TY - JOUR
T1 - Increased butyrate priming in the gut stalls microbiome associated-gastrointestinal inflammation and hepatic metabolic reprogramming in a mouse model of Gulf War Illness
AU - Seth, Ratanesh Kumar
AU - Kimono, Diana
AU - Alhasson, Firas
AU - Sarkar, Sutapa
AU - Albadrani, Muayad
AU - Lasley, Stephen K.
AU - Horner, Ronnie
AU - Janulewicz, Patricia
AU - Nagarkatti, Mitzi
AU - Nagarkatti, Prakash
AU - Sullivan, Kimberly
AU - Chatterjee, Saurabh
N1 - Funding Information:
The authors gratefully acknowledge the technical services of Benny Davidson at the IRF, University of South Carolina School of Medicine and AML Labs (Baltimore MD), and University of Georgia college of veterinary medicine for support in clinical blood chemistry test. We also thank the Instrumentation resource facility (IRF) at the University of South Carolina for equipment usage and consulting services.
Funding Information:
This work was supported by a pilot funding received from the Gulf War Illness Research Consortium to Saurabh Chatterjee (Parent DOD grant # W81XWH-13-2-0072 , PI: Dr. Kimberly Sullivan) and P01AT003961 (Project 4) to Saurabh Chatterjee, P01AT003961, P20GM103641, R01AT006888, R01ES019313, R01MH094755 and VA Merit Award BX001357 to Mitzi Nagarkatti and Prakash S. Nagarkatti.
Publisher Copyright:
© 2018
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Most of the associated pathologies in Gulf War Illness (GWI) have been ascribed to chemical and pharmaceutical exposures during the war. Since an increased number of veterans complain of gastrointestinal (GI), neuroinflammatory and metabolic complications as they age and there are limited options for a cure, the present study was focused to assess the role of butyrate, a short chain fatty acid for attenuating GWI-associated GI and metabolic complications. Results in a GWI-mouse model of permethrin and pyridostigmine bromide (PB) exposure showed that oral butyrate restored gut homeostasis and increased GPR109A receptor copies in the small intestine (SI). Claudin-2, a protein shown to be upregulated in conditions of leaky gut was significantly decreased following butyrate administration. Butyrate decreased TLR4 and TLR5 expressions in the liver concomitant to a decrease in TLR4 activation. GW-chemical exposure showed no clinical signs of liver disease but a significant alteration of metabolic markers such as SREBP1c, PPAR-α, and PFK was evident. Liver markers for lipogenesis and carbohydrate metabolism that were significantly upregulated following GW chemical exposure were attenuated by butyrate priming in vivo and in human primary hepatocytes. Further, Glucose transporter Glut-4 that was shown to be elevated following liver complications were significantly decreased in these mice after butyrate administration. Finally, use of TLR4 KO mice completely attenuated the liver metabolic changes suggesting the central role of these receptors in the GWI pathology. In conclusion, we report a butyrate specific mechanistic approach to identify and treat increased metabolic abnormalities in GWI veterans with systemic inflammation, chronic fatigue, GI disturbances, metabolic complications and weight gain.
AB - Most of the associated pathologies in Gulf War Illness (GWI) have been ascribed to chemical and pharmaceutical exposures during the war. Since an increased number of veterans complain of gastrointestinal (GI), neuroinflammatory and metabolic complications as they age and there are limited options for a cure, the present study was focused to assess the role of butyrate, a short chain fatty acid for attenuating GWI-associated GI and metabolic complications. Results in a GWI-mouse model of permethrin and pyridostigmine bromide (PB) exposure showed that oral butyrate restored gut homeostasis and increased GPR109A receptor copies in the small intestine (SI). Claudin-2, a protein shown to be upregulated in conditions of leaky gut was significantly decreased following butyrate administration. Butyrate decreased TLR4 and TLR5 expressions in the liver concomitant to a decrease in TLR4 activation. GW-chemical exposure showed no clinical signs of liver disease but a significant alteration of metabolic markers such as SREBP1c, PPAR-α, and PFK was evident. Liver markers for lipogenesis and carbohydrate metabolism that were significantly upregulated following GW chemical exposure were attenuated by butyrate priming in vivo and in human primary hepatocytes. Further, Glucose transporter Glut-4 that was shown to be elevated following liver complications were significantly decreased in these mice after butyrate administration. Finally, use of TLR4 KO mice completely attenuated the liver metabolic changes suggesting the central role of these receptors in the GWI pathology. In conclusion, we report a butyrate specific mechanistic approach to identify and treat increased metabolic abnormalities in GWI veterans with systemic inflammation, chronic fatigue, GI disturbances, metabolic complications and weight gain.
KW - Claudin-2
KW - Cytokines
KW - Gut dysbiosis
KW - Permethrin
KW - Pyridostigmine bromide
KW - TLR4
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UR - http://www.scopus.com/inward/citedby.url?scp=85047083306&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2018.05.006
DO - 10.1016/j.taap.2018.05.006
M3 - Article
C2 - 29751049
AN - SCOPUS:85047083306
SN - 0041-008X
VL - 350
SP - 64
EP - 77
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
ER -