Amazoniac
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How bile acids confer gut mucosal protection against bacteria
“Although most lipid absorption occurs in the proximal small intestine, conjugated bile acids themselves are not absorbed together with the solubilized lipids in the jejunum but pass to the distal small intestine, where they are efficiently absorbed by an active transport system present in the epithelium of the terminal ileum. Efficient intestinal reclamation of bile acids leads to the accumulation of a recycling pool of conjugated bile acids that circulates one or more times with each meal (3).”
“Work during the past decade (see below) has suggested that luminal conjugated bile acids have a second function: to inhibit the growth of bacteria in the small intestine. In a recent issue of PNAS, Inagaki et al. (4) present strong evidence for a previously undescribed mechanism by which conjugated bile acids mediate their antimicrobial effects in the distal small intestine. They show here that conjugated bile acids regulate expression of host genes whose products promote innate defense against luminal bacteria.”
“Unfortunately, in vitro studies (11) suggest that the antimicrobial effect of conjugated bile acids is quite weak when compared with that of unconjugated bile acids and cast doubt on the validity of the effect being mediated solely by conjugated bile acids. A possible explanation for this paradox is that the antimicrobial effect of administered conjugated bile acids may be comediated by fatty acids (partly present as soaps) that are associated with the conjugated bile acids in mixed micelles in the proximal small intestine. Long-chain fatty acids have been known for many decades to have potent antimicrobial effects (12*, 13). Nonetheless, irrespective of the mechanism, these experiments provided strong evidence for a second physiological function of conjugated bile acids in the proximal small intestine: to prevent bacterial overgrowth by their antimicrobial activity.”
“Based on these results, the authors propose that conjugated bile acids activate FXR [“an orphan receptor that is activated by conjugated bile acids. Activation of FXR by conjugated bile acids induced the expression of genes whose products prevent bacterial overgrowth and promote epithelial integrity.”] and that such activation, in turn, induces the expression of gene products that promote antimicrobial defense and epithelial integrity in the distal small intestine.”
“Bile acid concentrations fall to low, submicellar levels in the terminal ileum because of active bile acid absorption (18), and fatty acids are unlikely to be present as fatty acid absorption occurs in the proximal small intestine. Reflux of bacteria-rich cecal content across the ileocecal valve results in continuous bacterial seeding of the terminal ileum. A defense mechanism that inhibits luminal bacterial growth based on the carrier-mediated entry of conjugated bile acids into the ileal enterocyte should be more robust than one based on the luminal concentration of bile acids or fatty acids, because these substances are present in very low concentrations in the ileal lumen. If this reasoning is correct, conjugated bile acids, probably together with fatty acids, inhibit bacterial growth in the proximal small intestine directly by their pharmacological properties and in the distal small intestine indirectly by their signaling properties.”
“Multiple factors contribute to the low bacterial content of the human small intestine (19). These factors include gastric acidity that kills ingested organisms, IgA that is secreted in bile and by the intestinal epithelium, antimicrobial peptides (e.g., defensins) that are secreted by Paneth and other epithelial cells, and propulsive intestinal motility. Long-chain fatty acids solubilized in conjugated bile acid-mixed micelles also may play a role in the proximal small intestine as discussed. Inagaki et al. (4) describe the secretion in the distal small intestine of as-yet-unidentified microbial agents evoked by conjugated bile acids activating FXR in the ileal enterocyte. These different mechanisms are likely to act synergistically in controlling microbial levels in the small intestine.”
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My dog sensed a bad magnetic field coming from France, and warned me that I should take it easy. Questions this time should be addressed to jyb.
“Although most lipid absorption occurs in the proximal small intestine, conjugated bile acids themselves are not absorbed together with the solubilized lipids in the jejunum but pass to the distal small intestine, where they are efficiently absorbed by an active transport system present in the epithelium of the terminal ileum. Efficient intestinal reclamation of bile acids leads to the accumulation of a recycling pool of conjugated bile acids that circulates one or more times with each meal (3).”
