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,**,2,3
* Department of Medical Microbiology and Department of Paediatrics, University Medical Center Groningen, University of Groningen, Groningen, and ** Wageningen Centre for Food Sciences, Wageningen, The Netherlands
2 To whom correspondence should be addressed. E-mail: t.a.o.he{at}med.umcg.nl.
ABSTRACT
The results of our previous study suggested that in addition to the small intestinal lactase activity and transit time, colonic processing of lactose may play a role in lactose intolerance. We investigated whether colonic fermentation of lactose is correlated with lactose intolerance. After 28 Chinese subjects had undergone 1 glucose (placebo) and 2 lactose challenges, consistent lactose tolerant (n = 7) and intolerant (n = 5) subjects with no complaints after glucose administration were classified on the basis of the 6-h symptom scores. Before the challenges, fecal samples were collected for in vitro incubation with lactose. The incubation was carried out in a static system under anaerobic conditions for 5 h during which samples were taken for measurement of short-chain fatty acids, lactate, lactose, glucose, and galactose. Fecal bacterial composition was determined by fluorescent in situ hybridization. The tolerant and intolerant groups did not differ in the rate or degree of hydrolysis of lactose or production of glucose and galactose. The intolerant group produced D- and L-lactate, acetate, propionate, and butyrate significantly faster than the tolerant group. In the intolerant group, the amounts of acetate, propionate, butyrate, and L-lactate produced were higher than those in the tolerant group. Fecal bacterial composition did not differ between the 2 groups. The results indicate that the degree and rate of lactose hydrolysis in the colon do not play a role in lactose intolerance. However, after lactose is hydrolyzed, a faster and higher production of microbial intermediate and end metabolites may be related to the occurrence of symptoms.
KEY WORDS: • lactose intolerance • fecal microbiota • fermentation
Lactose intolerance refers to the gastrointestinal symptoms related to incomplete digestion of lactose. The adult-type lactase nonpersistence occurring in a large part of the world population leads to lactose maldigestion, which in turn can, though not in all cases, lead to lactose intolerance; however, this is not true in all cases. The origin of the symptoms of lactose intolerance is not well understood. The osmotic load caused by the undigested lactose cannot be regarded as the only mechanism behind the symptoms because lactose intolerance is poorly related to lactose maldigestion (1). This is supported by our recent study in which we observed that lactose-intolerant subjects with mild symptoms or with diarrhea did not differ in degree of lactose digestion in the small intestine or orocecal transit time (2). On the basis of these observations, we suggest that in addition to the lactose digestion capacity in the small intestine, the colonic processing of maldigested lactose may play a role in lactose intolerance.
The colonic microbiota, which ferments lactose, is an important factor in the colonic processing of lactose. The colonic microbiota can be studied on the levels of composition and of metabolic activity. In our recent study in which fecal bacteria were quantified with fluorescent in situ hybridization (FISH),4 the composition of the fecal microbiota did not differ between lactose-intolerant subjects with mild symptoms or with diarrhea, possibly because of large interindividual differences. However, there was a negative correlation between the total number of bacteria and the 6-h symptom score (SSC), suggesting that the fermentation capacity of the colonic microbiota may be correlated with lactose intolerance (3).
During colonic fermentation, lactose is first hydrolyzed to glucose and galactose, which are subsequently fermented, leading to the production of a series of intermediate (e.g., lactate, formate and succinate) and end-product metabolites [i.e., acetate, propionate, and butyrate, gases (H2, CO2 and CH4), and biomass] (4,5). In the present study, we investigated whether the colonic fermentation of lactose was correlated with lactose intolerance by comparing the in vitro lactose-fermenting indices of fecal bacteria from lactose tolerant and intolerant subjects. The degree and rate of hydrolysis of lactose and production of lactate and short-chain fatty acids (SCFA) were compared between the 2 groups.
SUBJECTS AND METHODS
Subjects. Healthy Chinese subjects (n = 28; temporarily living in The Netherlands, 16 women and 12 men, age range 20–31 y) were recruited for this study. The subjects did not have diabetes or gastrointestinal disorders, and had not taken antibiotics or laxatives during the 3 mo before the study. Every subject signed a declaration of informed consent. The study was approved by the Medical Ethical Committee of the Groningen University Hospital and Faculty of Medical Sciences.
