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Enteric glia: New role in mucosal defense identified
Gastroenterology News John H. Walsh, Section Editor
Does Olestra Stand a Fat Chance? s olestra, the recently approved fat substitute that tastes and feels like the real thing, too good to be true? Critics charge that it is, and the FDA, despite approving the soybeanbased product for salty snacks and chips, is requiring warning labels explaining that olestra can cause abdominal cramping and loose stools. Olestra is made from soybean oil, cottonseed oil, and sugar, through a process in which fatty acids are rearranged and attached to the sugar. Because the molecules are too large to digest, they pass through the body unabsorbed. ‘‘It’s different from fat in that it’s excreted unchanged,’’ says Nora Zorich, who conducted the safety studies for Procter & Gamble. ‘‘It’s a very inert, boring molecule, no different from a variety of other foods, such as high fibers, that do a little residence time in your body and then move on.’’ So why the warning labels? Zorich,
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Enteric Glia: New Role in Mucosal Defense Identified he intestinal mucosa is especially vulnerable to injury. Colitis or enteritis has been the cause of death in mice who have had one of the following genes ablated by recombinant knockout techniques: interleukin 2, interleukin 10, T-cell receptor, epithelial adhesion molecules, and certain G proteins. The lesions in these animals resemble those found in human inflammatory bowel disease, and it is hoped abnormalities in immune, epithelial, or neural function found in these animals can provide insights into inflammatory bowel disease pathophysiology. The importance of the enteric ner-
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without faulting the FDA, suggests that public concern has been fueled by critics’ unfounded charges. But Mark Brown of the Center for Science in the Public Interest counters that a highly touted P&G-funded study published in JAMA, which concluded that the olestra-containing chips do not cause any more stomach troubles than regular chips, lacked the statistical power to show significant differences in symptoms. ‘‘They had to know when they started the study that they weren’t going to turn up any bad news with that design,’’ Brown says. UCLA’s David Heber believes the weight of the evidence, including three other peer-reviewed papers published in 1997, indicates that gastrointestinal symptoms from moderate doses of the product are no worse than from regular fat. Heber says another concern about olestra, that it inhibits the absorption of some vitamins and other fat-soluble nutrients, can be offset with 5–10 servings a day of fruits and vegetables. Whether or not olestra is effective
as a weight-loss strategy is another question. ‘‘We’ve had artificial sweeteners for a couple of decades, and American rates of obesity are at an all-time high,’’ Brown notes. Says Heber, ‘‘The issue is whether you can enhance the taste of low-fat, high-fiber foods. As a taste enhancer, I believe olestra has some potential. ‘‘Bioengineering the food supply is a very important public health strategy for combating obesity, but obesity is more than just a public health problem; there are also individuals who have a medical condition in which diet plays only a partial role, and there’s a gene-nutrient interaction.’’ Heber believes it’s unfortunate that olestra is currently being marketed only in snack foods, because it is unlikely to have a major impact in that form. Expanding olestra to other foods will require another FDA application and possibly further testing, Zorich notes. ‘‘That’s not in the cards for us at the moment, but I don’t think we would have embarked on the program without a longer vision than just snacks,’’ she says.
vous system in mucosal protection was shown recently by disrupting the enteric glial cells that provide a supportive environment for enteric neurons. In an article published in Cell (April 17) by Bush et al., thymidine kinase was introduced into transgenic mice under direction of the promoter for a protein that is expressed specifically by glia and astrocytes. Cells containing thymidine kinase were then killed by exposing the mice to ganciclovir under conditions that preferentially killed glial cells in jejunum and ileum, leading to atrophy of myenteric plexus neurons in the small intestine. Disruption of glial cells caused a severe, fatal jejunoileitis that ap-
peared between 2 and 3 weeks of ganciclovir. The intestinal lesions resembled those of Crohn’s disease, but the esophagus, stomach, and colon appeared normal. Animals had severe gastrointestinal blood loss and became severely anemic. They also developed septicemia and had increased bacterial colonization of the ileum, but reducing the bacterial overgrowth with antibiotics did not alter their clinical course. Fergus Shanahan of the University of Cork believes the study shows that glial cells must be added to the list of mucosal elements that contribute to the protective local microenvironment. He notes that intestinal glial cells can produce cytokines and his-
GASTROENTEROLOGY 1998;115:3–4
Gastroenterology News continued
tocompatibility antigens that might directly affect not only nerves but also mucosal immune responses. Columbia University’s Michael Ger-
Substance P: Pivotal Roles in Pain and Pancreatitis
shon agrees that the study indicates that glia play an unexpected role in protecting the gut, and illustrates the importance of the enteric nervous
system in defense of the bowel. ‘‘This is a major advance, opening up a whole new area of thought and research,’’ he says.
