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National Institute for Agricultural Research, Gut Function and Human Nutrition Unit, Nantes, France
1To whom correspondence and reprint requests should be addressed. E-mail: cherbut{at}nantes.inra.fr.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSAssessment of colonic damage...Analysis of cecal contentRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • lactic acid bacteria • inflammation • intestine • prebiotics • short-chain fatty acids • rats
There is increasing evidence that commensal intestinal bacteria are involved in the pathogenesis and pathophysiology of inflammatory bowel disease (IBD), 2 a disorder that tends to occur in the region with the greatest bacterial load. The level of antibodies against intestinal bacteria is elevated in patients with IBD (1
). Furthermore, inflammation improves after fecal stream diversion (2
,3
) or antibiotic treatment (4
), whereas infusion of intestinal contents into surgically excluded ileum induces inflammatory lesions in patients with Crohn’s disease (5
). The deleterious role of normal resident bacterial flora in the development of chronic intestinal inflammation has been demonstrated in several rodent models of experimental colitis. For example, HLA-B27 transgenic rats raised under specific pathogen-free conditions developed colitis spontaneously, but not when maintained under germ-free conditions (6
). Similarly, colitis was detected or was greatly attenuated in T-cell receptor-
, interleukin (IL)-2 and IL-10 knockout mice kept under germ-free conditions (7
–9
). Moreover, in the rat model of trinitrobenzene sulfonic acid (TNBS) hapten-induced chronic colitis, infusion of anaerobe bacteria into a colonic segment excluded from transit induced transmural inflammation, whereas luminal washings with sterile culture resulted in low mucosal damage in response to TNBS (10
).
It is noteworthy that individual bacterial species within indigenous flora vary in their capacity to drive intestinal inflammation, and some may even have a beneficial effect on inflammation. Administration of probiotics (live nonpathogenic bacteria) could prevent or improve food allergy by modifying the composition of intestinal flora (11
), various bacterial infections (12
) and gut inflammation. For example, a preparation of nonpathogenic Escherichia coli was as efficient as the standard treatment with mesalazine in maintaining remission in patients with ulcerative colitis (13
). Similarly, a probiotic preparation containing bifidobacteria, lactobacilli and a strain of Streptococcus salivarius maintained remission in 75% of patients with ulcerative colitis who were intolerant of or allergic to 5-aminosalicylic acid (14
). Moreover, Lactobacillus species reduced the prevalence of colon cancer and mucosal inflammatory activity in IL-10 deficient mice (15
,16
) and the severity of methotrexate-induced enterocolitis in rats (17
). The mechanisms by which probiotic bacteria confer a therapeutic effect may be multiple, including interactions with commensal and pathogenic flora and varying effects on immune response.
Fructooligosaccharides (FOS) are short-chain polymers of fructose units that are not hydrolyzed in the human small intestine, but degraded by resident flora in the colon (18
). They mainly increase the growth of endogenous intestinal lactobacilli and bifidobacteria in humans and animals (19
,20
), which makes them part of the prebiotics complex (18
). In addition, FOS fermentation decreases colonic pH, produces short-chain fatty acids (SCFA) and lactate, and increases the proportion of butyrate (20
). The present study tested the hypothesis that FOS feeding improves intestinal inflammation in the rat model of TNBS-induced colitis and investigated which FOS fermentation factors might be involved.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSAssessment of colonic damage...Analysis of cecal contentRESULTSDISCUSSIONLITERATURE CITED |
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Male Wistar rats (Janvier, Le Genest Saint Isles, France), with an initial mean weight of 246 ± 6 g, were housed individually in suspended cages with wire-mesh bottoms and maintained at 23°C in an animal room with a 12-h light:dark cycle (light: 0800–2000 h). Food and water were consumed ad libitum, and food intake and body weight were recorded daily. The diet has been previously described in detail (20
). It contained (g/kg diet): gelatinized cornstarch (626), soluble casein (204), lard (58.5), a mineral mixture (43.7), cellulose (40), corn oil (18.5), a vitamin mixture (5.6) and DL-methionine (3.7). All experiments were in accordance with the recommendations of the local Animal Care and Use Committee of Nantes (France).
