- Email: [email protected]
Rifaximin in patients with lactose intolerance
Digestive and Liver Disease 37 (2005) 316–319
Alimentary Tract
Rifaximin in patients with lactose intolerance G. Cappello, L. Marzio ∗ Department of Medicine and Ageing, G. d’Annunzio University, Chieti-Pescara, Italy Received 14 May 2004; accepted 1 December 2004 Available online 23 February 2005
Abstract Background. Abdominal symptoms linked to lactose malabsorption may be caused by metabolic activity of colonic bacteria. Rifaximin, a non-absorbable rifampycin derivative, is active against colonic bacteria, it may be useful in the treatment of lactose intolerance. Aim. The aim of this study has been to evaluate short-term rifaximin therapy in patients with lactose intolerance. Methods. Thirty-two patients with lactose intolerance diagnosed using the hydrogen lactose breath test were studied. Fourteen patients received rifaximin 800 mg/day for 10 days, 13 patients followed a diet without milk for 40 days and 5 patients received a placebo for 10 days. Total breath H2 excretion expressed as area under the curve, and the symptom score were evaluated in all patients at the start, and subsequently after 10 and 40 days. Results. In the 14 patients who received rifaximin for 10 days, area under the curve at day 10 and day 40 was statistically significantly lower than the one computed at basal (P < 0.01). Diet reduced area under the curve progressively reaching statistical significance at day 40, while the placebo did not change area under the curve throughout the study. The total symptom score significantly improved after rifaximin and diet. Conclusion. In patients with lactose intolerance, a 10-day therapy with rifaximin as well as 40-day diet without lactose reduces the area under the curve and the symptom score. © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: H2 breath test; Lactose intolerance; Rifaximin
1. Introduction Lactose is a disaccharide made up of glucose and galactose present in milk and other diary products. Before absorption, lactose is hydrolysed in the small intestine by a Bgalactosidase lactase–phloritzin hydrolase, generally called lactase, into glucose and galactose [1]. The prevalence of lactose maldigestion is in more than 50% of the population in South America, Africa, Asia and varies from 2% in northern Europe to about 70% in the south of Italy [2]. The lactase deficiency alone in rare cases is congenital [3]; in the greater part of the cases, instead, may be primary (i.e. genetic) or secondary to disease that damages the intestinal epithelium [2]. Lactase deficiency may be associated with ∗
Corresponding author. Fax: +39 085 4295 547. E-mail address: [email protected] (L. Marzio).
several symptoms such as abdominal distention and pain, bloating and diarrhoea, a phenomenon called lactose intolerance [1]. Symptoms are determined by the metabolic activity of the anaerobic bacteria of the colon that produce H2 through the fermentation of lactose that arrives at the proximal colon unchanged, through the fermentation of carbohydrates [4]. Lactase deficiency may be treated successfully with a specific diet without milk and derivatives, but several side effects, which include calcium deficiency, may arise after long-term application of this diet. A modification of colonic anaerobic bacteria with probiotics or antibiotics may be an alternative way of treatment. A recent study has shown that short-term treatment with rifaximin reduces the curve of excretion of H2 in patients with bacterial overgrowth [5], suggesting a potential beneficial effect in patients with lactose intolerance as well. The aim of this study has been therefore to evaluate whether or not rifaximin modifies breath H2 hydrogen
1590-8658/$30 © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2004.12.007
G. Cappello, L. Marzio / Digestive and Liver Disease 37 (2005) 316–319
production and improves symptoms in patients with lactose intolerance.
317
was obtained from all patients who fulfilled the inclusion criteria. 2.1. Statistical analysis
2. Patients and methods Patients with symptoms characterised by abdominal pain, diarrhoea and bloating with positive breath H2 test for lactose intolerance were selected. Exclusion criteria were the following: previous abdominal surgery, positive colonoscopy for organic pathologies, older than 80 and younger than 18, antibiotic therapy within the previous 2 months and a lactosefree diet for 30-days prior to the study. The patients enrolled filled in a questionnaire related to the intensity of the following symptoms: bloating, abdominal pain, abdominal distension and diarrhoea (loose stools with >3 defections/day). The symptoms score referred to the 5 days preceding each evaluation and were scored as: 0, absent; 1, mild (awareness of a symptom but easily tolerated); 2, moderate (interference with normal activities); 3, severe (incapacitating); and 4, very severe. The gas intestinal production was measured with hydrogen lactose breath test (Quintron Model 12i Microlyzer, SPECTRA2000, Rome, Italy). The breath samples were collected after 12 h fasting and every 30 min for 4 h after ingestion of 200 ml of fresh whole milk. Patients were considered positive for lactose intolerance if their H2 excretion increased over basal values by more than 20 parts per million (ppm) for two consecutive samples. Total excretion of H2 in the 4 h study was computed according to Kotler et al. [6], and has been expressed as area under the concentration–time curves (AUC, ppm, 4 h). Patients enrolled were randomly allocated into one of the following three groups: one group received rifaximin orally (400 mg before breakfast and supper) for 10 days, another group received placebo (before breakfast and supper) for 10 days and the third group followed a diet without lactose for 40 days. Patients on the lactose-free diet were instructed to avoid milk and the following foods that contain dairy products: industrial milk, cheese and cream cheese, powdered milk, bread, pasta and milk biscuits, cakes with custard, animal giblets, meatballs and meat cutlets, all smoked and canned meat and fish, packed meats with powdered milk and other milk derivatives, peas, dried beans, beets, mashed potatoes, mayonnaise and white sauce, chocolate, ice-cream, whipped cream, sweets and custards made with milk, pastry cream, candies, chewing gum, all drinks made with milk, all food containing casein and lactalbumin. Patients on rifaximin or placebo were instructed not to modify their diet followed before the study. The total excretion of H2 was evaluated before the therapy, at the conclusion of the therapy and 1 month after the end of the therapy. The AUC and symptom score were evaluated in all patients at the study start, and at 10 and 40 days subsequently. The protocol was approved by the ethical committee of G. d’Annunzio University and a written informed consent
All data are expressed as mean ± S.D. Mann–Whitney Utest, Wilcokson’s rank sum test and Fisher exact probability test were used to analyse the symptom score and AUC. The Spearman rank correlation coefficient and regression line were also calculated between the symptom score of each symptom and AUC computed at study start and at 10 and 40 days subsequently. P value less than 0.05 was considered significant.
