The multiple beneficial effects on human health of the short-chain fatty acid butyrate, synthesized from non-absorbed carbohydrate by colonic microbiota, are well documented. At the intestinal level, butyrate plays a regulatory role on the transepithelial fluid transport, ameliorates mucosal inflammation and oxidative status, reinforces the epithelial defense barrier, and modulates visceral sensitivity and intestinal motility. In addition, a growing number of studies have stressed the role of butyrate in the prevention and inhibition of colorectal cancer. At the extraintestinal level, butyrate exerts potentially useful effects on many conditions, including hemoglobinopathies, genetic metabolic diseases, hypercholesterolemia, insulin resistance, and ischemic stroke. The mechanisms of action of butyrate are different; many of these are related to its potent regulatory effects on gene expression. These data suggest a wide spectrum of positive effects exerted by butyrate, with a high potential for a therapeutic use in human medicine.
Severe pain remains a major area of unmet medical need. Here we report that agonists of the nuclear receptor PPAR-␣ (peroxisome proliferator-activated receptor-␣) suppress pain behaviors induced in mice by chemical tissue injury, nerve damage, or inflammation. The PPAR-␣ agonists GW7647 [2-(4-(2-(1-cyclohexanebutyl)-3-cyclohexylureido)ethyl)phenylthio)-2-methylpropionic acid], Wy-14643 [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid], and palmitoylethanolamide (PEA) reduced nocifensive behaviors elicited in mice by intraplantar (i.pl.) injection of formalin or i.p. injection of magnesium sulfate. These effects were absent in PPAR-␣-null mice yet occurred within minutes of agonist administration in wild-type mice, suggesting that they were mediated through a transcriptionindependent mechanism. Consistent with this hypothesis, blockade of calcium-operated IK ca (K Ca 3.1) and BK ca (K Ca 1.1) potassium channels prevented the effects of GW7647 and PEA in the formalin test. Three observations suggest that PPAR-␣ agonists may inhibit nocifensive responses by acting on peripheral PPAR-␣. (i) PEA reduced formalin-induced pain at i.pl. doses that produced no increase in systemic PEA levels; (ii) PPAR-␣ was expressed in dorsal root ganglia neurons of wildtype but not PPAR-␣-null mice; and (ii) GW7647 and PEA prevented formalin-induced firing of spinal cord nociceptive neurons in rats. In addition to modulating nociception, GW7647 and PEA reduced hyperalgesic responses in the chronic constriction injury model of neuropathic pain; these effects were also contingent on PPAR-␣ expression and were observed following either acute or subchronic PPAR-␣ agonist administration. Finally, acute administration of GW7647 and PEA reduced hyperalgesic responses in the complete Freund's adjuvant and carrageenan models of inflammatory pain. Our results suggest that PPAR-␣ agonists may represent a novel class of analgesics.Current therapies do not control safely and effectively severe pain states-a broad spectrum of debilitating conditions that comprises acute, persistent inflammatory, and neuropathic pain. Even widely used drugs, such as opiates (e.g., morphine) or anticonvulsants (e.g., gabapentin), are only active in a fraction of the patient population and produce multiple, often serious, side effects. Thus, despite continuing progress in analgesic drug discovery, the need for therapeutic agents capable of blocking abnormal pain sensation without impairing normal abilities remains largely unmet.PPAR-␣ is a nuclear receptor that serves important functions in lipid nutrient utilization and inflammation (Taylor et al., 2002;Kostadinova et al., 2005). Like other members of the nuclear receptor superfamily, PPAR-␣ is activated
Fatty liver, oxidative stress, and mitochondrial dysfunction are key pathophysiological features of insulin resistance and obesity. Butyrate, produced by fermentation in the large intestine by gut microbiota, and its synthetic derivative, the N-(1-carbamoyl-2-phenyl-ethyl) butyramide, FBA, have been demonstrated to be protective against insulin resistance and fatty liver. Here, hepatic mitochondria were identified as the main target of the beneficial effect of both butyrate-based compounds in reverting insulin resistance and fat accumulation in diet-induced obese mice. In particular, butyrate and FBA improved respiratory capacity and fatty acid oxidation, activated the AMPK-acetyl-CoA carboxylase pathway, and promoted inefficient metabolism, as shown by the increase in proton leak. Both treatments consistently increased utilization of substrates, especially fatty acids, leading to the reduction of intracellular lipid accumulation and oxidative stress. Finally, the shift of the mitochondrial dynamic toward fusion by butyrate and FBA resulted in the improvement not only of mitochondrial cell energy metabolism but also of glucose homeostasis. In conclusion, butyrate and its more palatable synthetic derivative, FBA, modulating mitochondrial function, efficiency, and dynamics, can be considered a new therapeutic strategy to counteract obesity and insulin resistance.
Probiotic L rhamnosus strain GG warrants consideration as a therapeutic tool to treat hypertransaminasemia in hepatopathic obese children noncompliant with lifestyle interventions.
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