The rats were surgically equipped with a chronic catheter (1.6 mm i.d., 3.2 mm o.d., Tygon, Bioblock, Strasbourg, France) fixed either in the stomach, 5 cm before the pylorus, or in the proximal colon, 2 cm beyond the cecocolonic junction. The catheter was implanted through a small stab wound in the intestinal wall, fixed by a stitch, and exited to the dorsal cervical region through a subcutaneous tunnel. It passed through an anchoring button sutured to the muscle of the dorsal cervix and fixed with a strap. The dorsal extremity was kept closed between each infusion. These catheters were used to infuse FOS, LAB or saline into the stomach (Experiment 1), and butyrate, lactate or saline into the colon (Experiment 2). An additional group of 5 rats that were not equipped with a catheter received no treatment and served as controls.
Experiment 1.
Rats (n = 34) were randomly assigned to 6 groups and received 4 mL of one solution twice daily, into the stomach through an intragastric catheter for 7 or 14 d. Three different solutions were administered: 1 g/d FOS, lactic acid-producing bacteria (LAB), or saline (9 g/L NaCl). The LAB treatment delivered 1011 colony-forming units (cfu)/d of two strains of Lactobacillus sp. (Lactobacillus acidophilus and Lactobacillus casei subsp. rhamnosus) and one strain of Bifidobacterium sp. (Bifidobacterium animalis). The freeze-dried bacteria, stored in aliquots of 1012 cfu at -20°C, were diluted in 100 mL sterile saline each day. Rats administered saline served as controls for both FOS- and LAB-treated rats.
Experiment 2.
Rats (n = 48) were divided in 8 groups, each of which received a solution (3 mL) infused through an intracolonic catheter twice a day for 14 d. The effects of butyrate (pH 6.8, 100 and 30 mmol/L) and lactate (pH 5.5, 50 and 10 mmol/L) were compared with that of saline (pH 6.8 and pH 5.5). In addition, the effect of a solution containing 10 mmol/L lactate + 30 mmol/L butyrate, pH 5.8, was compared with that of the same solution supplemented with 10 9.5 cfu/L LAB.
Induction of experimental colitis.
After 7–8 d of postoperative recovery, TNBS was used to induce colitis in all rats (Experiments 1 and 2). This model has been described in detail elsewhere (21
). Briefly, after 24 h of food deprivation, rats were lightly anesthetized with pentobarbital. The distal colon was carefully cleaned with a small balloon catheter, and colitis was induced by a single intracolonic administration of TNBS (80 mg/kg body) dissolved in ethanol (400 g/L). This solution, which was freshly prepared on the day of treatment, was injected (0.5 mL) into the colon 8 cm proximal to the anus, using a cannula left in place for 1 min to ensure that the solution was not immediately expelled by the rat. The rats were then maintained in a head-down position for 30 min.
Experimental procedures.
Each treatment was administered twice daily (at 0800 and 1700 h), beginning 2 d before colitis induction and continuing for 7 or 14 d. At the end of treatment, the rats were killed by cervical dislocation, 3 h after the last infusion. The large bowel was dissected free from fat and mesentery, removed and opened along the mesenteric border, and carefully cleaned with cold 9 g/L NaCl. Colonic damage and inflammation were assessed as described below. Cecal contents were collected by squeezing the cecum, weighed and divided into 4 parts: 1) 0.8 g was collected into a sterile assay tube for bacterial enumeration; 2) 0.2 g was immediately frozen for further analysis of lactate; 3) 0.3 g was combined with 0.75 mL of 1 g/L HgCl2 and 0.105 mL of 50 g/L H3PO4 and then frozen for further analysis of SCFA; and 4) residual material was used for dry matter determination.
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Assessment of colonic damage and inflammation |
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TOPABSTRACTMATERIALS AND METHODSAssessment of colonic damage...Analysis of cecal contentRESULTSDISCUSSIONLITERATURE CITED |
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Gross colonic damage was scored without the scorer’s knowledge of the treatment according to a previously described scale (21
) (Table 1
). Each colon was assigned a score ranging from 0 (normal) to 15 (severe damage) indicative of ulcerations, gross inflammation of the colonic wall and diarrhea.
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The activity of intestinal myeloperoxidase (MPO), a specific enzyme marker of polymorphonuclear neutrophil primary granules, was measured using the method of Krawisz et al. (22
), with minor modifications. Briefly, colonic tissue samples (
50–100 mg) were collected 5 cm proximal to the anus, and homogenized on ice using a Polytron in a solution (pH 6, 1 mL/50 mg tissue) of 5 g/L hexadecyltrimethyl ammonium bromide in 50 mmol/L potassium phosphate buffer. After three freezing-thawing cycles, the samples were centrifuged (2500 g, 15 min) and the MPO assayed in the supernatant combined with O-dianisidine hydrochloride and hydrogen peroxide. Absorbance changes at 470 nm were recorded. One unit of MPO activity was defined as the quantity of enzyme able to convert 1 µmol of hydrogen peroxide into water in 1 min at room temperature. MPO activity was expressed in units per milligram of tissue.
