The Small Intestine Converts Dietary Fructose Into Glucose And Organic Acids

Mito

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http://www.cell.com/cell-metabolism/fulltext/S1550-4131(17)30729-5

Summary
Excessive consumption of sweets is a risk factor for metabolic syndrome. A major chemical feature of sweets is fructose. Despite strong ties between fructose and disease, the metabolic fate of fructose in mammals remains incompletely understood. Here we use isotope tracing and mass spectrometry to track the fate of glucose and fructose carbons in vivo, finding that dietary fructose is cleared by the small intestine. Clearance requires the fructose-phosphorylating enzyme ketohexokinase. Low doses of fructose are ∼90% cleared by the intestine, with only trace fructose but extensive fructose-derived glucose, lactate, and glycerate found in the portal blood. High doses of fructose (≥1 g/kg) overwhelm intestinal fructose absorption and clearance, resulting in fructose reaching both the liver and colonic microbiota. Intestinal fructose clearance is augmented both by prior exposure to fructose and by feeding. We propose that the small intestine shields the liver from otherwise toxic fructose exposure.

Study Limitations

There is substantial epidemiological and experimental evidence linking fructose consumption to metabolic disease, especially fatty liver. The link between fructose and metabolic disease, however, remains controversial (van Buul et al., 2014; Caliceti et al., 2017; Jegatheesan and De Bandt, 2017). Nothing in the present manuscript addresses whether fructose is more toxic than other sugars or carbohydrates.
We do, however, definitively determine the main site of dietary fructose clearance in mice: the small intestine. Because higher doses of fructose overwhelm the small intestine and spill over to the liver, it is tempting to speculate that fructose metabolism in the small intestine is safe (physiologic), whereas fructose metabolism in the liver drives metabolic disease (pathologic, at least for individuals with consistent access to abundant high-cal- orie foods). We do not, however, test this hypothesis. Indeed, it is possible that intestinal metabolism of fructose drives metabolic disease.
Another important limitation regards the dose response to fructose. In fasted mice, there is a shift toward greater hepatic fructose metabolism between 0.25 g/kg and 1 g/kg fructose gavage. We consider it likely that this basic trend is conserved across many mammals lower doses of fructose are cleared by the intestine and higher doses spill over to liver but our current data are limited to C57BL/6 mice. Moreover, even if the basic trend is conserved, the dose response may vary. Understanding the associated dose-response pattern in humans is of critical importance, but not addressed experimentally here.

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Travis

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Interesting. I had always hated that fructose‐basher (what's his name) since it's really not much different than glucose; glucose is, in fact, converted to fructose before it's cleaved into trioses. It's nice to know that its phosphorylated and delivered lymphatically, so the fructose‐bashers can't really object to sane amounts of fruit. This really is a natural food, and fructose appears no worse than other energy molecules such as glucose and palmitic acid.
 
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fiber makes SCFA
haha wow what a nootropic! TOP 15 BIOHACKS! enter your email for more coupons

fructose makes SCFA
OVERWHELMED CLEARANCE ! ! ! BEWARE OF TOXIC BURDEN enter your email for more coupons
 

Amazoniac

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What a great find! ♡

"small intestine plays a major role in dietary fructose metabolism, converting fructose to glucose and other circulating metabolites. In this manner, the small intestine shields the liver from fructose exposure. High doses of fructose overwhelm this shielding capacity. We hypothesize that the balance between fructose consumption and intestinal fructose clearance capacity determines liver exposure to dietary fructose and thereby fructose toxicity."

"sucrose and free fructose are metabolically equivalent and are consistent with literature indicating that consumption of sugar and of high-fructose corn syrup has similar pathological effects (Tappy and Lê, 2010)."

"While extensive data now link fructose to metabolic diseases, whether fructose is toxic per se, or toxic only in excessive amounts, remains unclear (Niewoehner et al., 1984, Stanhope et al., 2015). Resolving this question is of paramount importance for dietary recommendations. To gain insights into the metabolic consequences of fructose dose, we gavaged unlabeled glucose and 13C-fructose, in a 1:1 ratio, at doses from 0.25 g/kg to 2 g/kg each (Marriott et al., 2009, Macdonald, 2016). Intestinal glucose production from fructose increases linearly up to 0.5 g/kg and then begins to saturate (Figure 5A). In tandem with the saturation of gluconeogenesis, direct passage of fructose into the portal circulation steeply increases (Figure 5A). Accordingly, the ratio of labeled fructose to labeled glucose in portal blood dramatically increases with higher doses of fructose (Figure 5B, note that the y axis is in a log scale). In tandem, while labeled F1P in the jejunum is nearly maximal at 0.5 g/kg fructose, labeled F1P in the liver more than doubles between 0.5 g/kg and 1 g/kg (Figure 5C). Thus, the small intestine nearly completely clears low doses of fructose, but passes higher doses of fructose to the liver."