Collection of fecal samples.
The 28 subjects donated fecal samples for the in vitro fermentation experiment. Feces were collected in a sterile bag and maintained anaerobically with AnaeroGen COMPACT (Oxoid Limited). After arrival in the laboratory, samples were kept at <4°C. All samples were processed within 2 h after defecation. The processing procedure took 
20 min.
In vitro fermentation of lactose by fecal bacteria.
Fecal samples were diluted 5 times as described previously (6), brought into an anaerobic chamber (Anaerobic workstation, Concept 400; 10%H2, 10%CO2, 80%N2) and further diluted twice. For each fecal sample, 20 mL of this suspension was added to 20 mL of the anaerobic salt solution either with lactose (final concentration: 55.6 mmol/L or 0.4 g/g stool homogenate) or without lactose (control culture). The purpose of the control culture was to estimate the endogenous production of SCFA and lactate from carbohydrates, mucin, or other substrates in the original fecal samples. Both the control culture and the culture with lactose were examined in duplicate. In the incubation medium, the feces were diluted 20 times. The cultures were incubated at 37°C under anaerobic conditions for 5 h. During the incubation, samples were taken from the cultures at 0, 0.5, 1, 2, 3, and 5 h for quantification of SCFA, lactate, and sugars (lactose, glucose, and galactose). For measurement of lactate, the samples were immediately stored at –20°C until measurement. For measurement of SCFA and sugars, 1 mL of the samples was first mixed with 1.5 mL of 96% ethanol, centrifuged at 1500 x g for 5 min, and the supernatant was stored at –20°C until analysis.
Classification of lactose-tolerant and -intolerant subjects.
One to three weeks after donating fecal samples, the 28 subjects first underwent a glucose challenge (25 g) and a lactose challenge (25 g) in 2 single-blind tests. SSC was recorded during the 6 h after the challenge according to the method described earlier (2). The purpose of the glucose challenge was to select subjects who did not report complaints after glucose ingestion. A SSC <2 was considered to mean "no complaints." Among the 28 subjects, 20 reported a SSC of <2 after glucose and they underwent a second challenge of 25 g of lactose after which SSC was also recorded. The SSC after the glucose and the 2 lactose challenges were combined to define subjects who were "truly" lactose tolerant or intolerant according to the following criteria: 1) SSC 
2 after glucose challenge; and 2) consistent SSC after the 2 lactose challenges. Therefore, lactose-tolerant subjects are defined as having SSC 2 after glucose and the 2 lactose challenges, whereas intolerant subjects are defined as having SSC 2 after glucose and SSC >2 after the 2 lactose challenges. The SSC recorded during the second lactose challenge was used in the analysis of possible correlation between SSC and the composition of fecal bacteria.
Quantification of lactate, SCFA (acetate, propionate and butyrate) and sugars (lactose, glucose and galactose) in the in vitro fermentation samples. Of the 28 subjects, 12 were defined as lactose tolerant (n = 7) or intolerant (n = 5) according to the criteria mentioned above. Sugars, SCFA and lactate were quantified in the in vitro fermentation samples of these 12 subjects. Sugars were determined by GC using the method of Jansen et al. (7) with a few modifications, i.e., before derivatization, after methanol was added to the samples and the internal standard, the solution was completely evaporated without other processing steps; after derivatization, heptane was used for extraction instead of hexane; for GC analysis, GC-MS was used instead of GC, and 1 µL was injected instead of 2 µL. The L- and D-lactate were quantified by an enzymatic method using EnzytecTM L- and D-lactate kits (Scil Diagnostics ). For measurement of SCFA, 50 µL of 15 mmol/L isobutyrate in water (internal standard), 100 µL of the sample or SCFA standards (0–2 µmol):96% ethanol (1:1.5, v:v) and 900 µL 96% ethanol:water (3:2, v:v) were added to a headspace vial; 100 µL of 96% H2SO4 was added for acidification. The vials were stored at room temperature until analysis. The analysis is based on headspace GC. The SCFA were separated on a WCOT fused silica 25 m x 0.32 mm i.d. 0.2 mm Poraplot Q column (Varian) using an Agilent 6890 GC (Agilent technologies). The flow rate was kept constant at 1.1 mL/min. The temperature program was as follows: initial temperature 100°C; 10°/min to 150°C; 7.5°/min to 250°C. The gas phase sample was injected in the splitless mode using a 1-mL loop injection system. The injection temperature and flame ionization detector temperature were 250°C. The headspace device was an Agilent 7694 headspace sampler. The headspace conditions were as follows: headspace temperature 90°C, loop temperature 95°C, tray line 100°C, vial equilibration time 15 min, pressurizing time 3.0 min, loop fill time 1.0 min, loop equilibration time 0.25 min, and injection time 0.50 min.