stimulation, but were able to discriminate weak pain nor-mally. They also showed decreased visceral pain ubstance P is a neuropeptide responses after peritoneal injection found in visceral sensory nerves of acetic acid or MgSO4. Morphine and in the spinal cord and central had increased effectiveness in both nervous system. Its pivotal roles in groups during induction of modertransmission of pain and in mediaate pain. tion of inflammation have been Both types of knockout mice had shown in a recent series of articles decreased neurogenic inflammain which the genes for the peptide tion and capillary leakage when the precursor or for its major receptor ear was irritated with the pepper have been knocked out in mice. derivative capsaicin, but had norMichael Steer’s group at Harvard mal inflammatory responses to nonMedical School recently reported in neurogenic toxins. These results Proceedings of the National Acadare compatible with the known emy of Sciences USA (PNAS) that action of substance P to increase experimental pancreatitis, induced capillary permeability and to cause in mice by injecting the cholecystolocal edema. kinin-like peptide cerulein, was Leslie Iverson at Oxford pointed markedly attenuated in mice lackSubstance P neurons in the dorsal root ganglia out in an accompanying editorial ing the NK1 receptor, and that (DRG) send peripheral projections to the gut wall, that these results clearly implicate pancreatitis-induced lung injury where they innervate blood vessels and other struc- substance P and its NK1 receptor in tures, and to the spinal cord, where they interact in also was reduced. These findings laminae II and III with neurons that transmit pain some forms of pain and inflammaindicated a key role for substance sensations to the brain. The present knockout tion. A major implication of these P, interacting with the NK1 recep- experiments indicate that the most important spinal articles is that substance P NK1 receptors mediating pain and the most important tor in gastrointestinal inflammation. vascular and pancreatic receptors mediating neuro- receptor antagonists may prove useA pair of recent articles have genic inflammation and pancreatitis are neurokinin ful in treating a variety of illnesses pinpointed a role for substance P 1 (NK1) receptors. that include pain and neurogenic and the NK1 receptor in transmisinflammation. The PNAS article sugsion of moderate pain, including vis- Both groups studied pain responses gests that one of these diseases could ceral pain. The group of Allan Bus- and reported their results in the be pancreatitis. baum at UCSF produced mice in March 26 issue of Nature. Both types which the substance P precursor of mice appeared normal, showed Stories by Dan Gordon was knocked out, and a group that decreased pain-re-lated behavior The section editor can be sent (withdrawal from noxious stimuli) included Ste-phen Hunt at Camsuggestions for articles at [email protected] bridge knocked out the NK1 receptor. over a range of moderately severe
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Does Olestra Stand a Fat Chance? s olestra, the recently approved fat substitute that tastes and feels like the real thing, too good to be true? Critics charge that it is, and the FDA, despite approving the soybeanbased product for salty snacks and chips, is requiring warning labels explaining that olestra can cause abdominal cramping and loose stools. Olestra is made from soybean oil, cottonseed oil, and sugar, through a process in which fatty acids are rearranged and attached to the sugar. Because the molecules are too large to digest, they pass through the body unabsorbed. ‘‘It’s different from fat in that it’s excreted unchanged,’’ says Nora Zorich, who conducted the safety studies for Procter & Gamble. ‘‘It’s a very inert, boring molecule, no different from a variety of other foods, such as high fibers, that do a little residence time in your body and then move on.’’ So why the warning labels? Zorich,
I
Enteric Glia: New Role in Mucosal Defense Identified he intestinal mucosa is especially vulnerable to injury. Colitis or enteritis has been the cause of death in mice who have had one of the following genes ablated by recombinant knockout techniques: interleukin 2, interleukin 10, T-cell receptor, epithelial adhesion molecules, and certain G proteins. The lesions in these animals resemble those found in human inflammatory bowel disease, and it is hoped abnormalities in immune, epithelial, or neural function found in these animals can provide insights into inflammatory bowel disease pathophysiology. The importance of the enteric ner-
T
without faulting the FDA, suggests that public concern has been fueled by critics’ unfounded charges. But Mark Brown of the Center for Science in the Public Interest counters that a highly touted P&G-funded study published in JAMA, which concluded that the olestra-containing chips do not cause any more stomach troubles than regular chips, lacked the statistical power to show significant differences in symptoms. ‘‘They had to know when they started the study that they weren’t going to turn up any bad news with that design,’’ Brown says. UCLA’s David Heber believes the weight of the evidence, including three other peer-reviewed papers published in 1997, indicates that gastrointestinal symptoms from moderate doses of the product are no worse than from regular fat. Heber says another concern about olestra, that it inhibits the absorption of some vitamins and other fat-soluble nutrients, can be offset with 5–10 servings a day of fruits and vegetables. Whether or not olestra is effective
as a weight-loss strategy is another question. ‘‘We’ve had artificial sweeteners for a couple of decades, and American rates of obesity are at an all-time high,’’ Brown notes. Says Heber, ‘‘The issue is whether you can enhance the taste of low-fat, high-fiber foods. As a taste enhancer, I believe olestra has some potential. ‘‘Bioengineering the food supply is a very important public health strategy for combating obesity, but obesity is more than just a public health problem; there are also individuals who have a medical condition in which diet plays only a partial role, and there’s a gene-nutrient interaction.’’ Heber believes it’s unfortunate that olestra is currently being marketed only in snack foods, because it is unlikely to have a major impact in that form. Expanding olestra to other foods will require another FDA application and possibly further testing, Zorich notes. ‘‘That’s not in the cards for us at the moment, but I don’t think we would have embarked on the program without a longer vision than just snacks,’’ she says.