“Work during the past decade (see below) has suggested that luminal conjugated bile acids have a second function: to inhibit the growth of bacteria in the small intestine. In a recent issue of PNAS, Inagaki et al. (4) present strong evidence for a previously undescribed mechanism by which conjugated bile acids mediate their antimicrobial effects in the distal small intestine. They show here that conjugated bile acids regulate expression of host genes whose products promote innate defense against luminal bacteria.”
“Unfortunately, in vitro studies (11) suggest that the antimicrobial effect of conjugated bile acids is quite weak when compared with that of unconjugated bile acids and cast doubt on the validity of the effect being mediated solely by conjugated bile acids. A possible explanation for this paradox is that the antimicrobial effect of administered conjugated bile acids may be comediated by fatty acids (partly present as soaps) that are associated with the conjugated bile acids in mixed micelles in the proximal small intestine. Long-chain fatty acids have been known for many decades to have potent antimicrobial effects (12*, 13). Nonetheless, irrespective of the mechanism, these experiments provided strong evidence for a second physiological function of conjugated bile acids in the proximal small intestine: to prevent bacterial overgrowth by their antimicrobial activity.”
*Summary (1954):
"Fatty acids in very low concentrations may influence the growth of various microorganisms. The effect can be an inhibition or promotion of growth. The magnitude of the effect is dependent on the concentration and nature of the fatty acids and on the bacterial species involved. Generally, only gram positive organisms are susceptible to the action of fatty acids in minute amounts although influences on gram negative organisms also have been observed.
Growth inhibition is affected by both saturated and unsaturated fatty acids. The antibacterial activity of unsaturated fatty acids increases with the number of double bonds in the molecule, and the natural cis-forms are generally more active than the trans-isomers. Antibacterial activity of saturated fatty acids is optimal for a chain length around C12.
Growth stimulating properties are exhibited mostly by unsaturated long-chain fatty acids (C18). Saturated fatty acids may act as synergists. The stimulatory activity of unsaturated fatty acids decreases with increasing unsaturation, and also here the cis-forms are the more active.
Often growth promotion by unsaturated fatty acids appears to be a biotin-like effect. Possibly, the absence of biotin interferes with the bio-synthesis of essential unsaturated fatty acids so that addition of the latter as such provides the growth factor. In other cases the requirement for fatty acids is absolute and exists also in the presence of biotin; here, the fatty acids therefore act as indispensable nutrients.
In many instances the antibacterial activity of fatty acids may be neutralized by adding antagonists, e.g., serum albumin, starch, cholesterol, lecithin, saponin, or charcoal to the medium. Probably the mode of action is ascribable to adsorption of the fatty acids. Also fatty acids with growth promoting activity may be so adsorbed; since these substances can be inhibitory when present in sufficiently high concentration, their positive effect can sometimes be observed only when antagonists are simultaneously present, or when the fatty acid has been incorporated into a larger, water-soluble molecule.
The influence of fatty acids on microbial growth is sometimes of dualistic nature; a growth promoting effect can be changed into growth stimulation by lowering the fatty acid concentration beneath a critical level or by prolonging the period of incubation. Apart from the biotin substituting properties of stimulatory fatty acids on microbial growth, in both inhibitory and stimulatory respects, can best be described physicochemically. Although a wholly satisfactory theory has not yet been advanced at present, growth interference is best interpreted as the result of changes in cell permeability by fatty acids adsorbed at the cell membrane."
"Fatty acids in very low concentrations may influence the growth of various microorganisms. The effect can be an inhibition or promotion of growth. The magnitude of the effect is dependent on the concentration and nature of the fatty acids and on the bacterial species involved. Generally, only gram positive organisms are susceptible to the action of fatty acids in minute amounts although influences on gram negative organisms also have been observed.