Quantification of bacteria in feces with fluorescent in situ hybridization (FISH). 16S rRNA oligonucleotide probes were used to detect the numbers of total bacteria and major bacterial groups in the fecal samples from the 12 lactose tolerant and intolerant subjects (Table 1). With this set of probes, >90% of the total bacterial cells in the feces of adults could be detected (8,9). The hybridization and visualization of fluorescent cells were carried out according to the methods described previously (8,10). 4',6-Diamidino-2-phenylindole (DAPI)-staining was used to enumerate the total amount of cells in feces (10).
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Data analysis. Data are expressed as mean ± SD. Logarithmic transformation of the data was performed when necessary to obtain normally distributed data; when the data remained skewed after logarithmic transformation, nonparametric tests were applied. The hydrolysis rates of lactose and the production rates of SCFA, lactate, glucose, and galactose were calculated for periods within 0–0.5, 0.5–1, 1–2, 2–3, and 3–5 h of incubation (Table 2). The slope of the curve between 2 sampling points was calculated and taken as the rate of the time period. The slope of the curve between 0 and 5 h was calculated and taken as the overall rate. Because the rate of fermentation during different periods of incubation can differ among subjects, which might be correlated with the occurrence of symptoms, the comparison between the tolerant and intolerant groups took all of the rates or concentrations of metabolites of different periods into consideration. The univariate test was applied to assess the overall differences between the lactose-tolerant and -intolerant groups in the rates of hydrolysis and production, and the overall differences in the concentrations of sugars, SCFA, and lactate at 0, 0.5, 1, 2, 3 and 5 h. Student's t test (unpaired, two-tailed), the Mann-Whitney U-test, and the Multivariate test were applied to assess the difference between the 2 groups in the numbers of total cells (DAPI), total bacteria (Eub338), and major bacterial groups in feces (Bac303, Erec482, Fprau645, Bif164y, Ato291, and Rbro729/Rfla730), respectively. Correlations were assessed by calculating the Spearman correlation coefficients. Differences with P < 0.05 were regarded as significant. All analyses were performed using SPSS 12.0 for Windows software.
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RESULTS
Classification of lactose tolerant and intolerant subjects.
After the 28 subjects had undergone 1 glucose and 2 lactose challenges, 12 subjects were defined as lactose intolerant (n = 5) or tolerant (n = 7) according to the following criteria: 1) SSC 2 after glucose challenge; 2) consistent SSC after the 2 lactose challenges; 3) tolerant when SSC 2 and intolerant when SSC > 2.
Hydrolysis of lactose. During the 5-h incubation, the tolerant and intolerant groups did not differ in the hydrolysis rates of lactose (P > 0.1), in the production rates of glucose (P > 0.1) and galactose (P = 0.09) (Table 2), or in the concentrations of lactose (Fig. 1), glucose, and galactose (data not shown).
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Normalization of the data to the number of total bacteria. After normalization, the results of the comparison between the 2 groups did not change except that the tolerant group produced more galactose (P = 0.01) more rapidly (P = 0.05) than the intolerant group (data not shown).
DISCUSSION
In the present study, in vitro incubation with lactose showed that the fecal microbiota from lactose-intolerant subjects had faster production rates of D- and L-lactate, acetate, propionate, and butyrate than that from the tolerant subjects. The amounts of L-lactate and SCFA (acetate, propionate, and butyrate) produced were higher in the intolerant than in the tolerant subjects. The rate or degree of the hydrolysis of lactose did not differ between the 2 groups.