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Analysis of cecal content |
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TOPABSTRACTMATERIALS AND METHODSAssessment of colonic damage...Analysis of cecal contentRESULTSDISCUSSIONLITERATURE CITED |
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Samples for enumeration of selected genera of cecal bacteria were serially diluted 10-fold with anoxic one-fourth strength peptone-water immediately after collection; 100 µL of the appropriate dilutions was inoculated onto duplicate plates using unselective media for the enumeration of total anaerobes (Wilkins Chalgren Agar) and selective media for total lactic acid-producing bacteria (Man Rogosa Sharp Agar) and Lactobacillus sp. (Rogosa Agar). Plates were incubated in an anaerobic chamber (H2/CO2/N2, 5:10:85) for 72 h. After incubation, single colonies were counted, and the results were expressed as the log10 of cfu/g dry cecal contents.
SCFA and lactate analysis.
Lactate concentrations were determined by gas chromatography after methylation and chloroform extraction from cecal contents (23
). Malonic acid was used as an internal standard. SCFA were analyzed by gas chromatography (24
) on supernatants of thawed samples centrifuged at 8000 x g for 10 min. 4-Methyl valeric acid was used as an internal standard.
Chemicals.
We used short-chain FOS from Actilight (Eridania-Beghin-Say, Vilvoorde, Belgium), which consists of 44% 1-kestose, 46% nystose and 10% 1F-ß-fructofuranosyl nystose. The probiotic preparation of LAB was a gift of Rhodia-Texel (Dangé-St Romain, France). Microbiological media were purchased from Oxoid (Unipath, Dardilly, France) and picrylsulfonic acid (TNBS) from Fluka Sigma Aldrich Chimie SARL (St Quentin-Fallavier, France). All other chemicals were obtained from Sigma Chemical (St Quentin-Fallavier, France).
Statistical analysis.
Statistical analysis was performed using the Statview 5.0 package (SAS Institute, Berkeley, CA). Two-way ANOVA was used to assess the effects of treatments, time of exposure to treatments and interactions between treatments and time. Then, individual means were compared by Fisher’s Protected Least Significant Difference test. Significant difference was accepted at P < 0.05. Data are expressed as means ± SEM.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSAssessment of colonic damage...Analysis of cecal contentRESULTSDISCUSSIONLITERATURE CITED |
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The daily food intake of rats decreased dramatically for 5 d after administration of TNBS (4.2 ± 1.1 g/d 48 h after TNBS vs. 21.6 ± 0.9 g/d before TNBS, P < 0.05). However, this anorectic period was only 3 d in rats administered intragastric FOS (11.9 ± 1.0 g/d 48 h after TNBS). Body weight decreased markedly in rats treated with saline, but only slightly in those treated with FOS (Fig. 1
).
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). Like FOS, intragastric LAB inhibited the anorexia associated with colitis and prevented the weight loss that occurred in controls during the first days after TNBS administration (Fig. 1)
. Intragastric LAB had the same effects as FOS on colitis, significantly decreasing the macroscopic damage score and MPO activity in colonic mucosa after 14 d (Fig. 2)
.
|
). The cecal lactate concentration was higher in rats administered FOS throughout the experiment (Table 2)
. Due to the elevated concentrations of SCFA and lactate, the pH of the cecal contents was lower in FOS-treated rats than in those administered saline. FOS increased the concentration of total lactic acid bacteria (P < 0.05; Fig. 3
) and tended to increase the Lactobacillus sp. concentration (P = 0.07).
|
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). Intragastric LAB produced also increased (P < 0.05) cecal concentrations of total lactic acid bacteria and Lactobacillus sp. (Fig. 3)
. Experiment 2.
