Introduction
Dietary fiber influences the intestinal mucosa and improves intestinal function. The beneficial role of fiber is thought to be mediated by short chain fatty acids (SCFAs) - the main fermentation products of dietary fiber. Glucagon-like peptide-1 (GLP-1) is known to protect against intestinal injury and mice fed a fiber-free (FF) diet have shown loss of intestinal mass and decreased tissue levels of GLP-1. Here, we aimed to 1) investigate how a FF diet might affect the colonic luminal content of SCFAs 2) investigate ability of SCFAs to drive colonic GLP-1 secretion and 3) assess the impact of a low fiber diet on the colonic vulnerability to intestinal injury. We also aimed to investigate the involvement of the free fatty acid receptors 2 (FFAR2) and 3 (FFAR3) and the GLP-1 receptor (GLP-1R) in a model of intestinal injury.
Aims & Methods
Female C57BL/6JRj mice were fed a FF diet (Altromin 1013), or standard chow diet (Altromin C1310) for 21 days and the SCFA concentrations in colonic contents were analyzed by liquid chromatography–mass spectrometry. A SCFA mix (100 mM) was applied luminally in our isolated perfused colon model and GLP-1 levels were measured in the venous effluent. Female C57BL/6JRj mice fed a FF diet or chow were exposed to 3% dextran sulfate sodium (DSS) in drinking water for up to 7 days to induce colitis. Mice were killed at day 13. This was repeated in FFAR2/3 knock out (KO) mice and in GLP-1R KO mice. Wild type (WT) littermates were used as controls. End points were body weight (BW) loss, disease activity index (DAI), colon weight, colon length and histological severity score.
Results
21 days of FF feeding decreased the concentrations of SCFA in colon content significantly. Overall, the total measured SCFAs were decreased by more than 50% in the FF fed group (p<0.05) with specific decreases in acetate (p<0.05), propionate (p<0.05), and butyrate (p<0.001).
SCFAs delivered to the isolated perfused colon increased GLP-1 secretion by 40% (p<0.01). In the DSS model, the removal of dietary fiber increased the severity of colitis and delayed the recovery. At day 4 FF fed mice had bloody diarrhea and DSS treatment was discontinued. From day 4 to the end of the experiment, FF fed mice had a significantly larger BW loss than chow fed mice (day 7: 25% vs 10%, p<0.001). At day 13 all chow fed mice had recovered their BW, but FF fed still showed a significant BW loss of 15% of baseline BW. DAI was significantly increased in the FF fed mice. Only 50% of the FF fed mice survived to day 13 whereas all mice fed chow survived. At day 13 colonic weight was increased (p<0.001), colonic length decreased (p<0.05) and histological severity score increased (p<0.001) in the FF fed mice. GLP-1 KO mice exposed to DSS had a significant larger BW loss from day 10 to day 13 day compared to WT (p<0.05). WT mice recovered their BW to normal at the end of experiment, whereas GLP-1R KO mice had a weight loss of 8% of baseline BW. No other parameters in the GLP-1R KO mice differed from WT mice. Colitis severity was independent of FFAR2 and FFAR3 signaling, FFAR2/3 KO mice were comparable to WT littermates in all parameters.
Conclusion
A low intake of dietary fiber reduced the colonic SCFA and reduced the resilience to colitis. Luminal SCFA were able to increase GLP-1 secretion in the isolated perfused colon and GLP-1 receptor signaling showed importance in the maintenance of BW in the diseased mouse. However, the pathway from a low fiber diet to severe colitis seemed to be independent of FFAR2/3 signaling.
References
A low intake of dietary fiber reduced the colonic SCFA and reduced the resilience to colitis. Luminal SCFA were able to increase GLP-1 secretion in the isolated perfused colon and GLP-1 receptor signaling showed importance in the maintenance of BW in the diseased mouse. However, the pathway from a low fiber diet to severe colitis seemed to be independent of FFAR2/3 signaling.
Disclosure
MY is affiliated with AbbVie A/S, however this work was performed prior to his employment and is not related to AbbVie A/S. MY is still affiliated with UCPH