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. 2008 Mar 27:9:144.
doi: 10.1186/1471-2164-9-144.

Impaired barrier function by dietary fructo-oligosaccharides (FOS) in rats is accompanied by increased colonic mitochondrial gene expression

Wendy Rodenburg  1 , Jaap Keijer, Evelien Kramer, Carolien Vink, Roelof van der Meer, Ingeborg M J Bovee-Oudenhoven
Affiliations

Impaired barrier function by dietary fructo-oligosaccharides (FOS) in rats is accompanied by increased colonic mitochondrial gene expression

Wendy Rodenburg et al. BMC Genomics. .

Abstract

Background: Dietary non-digestible carbohydrates stimulate the gut microflora and are therefore presumed to improve host resistance to intestinal infections. However, several strictly controlled rat infection studies showed that non-digestible fructo-oligosaccharides (FOS) increase, rather than decrease, translocation of Salmonella towards extra-intestinal sites. In addition, it was shown that FOS increases intestinal permeability already before infection. The mechanism responsible for this adverse effect of FOS is unclear. Possible explanations are altered mucosal integrity due to changes in tight junctions or changes in expression of defense molecules such as antimicrobials and mucins. To examine the mechanisms underlying weakening of the intestinal barrier by FOS, a controlled dietary intervention study was performed. Two groups of 12 rats were adapted to a diet with or without FOS. mRNA was collected from colonic mucosa and changes in gene expression were assessed for each individual rat using Agilent rat whole genome microarrays.

Results: Among the 997 FOS induced genes we observed less mucosal integrity related genes than expected with the clear permeability changes. FOS did not induce changes in tight junction genes and only 8 genes related to mucosal defense were induced by FOS. These small effects are unlikely the cause for the clear increase in intestinal permeability that is observed. FOS significantly increased expression of 177 mitochondria-related genes. More specifically, induced expression of genes involved in all five OXPHOS complexes and the TCA cycle was observed. These results indicate that dietary FOS influences intestinal mucosal energy metabolism. Furthermore, increased expression of 113 genes related to protein turnover, including proteasome genes, ribosomal genes and protein maturation related genes, was seen. FOS upregulated expression of the peptide hormone proglucagon gene, in agreement with previous studies, as well as three other peptide hormone genes; peptide YY, pancreatic polypeptide and cholecystokinin.

Conclusion: We conclude that altered energy metabolism may underly colonic barrier function disruption due to FOS feeding in rats.

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Figures

Figure 1
Figure 1
Average urinary CrEDTA excretion in the control and FOS group. Daily dietary CrEDTA intake was 54 μmol. Urines were collected at days 14 and 15. Results are expressed as mean ± SEM (n = 6 per diet group). The FOS group significantly differed from the control group (***p
Figure 2
Figure 2
Classification of the genes affected by FOS into biological processes. Analyzed by Metacore, GSEA and data mining.
Figure 3
Figure 3
Mucosal scrapings (pool of n = 12 per group) were examined for complex IV subunit COXII protein levels. The experiment was performed three times with independent, pools, showing a 1.5; 1.7 and 2.7 fold difference in COXII protein expression relative to Actin, respectively. The 1.5 fold increase is shown.
Figure 4
Figure 4
Relative expression of Proglucagon mRNA (gray bar) and GLP-1 protein (black bar) in colonic mucosa of a random selection of control fed and FOS fed rats. mRNA and protein levels were normalized to Actin levels. Expression is shown as means ± SEM (n = 7). **p
Figure 5
Figure 5
Proposed mechanism of dietary FOS induced intestinal permeability. 1 High levels of FOS fermentation products increase intestinal permeability in vivo [5, 40, 41]. 2 Excess SCFAs cause intracellular acidification of epithelial cells. When protonated-SCFA diffuse from the gut lumen into epithelial cells [47, 84]. The SCFA cause intracellular acidification and induce proton pump activity (NHE and NBC transporters) which may lead to ATP depletion [43, 45]. 3 Reduced ATP levels, by increased energy demand, chronic mitochondrial uncoupling or any other cause of disturbed energy metabolism, are compensated by increased mitochondrial gene expression and mitochondrial biogenesis [27, 85]. 4 Disturbed energy metabolism leads to increased permeability. In agreement: ATP-depletion in epithelial cell lines causes paracellular hyperpermeability [28-30] and uncoupling of intestinal mitochondria leads to increased bacterial translocation, immune cell infiltration and ulceration in rats [31, 32]. Calcium supplementation of a FOS diet counteracts FOS induced intestinal permeability. Calcium prevents acidification of intestinal contents during fermentation and thus formation of protonated-SCFA.
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