Whether colonic fermentation of lactose would influence the occurrence of lactose intolerance, either aggravate or alleviate it, depends on the balance between the ability of the colonic microbiota to ferment lactose and the ability of the colon to remove the fermentation metabolites. A low lactose-fermenting capacity of the colonic microbiota, which leads to inefficient removal of the maldigested lactose (and/or its intermediate fermentation metabolites), or a low absorption capacity of the colon, which leads to inefficient removal of the fermentation metabolites, may contribute to the occurrence of symptoms. When lactose is converted to SCFA by fermentation, the osmotic load is increased by 8-fold, which makes the efficiency of the colon to absorb these fermentation metabolites an important determinant for the outcome of the osmotic load caused by malabsorbed lactose (11). It is generally believed that the colon has a high capacity to absorb SCFA (12,13); the absorption rate is 6.1–12.6 µmol/(cm2·h) (14,15). However, there are differences among segments in colonic permeability for the 3 major SCFA. Acetate is absorbed at the highest rate in the cecum and proximal colon, and butyrate in the distal colon; propionate is absorbed at a similar rate in the proximal and distal colon (16). Lactate is an intermediary organic acid in the bacterial fermentation of carbohydrates and is further converted to SCFA; as a result, it is rarely present in large amounts in feces (15,17,18). If the colon can absorb SCFA at a sufficient rate, a higher lactose-fermenting capacity of the colonic microbiota may help to alleviate lactose intolerance.
However, our results do not support this assumption. A possible explanation for our observations could be that although the colon is thought to possess a high capacity to absorb SCFA, the absorption rate might not be sufficient to remove in a short period in situ all of the SCFA produced from rapid fermentation of lactose. Several studies reported increased cecal SCFA pools or lactate concentration in rats fed oligosaccharides or fructooligosaccharides, indicating colonic accumulation of organic acids produced from rapid fermentation of those carbohydrates (19–21). Accordingly, the rapid fermentation of undigested lactose may result in temporary accumulation of SCFA in the lumen, which causes symptoms. Lactate and other intermediate metabolites can also accumulate temporarily if their further conversion and absorption by the colon cannot counteract their production. Segmental differences existing in colonic absorption rates of SCFA might play a role in the accumulation of SCFA in certain parts of the colon. For instance, the absorption rate of butyrate is lower in the cecum and proximal colon (16), which is a major site of carbohydrate fermentation. Therefore, fermentation of lactose might lead to an accumulation of butyrate in this part of the colon. In the present study, we observed that the production rate of butyrate in vitro was faster in lactose-intolerant subjects than -tolerant subjects.
Several hypotheses may explain why the temporarily accumulated fermentation metabolites could cause symptoms. First, the osmotic load posed by those temporarily accumulated metabolites will draw fluid to the colonic lumen. The 12 lactose tolerant and intolerant subjects digested 38 ± 12% of the 25 g of lactose in the small intestine (data not shown) as estimated by the lactose digestion index (22). In principle, colonic fermentation converts 1 mol of lactose to 3.7 mol of organic acids (23), but in reality, the production will be less because a considerable part of hexose will be incorporated into the bacterial mass (24). The malabsorbed lactose (25 g x 60% = 15 g), which we assume is completely converted to organic acids, represents an osmotic load of 190 mOsm, which will result in 633 mL of water in the colon (11). But this amount of fluid is unlikely to cause symptoms considering the high capacity of the colon to absorb fluid (25). Second, symptoms could appear because of the altered intestinal motility. The temporarily accumulated fermentation metabolites could trigger motor events in the intestine. Colonic fermentation of indigestible carbohydrates or/and its products may affect the motility of the proximal part of the gastrointestinal tract (26–28). SCFA affect motility in rat colon in vitro (29,30) and in vivo (31,32). SCFA also affect the motility of the upper gut. The motor effects of SCFA are dose dependent, suggesting that excessive amounts of rapidly fermented sugars might induce undesirable motor and visceral sensitivity effects. However, those effects of SCFA have not yet been observed in humans (33). Furthermore, chemosensitive intestinal receptors, e.g., glucoreceptors, acid and alkali receptors, are present in the stomach and the small intestine (34). It is not known whether chemosensitive receptors are also present in the colon and if so, whether they will respond by altering the motility of the intestine upon chemical stimulation of fermentation metabolites. Alterations in motility of the gastrointestinal tract are believed to play an important role in the origin of symptoms in functional gastrointestinal disorders (35,36), whose symptoms resemble those of lactose intolerance. It is not clear whether changes in intestinal motility are correlated with symptoms of lactose intolerance. Jouet et al. (37) found that only 37% of the symptoms after intake of 40 g lactulose coincided in time with colonic motor events. Moreover, the temporary accumulation of fermentation metabolites can cause colonic hypersensitivity. In 2 recent studies, butyrate enemas elicited colonic hypersensitivity in rats (38); this was used to develop a model of chronic colonic hypersensitivity as a tool for studying irritable bowel syndrome (39).
