Increased butyrate priming in the gut stalls microbiome associated-gastrointestinal inflammation and hepatic metabolic reprogramming in a mouse model of Gulf War Illness

Ratanesh Kumar Seth, Diana Kimono, Firas Alhasson, Sutapa Sarkar, Muayad Albadrani, Stephen K. Lasley, Ronnie Horner, Patricia Janulewicz, Mitzi Nagarkatti, Prakash Nagarkatti, Kimberly Sullivan, Saurabh Chatterjee

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)64-77
Number of pages14
JournalToxicology and Applied Pharmacology
Volume350
DOIs
StatePublished - Jul 1 2018
Externally publishedYes

Keywords

  • Claudin-2
  • Cytokines
  • Gut dysbiosis
  • Permethrin
  • Pyridostigmine bromide
  • TLR4

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

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