FODMAP diet modulates visceral nociception by lipopolysaccharide-mediated intestinal inflammation and barrier dysfunction

J Clin Invest. 2018 Jan 2;128(1):267-280. doi: 10.1172/JCI92390. Epub 2017 Nov 27.


Foods high in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) exacerbate symptoms of irritable bowel syndrome (IBS); however, their mechanism of action is unknown. We hypothesized that a high-FODMAP (HFM) diet increases visceral nociception by inducing dysbiosis and that the FODMAP-altered gut microbial community leads to intestinal pathology. We fed rats an HFM and showed that HFM increases rat fecal Gram-negative bacteria, elevates lipopolysaccharides (LPS), and induces intestinal pathology, as indicated by inflammation, barrier dysfunction, and visceral hypersensitivity (VH). These manifestations were prevented by antibiotics and reversed by low-FODMAP (LFM) diet. Additionally, intracolonic administration of LPS or fecal supernatant (FS) from HFM-fed rats caused intestinal barrier dysfunction and VH, which were blocked by the LPS antagonist LPS-RS or by TLR4 knockdown. Fecal LPS was higher in IBS patients than in healthy subjects (HS), and IBS patients on a 4-week LFM diet had improved IBS symptoms and reduced fecal LPS levels. Intracolonic administration of FS from IBS patients, but not FS from HS or LFM-treated IBS patients, induced VH in rats, which was ameliorated by LPS-RS. Our findings indicate that HFM-associated gut dysbiosis and elevated fecal LPS levels induce intestinal pathology, thereby modulating visceral nociception and IBS symptomatology, and might provide an explanation for the success of LFM diet in IBS patients.

Keywords: Cytokines; Gastroenterology; Pain; Translation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dietary Carbohydrates / adverse effects*
  • Dietary Carbohydrates / pharmacology
  • Dysbiosis* / chemically induced
  • Dysbiosis* / genetics
  • Dysbiosis* / metabolism
  • Dysbiosis* / microbiology
  • Gastrointestinal Microbiome*
  • Gene Knockdown Techniques
  • Intestines / microbiology*
  • Irritable Bowel Syndrome* / chemically induced
  • Irritable Bowel Syndrome* / genetics
  • Irritable Bowel Syndrome* / metabolism
  • Irritable Bowel Syndrome* / microbiology
  • Lipopolysaccharides / toxicity*
  • Male
  • Nociception*
  • Rats
  • Rats, Wistar
  • Toll-Like Receptor 4 / genetics
  • Toll-Like Receptor 4 / metabolism


  • Dietary Carbohydrates
  • Lipopolysaccharides
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4