Oral Presentation Australian and New Zealand Obesity Society Annual Scientific Conference 2026

Butyrate signalling epigenetically reprograms intestinal proglucagon through gut microbial modulation (144940)

Madilyn Coles 1 , Nhan Ho Trong Pham 1 , Alyssa Kocoski 1 , Hrishikesh P Hardikar 1 , Ehsan Alvandi 1 , Han Ngoc Bao Luong 1 , Ingrid M Wagnon 2 , Stephen M Kwong 3 , Rie Joensson 2 , Margaret J Morris 4 , Slade O Jensen 3 , Karen A Krogfelt 2 , Louise T Dalgaard 2 , Mugdha V Joglekar 1 , Anand A Hardikar 1
  1. Diabetes and Islet Biology Group, School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
  2. Department of Science and the Environment, Roskilde University Copenhagen, Roskilde, Denmark
  3. Microbiology and Wound Research Group, Ingham Institute for Applied Medical Research, Sydney, NSW, Australia
  4. School of Pharmacology, University of New South Wales, Sydney, NSW, Australia

Gut dysbiosis, including reduced abundance of short-chain fatty acid (SCFA; e.g., butyrate)-producing bacteria, is linked with obesity and metabolic dysfunction. Consistent with this, our recent meta-analysis highlighted that increasing SCFA concentrations in the gut (and/or circulation) improves insulin sensitivity (1). Here, we investigated whether sodium butyrate (NaB) ameliorates diet-induced metabolic dysfunction through gut microbiome modulation and epigenetic regulation of intestinal GLP1 (proglucagon/GCG) gene expression, and whether diet-induced fluctuations in microbial butyrate availability during weight-cycling alters these effects.

Anaerobically maintained human faecal cultures with 10mM NaB for 20-h resulted in reduced Simpson diversity and altered relative abundances of Romboutsia, Eggerthellaceae, Gordonibacter, Lachnoclostridium, and Paraclostridium. Next, we found that 4-day 10mM NaB exposure to human colonic epithelial cells resulted in increased GCG and reduced HDAC1, HDAC6, and HDAC7 transcript expression. Concurrently, we found increased histone H3+H4 acetylation and reduced H3K9 tri-methylation at the GCG promoter region. Interestingly, in cells exposed to oscillating NaB, as may occur during weight-cycling, the amplitude of GCG transcriptional response progressively declined, potentially indicating a shift towards a less active chromatin state. Furthermore, oscillating (high)-fat-diet (HFD)/chow and cafeteria (CAF)/chow diets resulted in equally decreased faecal SCFA and adverse metabolic outcomes compared to continuous HFD/CAF control mice.

In 60% HFD-fed mice, 4-day NaB infusion (0.11µL/min) into the proximal colon reversed gut dysbiosis and improved glucose clearance. Furthermore, following a metabolic dysfunction induction period (4-week CAF diet feeding, better reflective of Western diet variety and palatability compared to HFD (2)), 7-week 100mM NaB drinking water supplementation attenuated both CAF-induced fasting hyperglycaemia and percentage weight gain in male mice. Endpoint (23-week) glucose and insulin tolerance, serum GLP-1, behavioural outcomes, faecal microbial profile and colonic GCG promoter chromatin analyses will be presented.

These findings support a model in which butyrate reverses metabolic disease through complementary microbial and epigenetic mechanisms, with fluctuating butyrate availability influencing intestinal GCG responsiveness and downstream metabolic signalling.

  1. Pham NHT, Joglekar MV, Wong WKM, Nassif NT, Simpson AM, Hardikar AA. Short-chain fatty acids and insulin sensitivity: a systematic review and meta-analysis. Nutr Rev. 2024;82(2):193–209.
  2. Leigh SJ, Kendig MD, Morris MJ. Palatable Western-style cafeteria diet as a reliable method for modeling diet-induced obesity in rodents. J Vis Exp. 2019;(153).