstractNote = {Micron scale crystalline and fibrillar cellulose materials are “generally regarded as safe” (GRAS) as binders and thickeners in food products. Yet, partly due to a lack of relevant toxicological data, nanocellulose (NC) materials, which have unique properties that can be exploited to improve food quality and safety, have yet to receive FDA approval as food ingredients. Results of in vitro and in vivo toxicological studies of ingested NC, detailed in a recent companion report, revealed minimal acute in vitro cytotoxicity, and no toxicity in a subacute rat gavage model, suggesting that NC materials are non-hazardous. However, ingested materials may also modulate gut microbial populations, or alter aspects of intestinal function not evaluated in standard totoxicity testing, which could have important health implications. Here, we report the results of studies of the effects of ingested cellulose nanofibrils (CNF) on the fecal microbiome and metabolome, intestinal (ileal) epithelial cell mRNA expression of cell junction genes, and ileal cytokine production. Feces, plasma, and ileum samples were collected from Wistar Han rats before and after five weeks of biweekly gavages of water or cream, with or without 1% w/w CNF. Analysis of fecal microbial populations revealed that CNF caused changes in both genus and species diversity, with specific effects on species that produce short chain fatty acids, and that have been associated with increased IgA production and elevation of insulin levels. Fecal metabolomic analysis revealed relatively few effects of CNF, with significant changes in the levels of only ten metabolites out of 366 measured. Exposure to CNF also caused differential regulation of mRNA expression of several genes involved in epithelial cell junctions, and increased production of cytokines that both promote and inhibit proliferation of CD8 T cells. These perturbations in intestinal homeostasis contrast somewhat with the absence of in vitro and in vivo toxicity observed previously but would appear to represent minor effects. Additionally, the gut microbiome is highly sensitive to ingested substances, and such disturbances of the intestinal microbial ecosystem do not necessarily represent or predict meaningful pathology. Further studies, including chronic feeding studies, are needed to assess the real health implications, if any, of these changes.},
doi = {10.1016/j.impact.2020.100216},
url = {https://www.osti.gov/biblio/1607654}, journal = {NanoImpact},
issn = {2452-0748},
number = C,
volume = 18,
place = {United States},
year = {2020},
month = {2}
}

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