Iron deficiency anaemia (IDA) is a worldwide healthcare problem affecting approximately 25% of the global population. The most common IDA treatment is oral iron supplementation, which has been associated with gastrointestinal (GI) side effects such as constipation and bloating. These can result in treatment non-adherence and the persistence of IDA. Intravenous iron does not cause GI side effects, which may be due to the lack of exposure to the intestinal lumen. Luminal iron can cause changes to the gut microbiota, aiding the promotion of pathogenic species and decreasing beneficial protective species. Iron is vital for methanogenic archaea, which rely on iron for growth and metabolism. Increased intestinal methane has been associated with slowing of intestinal transit, constipation, and bloating. Here we explore the literature to understand a potential link between iron and methanogenesis as a novel way to understand the mechanism of oral iron supplementation induced GI side effects.

Objective: This clinical trial investigated the effects of 3-week ingestion of a proprietary gut health supplement containing the bioactives N-trans caffeoyltyramine (NCT) and N-trans feruloyltyramine (NFT), on intestinal barrier function and on severity of GI symptoms in individuals with diarrhea predominant-irritable bowel syndrome (IBS-D). Methods: Participants included 29 males and females diagnosed with IBS-D in accordance with the ROME IV criteria, having lipopolysaccharide (LPS) levels >0.21 ng/ml, and experiencing symptoms related to IBS-D. A randomized, double-blind, placebo-controlled, parallel design was used with 3-week supplementation period with a dietary supplement providing 120mg of NCT and NFT. The primary outcome measure was Lactulose/Mannitol (L/M) ratio, a measure of intestinal permeability. Secondary endpoints included changes in other biomarkers of intestinal permeability (serum LPS, LBP, sCD14, Zonulin, LCN2) and subjective changes in stool frequency and consistency using the Bristol Stool Chart and bloating and abdominal pain using the IBS Symptom Severity Scale (IBS-SSS). Results: The NCT/NFT supplementation group showed significant improvements in L/M ratio (p=0.048), lipopolysaccharide-binding protein (LBP) levels (p=0.018), and the IBS-SSS abdominal distention scores (p=0.044) compared to the placebo group, demonstrating improvement in gut barrier integrity and in GI comfort. No between-group differences were found for other endpoints. No adverse events were reported and study compliance was high. Conclusions: NCT/NFT intake for 3 weeks led to a significant improvement in L/M ratio, LBP and IBS-SSS abdominal distention scores, and a trend for a decrease in abdominal pain scores, thereby demonstrating marked improvement in both objective and subjective outcomes supporting gut barrier function. This propriety gut health supplement shows promise for restoring a healthy gut barrier.