Intracolonic butyrate dose-dependently decreased inflammation of the colonic mucosa. The pharmacologic dose (100 mmol/L) reduced (P < 0.05) the gross damage score and MPO activity (Table 3
). This effect was not due to infusion because a similar intracolonic administration of saline at the same pH (6.8) had no effect. However, intracolonic infusion of butyrate at the concentration found in the cecal contents of FOS-treated rats (30 mmol/L) did not improve colitis (P = 0.09, Table 3
). Lactate (50 mmol/L) also reduced inflammation when administered into the colon. The decrease in the gross score but not that in MPO activity was greater (P = 0.002) than that induced by intracolonic saline at the same pH (5.5). The lower dose of lactate (10 mmol/L) did not affect either measure of inflammation (P = 0.1). It is noteworthy that inflammatory indices were significantly affected by saline at pH 5.5, but not at pH 6.8 (Table 3)
. Nevertheless, intracolonic saline (pH 5.5) did not lower MPO activity to the same extent as intragastric FOS (P < 0.001).
|
). On the contrary, addition of LAB to the intracolonic mixture decreased both indices (P < 0.05) and reproduced the intragastric FOS-induced reduction of MPO activity (Fig. 4)
.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSAssessment of colonic damage...Analysis of cecal contentRESULTSDISCUSSIONLITERATURE CITED |
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), is associated with transient anorexia, possibly due to hyperleptinemia (26
). FOS decreased the duration and extent of this anorexia, suggesting that FOS may have modulated initiating factors. Nevertheless, the improvement in intestinal inflammation was significant only after 14 d, indicating that oral FOS acts mainly on the amplification of inflammation and/or the healing of the mucosa. This finding confirms previous suggestions that certain fermentable carbohydrates may protect against intestinal inflammation (27
–31
). FOS probably decreased colonic damage by modifying the chemical, physicochemical and bacterial composition of cecal contents. As expected (19
,20
), the main changes were an increase in total lactic acid bacteria counts, increases in butyrate and, especially, lactate concentrations, and a decrease in pH.
FOS is a prebiotic, i.e., it is capable of promoting the growth of intestinal lactic acid bacteria in the colon. Its beneficial effect on colitis could be related to this property. Intragastric administration of LAB, a cocktail of two Lactobacillus sp. strains and one Bifidobacterium sp. strain, reproduced the effects of FOS, i.e., inhibition of the early loss of weight, significant reductions of mucosal damage and MPO activity after 14 d, and modification of the chemical composition of colonic contents. The dose of oral LAB (1011 cfu/d) administered to rats was high compared with the concentration of total lactic acid bacteria measured in cecal contents during FOS treatment. Accordingly, higher concentrations of total lactic acid bacteria and Lactobacillus sp. were found in the cecum of rats administered LAB than in those given FOS. Therefore, it is possible that a lower dose of intragastric LAB would have had a lesser effect similar to FOS-induced bacterial proliferation. Nevertheless, these results are consistent with those reported in rats with methotrexate-induced enterocolitis that were infused intragastrically for 6 d with 4 x 109 cfu/d of two strains of Lactobacillus sp. (17
). Treatments with lactobacilli reduced MPO activity in the ileum and colon of these rats, decreased body weight loss and intestinal permeability, and increased bowel mucosal mass. More recently, daily rectal delivery of 3 x 107 cfu/d of Lactobacillus reuteri reduced colonic mucosal adherent aerobic bacteria and attenuated the development of spontaneously occurring colitis in IL-10 gene-deficient mice (15
). Oral administration of lactulose, a prebiotic fermentable carbohydrate, led to similar effects.
The exact mechanisms involved in the protective effect of lactic acid bacteria against intestinal inflammation are unclear. Lactic acid bacteria are presumed to be antagonistic to pathogenic bacteria through production of antimicrobial substances and the reduction in luminal pH (32
,33
). They might also adhere to mucosal surfaces and inhibit the attachment of aerobic gram-negative bacteria. Thus, they could promote nonspecific stimulation of the immune system, including cell proliferation (34
,35
), enhanced phagocytic activity (36
) and increased production of secretory immunoglobulin (Ig)A (34
,37
,38
).