vous system in mucosal protection was shown recently by disrupting the enteric glial cells that provide a supportive environment for enteric neurons. In an article published in Cell (April 17) by Bush et al., thymidine kinase was introduced into transgenic mice under direction of the promoter for a protein that is expressed specifically by glia and astrocytes. Cells containing thymidine kinase were then killed by exposing the mice to ganciclovir under conditions that preferentially killed glial cells in jejunum and ileum, leading to atrophy of myenteric plexus neurons in the small intestine. Disruption of glial cells caused a severe, fatal jejunoileitis that ap-
peared between 2 and 3 weeks of ganciclovir. The intestinal lesions resembled those of Crohn’s disease, but the esophagus, stomach, and colon appeared normal. Animals had severe gastrointestinal blood loss and became severely anemic. They also developed septicemia and had increased bacterial colonization of the ileum, but reducing the bacterial overgrowth with antibiotics did not alter their clinical course. Fergus Shanahan of the University of Cork believes the study shows that glial cells must be added to the list of mucosal elements that contribute to the protective local microenvironment. He notes that intestinal glial cells can produce cytokines and his-
GASTROENTEROLOGY 1998;115:3–4
Gastroenterology News continued
tocompatibility antigens that might directly affect not only nerves but also mucosal immune responses. Columbia University’s Michael Ger-
Substance P: Pivotal Roles in Pain and Pancreatitis
shon agrees that the study indicates that glia play an unexpected role in protecting the gut, and illustrates the importance of the enteric nervous
system in defense of the bowel. ‘‘This is a major advance, opening up a whole new area of thought and research,’’ he says.
stimulation, but were able to discriminate weak pain nor-mally. They also showed decreased visceral pain ubstance P is a neuropeptide responses after peritoneal injection found in visceral sensory nerves of acetic acid or MgSO4. Morphine and in the spinal cord and central had increased effectiveness in both nervous system. Its pivotal roles in groups during induction of modertransmission of pain and in mediaate pain. tion of inflammation have been Both types of knockout mice had shown in a recent series of articles decreased neurogenic inflammain which the genes for the peptide tion and capillary leakage when the precursor or for its major receptor ear was irritated with the pepper have been knocked out in mice. derivative capsaicin, but had norMichael Steer’s group at Harvard mal inflammatory responses to nonMedical School recently reported in neurogenic toxins. These results Proceedings of the National Acadare compatible with the known emy of Sciences USA (PNAS) that action of substance P to increase experimental pancreatitis, induced capillary permeability and to cause in mice by injecting the cholecystolocal edema. kinin-like peptide cerulein, was Leslie Iverson at Oxford pointed markedly attenuated in mice lackSubstance P neurons in the dorsal root ganglia out in an accompanying editorial ing the NK1 receptor, and that (DRG) send peripheral projections to the gut wall, that these results clearly implicate pancreatitis-induced lung injury where they innervate blood vessels and other struc- substance P and its NK1 receptor in tures, and to the spinal cord, where they interact in also was reduced. These findings laminae II and III with neurons that transmit pain some forms of pain and inflammaindicated a key role for substance sensations to the brain. The present knockout tion. A major implication of these P, interacting with the NK1 recep- experiments indicate that the most important spinal articles is that substance P NK1 receptors mediating pain and the most important tor in gastrointestinal inflammation. vascular and pancreatic receptors mediating neuro- receptor antagonists may prove useA pair of recent articles have genic inflammation and pancreatitis are neurokinin ful in treating a variety of illnesses pinpointed a role for substance P 1 (NK1) receptors. that include pain and neurogenic and the NK1 receptor in transmisinflammation. The PNAS article sugsion of moderate pain, including vis- Both groups studied pain responses gests that one of these diseases could ceral pain. The group of Allan Bus- and reported their results in the be pancreatitis. baum at UCSF produced mice in March 26 issue of Nature. Both types which the substance P precursor of mice appeared normal, showed Stories by Dan Gordon was knocked out, and a group that decreased pain-re-lated behavior The section editor can be sent (withdrawal from noxious stimuli) included Ste-phen Hunt at Camsuggestions for articles at [email protected] bridge knocked out the NK1 receptor. over a range of moderately severe
S
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