"In addition to the saturation of intestinal gluconeogenesis around 1 g/kg fructose, we also observed a flattening of the total amount of fructose-derived carbon in the portal vein (Figure 5A). In contrast, for dietary glucose, no such flattening was observed (Figure S4A). A simple explanation is saturation of fructose, but not glucose absorption from the gut lumen (Kiyasu and Chaikoff, 1957). Consistent with this, high fructose doses result in undigested fructose in feces (Figure 5D). This fructose is then utilized by intestinal microorganisms via hexokinase, as demonstrated by time- and dose-dependent increases in the small intestinal and to a much greater extent cecal contents and feces of labeled F6P, but not F1P (Figures 5E and S4B). Furthermore, intestinal bacteria use fructose carbons to generate TCA intermediates, essential amino acids, and short-chain fatty acids (Figures 5F, S4C, and S4D). The production of these species from labeled fructose was not observed in antibiotic-treated mice (Figures S4C–S4F). We did not observe detectable levels of bacteria-produced metabolic products containing fructose carbons in the systemic circulation (Figure S4G). In the case of amino acids, this likely reflects that the bacterial contribution, at least from this single-dose gavage, is negligible compared with the flux from protein in food. In the case of the short-chain fatty acids, it likely reflects nearly complete hepatic clearance, with butyrate readily detected in the portal, but not systemic, circulation (Figure S3A). Collectively, these data show that dietary fructose in excess of intestinal metabolic capacity spills over to liver and the microbiome, where it may cause disease by impacting hepatic function or microbial composition (Di Luccia et al., 2015, Zhang et al., 2017)."

"The above results indicate that intestinal fructose absorption is incomplete at high doses. Studies have shown that in pups, previous fructose exposure enhances fructose absorption and clearance by inducing genes related to fructose metabolism in the small intestine (David et al., 1995, Cui et al., 2004, Patel et al., 2015b). To test if this adaptation occurs also in adults, we fed 10- to 12-week-old mice high doses of glucose and fructose (2 g/kg each) once daily for 5 days and quantified systemic fructose metabolism on days 1, 3, and 5. On day 3, we observed increased direct fructose absorption into the systemic circulation (Figure S5A), enhanced gluconeogenesis from fructose (Figure 6A), and elevated circulating and small intestinal glycerate (Figures S5B and S5C). No significant differences were observed between day 3 and day 5. Thus, a few days of prior exposure are sufficient to enhance fructose absorption and catabolism." "fructose absorption and metabolism is adaptive"

"The liver plays a major role in carbohydrate homeostasis, controlling glucose levels by synthesizing and degrading glycogen and making glucose via gluconeogenesis. In addition, the liver has generally been assumed to be the main site of fructose metabolism (Caliceti et al., 2017, Jegatheesan and De Bandt, 2017). This assumption is consistent with the liver's general metabolic importance, high levels of expression of fructose catabolic enzymes, and sensitivity to fructose, which causes fatty liver disease (Ishimoto et al., 2012, Ishimoto et al., 2013, Lanaspa et al., 2013, Zhang et al., 2017)."

"The extent of passage of unmetabolized fructose through the small intestine to the liver depended on dose. Conversion of doses between mice and humans is not straightforward. Across mammals, total metabolic activity more closely mirrors body surface area than mass. For a typical adult mouse, daily intake is ~12 kcal, versus ~2,400 kcal for an adult human. One sensible way of converting doses of macronutrients is based on caloric intake: a dose of 0.5 g/kg fructose in mouse is ~0.5% of daily calorie intake, or the same as 3 g of fructose in a person (one orange or about 2 ounces of soda). Thus, the doses that we study here are in the range of typical human fructose consumption (Marriott et al., 2009, Macdonald, 2016)."

"How, then, does fructose cause fatty liver? One possibility is that the small intestine (or intestinal microbiota) converts fructose into a hepatotoxic metabolite."

"Another possible mechanism by which fructose may induce liver toxicity is via itself reaching the liver (Kim et al., 2016, Zhang et al., 2017). Fructose may cause liver ATP depletion (as Khk consumes ATP) or lipogenesis (as fructose catabolism bypasses the key regulated step of glycolysis, phosphofructokinase, and thereby provides an uncontrolled source of trioses). While we find that low doses of fructose are ~90% cleared in the small intestine, higher doses pass substantially (>30%) to the liver. This reflects saturation of small intestine fructose clearance. Based on these findings, we propose that the small intestine shields the liver from fructose and that excessive doses of fructose overwhelm the small intestine, spilling over to the liver where they cause toxicity (Figure 7)."

"A key difference between the health effects of fiber-rich fruits (and perhaps even solid sweets like cake) and juices/sodas is their rate of intestinal fructose release. Based on our findings, although we did not directly modulate fructose delivery rate, it is likely that the appearance rate of free fructose in the small intestine plays a critical role in dictating its metabolic fate: like the lower doses in our experiments, a slower rate of fructose appearance will result in more complete intestinal fructose clearance, whereas higher doses and faster rates result in fructose overflow to the liver."

"While much work remains to identify the sites and mechanisms of fructose toxicity, our fundamental findings that physiological fructose doses are cleared in small intestine, toxic doses spill over to the liver, and such spillover is decreased in the fed state are consistent with old-fashioned wisdom about sweets: eat sweets in moderation after [?] meals."
 

X3CyO

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So the gas issue isnt something you can get around it seems if following a high sugar diet.
 

Mito

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I thought fructose was a problem because we can only absorb a limited amount per day/per sitting.

I'm sure it depends on the person, but this study concluded that the absorption limit is around 1g/kg.
 
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