The hydrolysis of lactose to glucose and galactose is the first step of colonic fermentation of lactose, catalyzed by the enzyme ß-galactosidase. ß-Galactosidase is often measured as an indicator of the colonic capacity to ferment lactose (40–42). However, we observed recently that the majority (80.6%) of the fecal microbiota from lactase-nonpersistent subjects possesses ß-galactosidase activity (6). It is unlikely that lactose itself will present a large osmotic threat in the colon because it should be quickly hydrolyzed by the colonic microbiota. Results from the present study agree with this assumption. There were no differences in the hydrolysis of lactose between the lactose-tolerant and -intolerant subjects in the in vitro incubation. On the basis of the above observation, we conclude that the hydrolysis of lactose does not play a role in lactose intolerance. Instead, the fermentation steps after the hydrolysis of lactose are related to the development of symptoms.
Similar to what we found in a previous study (3), the composition of fecal microbiota was not different between the lactose tolerant and intolerant subjects. The possible reasons why differences in the fecal microbiota between the 2 groups were found in metabolic activities but not in composition could be that the detection of bacteria with FISH is not based on a strain-specific but a genus- or group-specific level. Bacterial strains of the same genus or group may have different metabolic capacities. Furthermore, the detection limit of bacteria in feces with FISH is 106–107cells/g feces (0.001–0.01% of the total fecal bacteria). Bacterial groups whose numbers are below this level cannot be detected with FISH. In addition, large variations in bacterial numbers among individuals are often reported (3,8), which makes it difficult to clarify the differences in bacterial composition.
Feces are often used in studies on the fermentation properties of the colon, considering the difficulties in sampling the colon directly and the observations that the indices of in vitro incubation with feces can be used to predict or interpret in vivo conditions; these conditions are rather stable through time and vary among individuals (43–46). However, there might be differences between metabolic activities determined with in vitro fermentation of fecal bacteria and that present in the colon, especially in the cecum and proximal colon, the major site of carbohydrate fermentation. In vivo studies, e.g., those in which stable isotope techniques are applied (47), may help to shed more light on colonic fermentation of carbohydrates.
In summary, by comparing the in vitro lactose-fermenting indices of fecal bacteria from lactose-tolerant and -intolerant subjects, we suggest that the colonic fermentation of lactose by the microbiota plays a role in lactose intolerance. The fermentative processes after lactose is hydrolyzed are related to the development of symptoms, whereas the hydrolysis of lactose is not. Studies are warranted to further investigate the mechanisms by which those fermentative processes after hydrolysis of lactose and the intermediate and end metabolites of those processes influence the development of symptoms. Furthermore, the reaction of the colon toward those metabolites, i.e., absorption rate and motility alterations, provides an interesting issue for studies on lactose intolerance.
ACKNOWLEDGMENTS
We gratefully acknowledge Klaas Bijsterveld and Albert Gerding, Renze Boverhof, and Toos Dalenoort for their assistance in measurement of sugars, SCFA, and lactate measurement, respectively. The help from Janneke Heimweg and Marianne Schepers in the glucose and lactose challenge tests is greatly appreciated as is that of Gerwin Raangs and Marga Wester with the in vitro fermentation experiment. We thank Koen Venema of the Wageningen Centre for Food Sciences, the Netherlands, for critically reading the manuscript and helpful discussions.
FOOTNOTES
1 Financed by the Wageningen Centre for Food Sciences, Wageningen, The Netherlands. 
3 Present address: Guiyang Medical College, Guizhou, China.
4 Abbreviations used: DAPI, 4',6-diamidino-2-phenylindole; FISH, fluorescent in situ hybridization; SCFA, short-chain fatty acids; SSC, 6-h symptom score.
Manuscript received 26 August 2005. Initial review completed 14 September 2005. Revision accepted 25 October 2005.
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