Growth inhibition is affected by both saturated and unsaturated fatty acids. The antibacterial activity of unsaturated fatty acids increases with the number of double bonds in the molecule, and the natural cis-forms are generally more active than the trans-isomers. Antibacterial activity of saturated fatty acids is optimal for a chain length around C12.
Growth stimulating properties are exhibited mostly by unsaturated long-chain fatty acids (C18). Saturated fatty acids may act as synergists. The stimulatory activity of unsaturated fatty acids decreases with increasing unsaturation, and also here the cis-forms are the more active.
Often growth promotion by unsaturated fatty acids appears to be a biotin-like effect. Possibly, the absence of biotin interferes with the bio-synthesis of essential unsaturated fatty acids so that addition of the latter as such provides the growth factor. In other cases the requirement for fatty acids is absolute and exists also in the presence of biotin; here, the fatty acids therefore act as indispensable nutrients.
In many instances the antibacterial activity of fatty acids may be neutralized by adding antagonists, e.g., serum albumin, starch, cholesterol, lecithin, saponin, or charcoal to the medium. Probably the mode of action is ascribable to adsorption of the fatty acids. Also fatty acids with growth promoting activity may be so adsorbed; since these substances can be inhibitory when present in sufficiently high concentration, their positive effect can sometimes be observed only when antagonists are simultaneously present, or when the fatty acid has been incorporated into a larger, water-soluble molecule.
The influence of fatty acids on microbial growth is sometimes of dualistic nature; a growth promoting effect can be changed into growth stimulation by lowering the fatty acid concentration beneath a critical level or by prolonging the period of incubation. Apart from the biotin substituting properties of stimulatory fatty acids on microbial growth, in both inhibitory and stimulatory respects, can best be described physicochemically. Although a wholly satisfactory theory has not yet been advanced at present, growth interference is best interpreted as the result of changes in cell permeability by fatty acids adsorbed at the cell membrane."
“Based on these results, the authors propose that conjugated bile acids activate FXR [“an orphan receptor that is activated by conjugated bile acids. Activation of FXR by conjugated bile acids induced the expression of genes whose products prevent bacterial overgrowth and promote epithelial integrity.”] and that such activation, in turn, induces the expression of gene products that promote antimicrobial defense and epithelial integrity in the distal small intestine.”
“Bile acid concentrations fall to low, submicellar levels in the terminal ileum because of active bile acid absorption (18), and fatty acids are unlikely to be present as fatty acid absorption occurs in the proximal small intestine. Reflux of bacteria-rich cecal content across the ileocecal valve results in continuous bacterial seeding of the terminal ileum. A defense mechanism that inhibits luminal bacterial growth based on the carrier-mediated entry of conjugated bile acids into the ileal enterocyte should be more robust than one based on the luminal concentration of bile acids or fatty acids, because these substances are present in very low concentrations in the ileal lumen. If this reasoning is correct, conjugated bile acids, probably together with fatty acids, inhibit bacterial growth in the proximal small intestine directly by their pharmacological properties and in the distal small intestine indirectly by their signaling properties.”
“Multiple factors contribute to the low bacterial content of the human small intestine (19). These factors include gastric acidity that kills ingested organisms, IgA that is secreted in bile and by the intestinal epithelium, antimicrobial peptides (e.g., defensins) that are secreted by Paneth and other epithelial cells, and propulsive intestinal motility. Long-chain fatty acids solubilized in conjugated bile acid-mixed micelles also may play a role in the proximal small intestine as discussed. Inagaki et al. (4) describe the secretion in the distal small intestine of as-yet-unidentified microbial agents evoked by conjugated bile acids activating FXR in the ileal enterocyte. These different mechanisms are likely to act synergistically in controlling microbial levels in the small intestine.”
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My dog sensed a bad magnetic field coming from France, and warned me that I should take it easy. Questions this time should be addressed to jyb.
