Abstract
A causal correlation between the metabolic disorders associated with sugar intake and disruption of the gastrointestinal (GI) homeostasis has been suggested, but the underlying mechanisms remain unclear. To unravel these mechanisms, we investigated the effect of physiological amounts of fructose and glucose on barrier functions and inflammatory status in various regions of the GI tract and on the cecal microbiota composition. C57BL/6 mice were fed chow diet and given 15% glucose or 15% fructose in drinking water for 9 weeks. We monitored caloric intake, body weight, glucose intolerance, and adiposity. The intestinal paracellular permeability, cytokine, and tight junction protein expression were assessed in the jejunum, cecum, and colon. In the cecum, the microbiota composition was determined. Glucose-fed mice developed a marked increase in total adiposity, glucose intolerance, and paracellular permeability in the jejunum and cecum while fructose absorption did not affect any of these parameters. Fructose-fed mice displayed increased circulation levels of IL6. In the cecum, both glucose and fructose intake were associated with an increase in Il13, Ifnγ, and Tnfα mRNA and MLCK protein levels. To clarify the relationships between monosaccharides and barrier function, we measured the permeability of Caco-2 cell monolayers in response to IFNγ+TNFα in the presence of glucose or fructose. In vitro, IFNγ+TNFα-induced intestinal permeability increase was less pronounced in response to fructose than glucose. Mice treated with glucose showed an enrichment of Lachnospiracae and Desulfovibrionaceae while the fructose increased relative abundance of Lactobacillaceae. Correlations between pro-inflammatory cytokine gene expression and bacterial abundance highlighted the potential role of members of Desulfovibrio and Lachnospiraceae NK4A136 group genera in the inflammation observed in response to glucose intake. The increase in intestinal inflammation and circulating levels of IL6 in response to fructose was observed in the absence of intestinal permeability modification, suggesting that the intestinal permeability alteration does not precede the onset of metabolic outcome (low-grade inflammation, hyperglycemia) associated with chronic fructose consumption. The data also highlight the deleterious effects of glucose on gut barrier function along the GI tract and suggest that Desulfovibrionaceae and Lachnospiraceae play a key role in the onset of GI inflammation in response to glucose.
Highlights
Increase in consumption of sugar has been tightly linked to the surge in metabolic diseases such as obesity, nonalcoholic fatty liver disease, hypertriglyceridemia, type 2 diabetes, and metabolic syndrome [1,2,3,4,5,6]
Nine weeks of chronic intake of fructose was associated with a significant increase in plasmatic levels of interleukin 6 (IL6) when compared to the control group (Figure 1E) while the plasmatic levels of tumor necrosis factor a (TNFa) and interferon gamma (IFNg) remained unchanged among the three groups (Figures 1F, G)
We provide experimental evidence that chronic intake of enriched fructose beverage did not alter the paracellular permeability in the jejunum, cecum, and colon and this despite a clear increase in systemic and cecal inflammation in these mice
Summary
Increase in consumption of sugar (mainly sucrose and high fructose corn syrup-containing soft drinks) has been tightly linked to the surge in metabolic diseases such as obesity, nonalcoholic fatty liver disease, hypertriglyceridemia, type 2 diabetes, and metabolic syndrome [1,2,3,4,5,6]. There is rising evidence that in these sweeteners, fructose and, in a lesser extent, glucose favor the development of metabolic diseases associated with sugar intake [7,8,9,10]. Obesity-associated chronic low-grade inflammation characterized by high levels of plasmatic inflammatory markers [C-reactive protein, interleukin 6 (IL6) or tumor necrosis factor a (TNFa)] largely contributes to the development of the obesityrelated chronic metabolic diseases [11,12,13]. To maintain the intestinal barrier function, the preservation of the paracellular permeability is essential. The intestinal paracellular permeability depends on TJ protein expression levels, their phosphorylation status, and their subcellular organization [17,18,19]. While the events involved in the loss of the barrier function are not fully understood, cytokines such as IL1b, IL13, interferon gamma (IFNg), and TNFa have been shown to remodel the TJ architecture and
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