In addition to its promoting effect on lactic acid bacteria growth, oral FOS increased lactate and, at d 7, butyrate concentrations in the rat colonic contents, which might contribute to the beneficial effect of FOS in colitis. Lactate is produced by lactic acid bacteria (39
), whereas butyrate is not an end product of lactobacilli or bifidobacteria. Thus, the increase in butyrate concentration at d 7 originated from other bacterial populations. However, we could not identify these bacteria. Butyrate is the preferred nutrient of colonocytes, and it has been suggested that intracellular butyrate oxidation is impaired in patients with ulcerative colitis (40
,41
). Decreased ß-oxidation in colonic epithelial cells similar to that in ulcerative colitis was shown recently in dextran sulfate-induced colitis in mice (42
). This metabolic defect may be overcome by massive butyrate supply. In addition, butyrate affects key functions of the colonic epithelium, such as proliferation and differentiation (43
), tight junction permeability (44
) and epithelial restitution (45
). Moreover, butyrate exerts immunomodulatory effects (46
). In agreement with numerous reports (47
–51
), our findings indicate that intracolonic infusion of highly concentrated butyrate improves inflammation. However, a lower dose, close to the concentration in the colon of rats administered FOS or LAB, did not significantly affect inflammatory indices, although it seemed to produce a slight improvement in the macroscopic appearance of the mucosa (not shown). In this study, butyrate concentration was measured in the rat cecum 3 h after intragastric administration of FOS. In another unpublished experiment, we measured cecal SCFA and lactate concentrations 1, 3, 6 and 12 h after an intragastric bolus of 0.5 g FOS in normal food-deprived rats. Butyrate concentration was maximal at 3 h and remained elevated at 6 h, whereas lactate concentration rose from 1 h to peak at 3 h. Thus, the butyrate and lactate concentrations measured in the present study should have been close to the maximal concentration produced by intragastric FOS. However, we cannot be certain that the concentrations we measured in the cecum at one point in time are indicative of the concentrations occurring in the colon over a 1-d period. Thus, it is possible that the beneficial effect of FOS may have been mediated by butyrate, but such a mechanism would not explain the full effect of FOS.
Similarly, intracolonic infusion of a high dose of lactate decreased inflammation significantly, whereas a lower dose had only a minor, nonsignificant effect on the gross score of inflammatory damage. Previous studies have shown that high concentrations of lactic acid (75–800 mmol/L) induced erosions of the surface epithelium and inflammatory infiltration of the submucosa in rat colonic segments, but only when the pH was <4.5 (52
,53
). In the present study, lactate (50 mmol/L, pH 5.5) stimulated mucosal repair. This is consistent with the finding that L-lactic acid (150 mmol/L, pH 5) stimulated mitosis of epithelial cells in rat cecum (54
). However, the effects of lactate that we observed were reproduced in part by a solution of saline having the same pH. This suggests that acidification of the colonic contents may contribute to the improvement of colitis. An acid luminal environment might have inhibited the growth of deleterious bacteria and favored proliferation and activity of lactic acid bacteria. Moreover, it has been suggested that acidification of the colonic contents leads to increased colonic epithelial cell proliferation (55
). Nevertheless, neither pH nor intracolonic lactate and butyrate alone can totally account for the beneficial effect of intragastric FOS and LAB. Moreover, addition of intracolonic LAB to the mixture of lactate and butyrate significantly decreased both macroscopic damage and MPO activity compared with the mixture alone. Thus, these results suggest that stimulation of lactic acid bacteria growth was an essential step for the colitis-reducing effect of FOS. This hypothesis is consistent with a previous study showing that nonprebiotic fibers, such as pectin and oat fiber, did not modulate the gut-associated lymphoid tissue function in rats with enterocolitis, whereas administration of lactobacilli increased intestinal secretory IgA level significantly and augmented CD4 and CD8 numbers in the same rats (34
).
In conclusion, oral FOS has a beneficial effect on intestinal inflammation in rats. It diminishes the anorexia and weight loss associated with the onset of inflammation; it then reduces the extent of the damage and promotes epithelial healing. End products of FOS fermentation, such as lactate and possibly butyrate, as well as acidification of the luminal contents, could contribute to this beneficial effect, but they cannot explain the full effect of FOS. Administration of living lactic acid bacteria reproduced the therapeutic effect of FOS. Therefore, the prebiotic property of FOS, i.e., its capacity to increase intestinal lactic acid bacteria counts in the colon, appeared to be the main factor responsible for improvement of colitis in the present experiments. This study supports the hypothesis that fermentable fibers could improve epithelial nutritional status and the trophicity and permeability functions of the mucosa, but that only prebiotic fibers evoke a local immune stimulus sufficient to protect against inflammation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 8 August 2002. Initial review completed 25 August 2002. Revision accepted 27 September 2002.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSAssessment of colonic damage...Analysis of cecal contentRESULTSDISCUSSIONLITERATURE CITED |
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