3. Results Sixteen patients were included in the rifaximin group, 16 in the diet group and 8 in the placebo group. Two patients in the group of rifaximin and three in the group of diet and placebo, respectively, did not return to control, therefore they were excluded from the study. The following data are referred to the patients who completed the study. Fourteen patients (12 F, 2 M, mean age 41 ± 16 years) received rifaximin, 13 patients (10 F, 3 M, mean age 46 ± 21 years) diet without lactose and 5 patients (2 F, 3 M, mean age 46 ± 16 years) received placebo. The 14 patients who received rifaximin at the end of therapy showed an AUC that was statistically significantly lower than the one computed before therapy (Table 1). Forty days from the beginning of therapy, although increased in comparison to the one computed after 10 days, AUC was still significantly lower than the one computed at basal (Table 1). Diet reduced AUC progressively with a statistical significance 40 days from start, while placebo did not change the AUC throughout the study (Table 1). Intensity of each symptom significantly improved with rifaximin and diet at day 10 and day 40 from the start of study (Table 2). In the placebo group, the basal score of distension and pain was clearly less than the one of the group of rifaximin and diet. This difference however was not statistically significant. The symptom score in patients who received placebo did not change throughout the study (Table 2). A statistically significant correlation was found between the score of bloating, distension, diarrhoea but not pain and AUC computed at each step of the study (basal, 10 and 40 days). Since each patient was tested three times, a total of 96 AUC after lactose load and 96 scores for each symptom were collected (Fig. 1). Table 1 AUC in 14 patients treated with rifaximin, 13 with diet and 5 with placebo
Rifaximin Diet Placebo ∗
Basal
10 days
40 days
5955 ± 3132 6099 ± 4207 6068 ± 2116
1639 ± 1302*
3343 ± 2624* 2374 ± 1987* 6058 ± 2109 n.s.
5597 ± 5508 n.s. 6982 ± 2746 n.s.
P < 0.01 vs. before therapy, n.s. vs. before therapy.
318
G. Cappello, L. Marzio / Digestive and Liver Disease 37 (2005) 316–319
Table 2 Symptoms intensity in 14 patients treated with rifaximin 800 mg for 10 days, 13 with lactose-free diet for 40 days and 5 with placebo for 10 days Rifaximin Basal Distension Pain Bloating Diarrhoea ∗
2.4 2.0 2.5 1.3
± ± ± ±
Diet 10 days
1.1 1.1 1 1.7
1.4 ± 0.9*
0.6 ± 0.7* 1.6 ± 0.9* 0.4
40 days 1.5 1 1.6 0.2
± ± 1.2* ± 0.9* ± 0.6* 1.2*
Basal 1.8 ± 1.6 1.3 ± 1.0 2.5 ± 1.1 2.2
Placebo 10 days 1.2 0.7 1.9 1.0
± ± 1.0* ± 1.3* ± 0.9* 1.4*
40 days 1.5 0.5 1.8 0.7
± ± 0.7* ± 1.2* ± 1.1* 1.1*
Basal 1.6 1.0 2.8 1.3
± ± ± ±
10 days 1.3 1.4 1.0 1.7
1.5 1.0 2.7 1.4
± ± ± ±
1.0 1.4 0.5 0.9
40 days 1.7 0.7 2.7 1.0
± ± ± ±
1.7 0.9 1.2 0.9
P < 0.05 vs. before therapy, n.s. vs. before therapy.
Fig. 1. Spearman correlation coefficient and regression line between AUC after lactose load and symptoms score of the 5 days preceding the test in 14 patients treated with rifaximin, 5 with placebo and 13 with lactose-free diet evaluated at basal, after 10 and 40 days from the beginning of the study for a total of 96 evaluations.
4. Discussion This study shows that in patients with lactose intolerance, abdominal symptoms such as fullness, bloating and diarrhoea and not pain are correlated with the amount of colonic gas production. It is also shown that a 10-day therapy with rifaximin at 800 mg/day reduces symptoms score and normalises the breath H2 hydrogen curve in patients with lactose intolerance. The pathogenesis of abdominal distension and pain in patients with lactose intolerance is not fully understood. While pain seems to be more related with intestinal motility and perception rather than increased colonic gas volumes [7], diarrhoea may be due to an osmotic effect of the excess of acidic products of fermentation formed in the colon by various bacteria [8]. Bloating and fullness and flatulence seem to be generated by events occurring in the colon [9], however studies on healthy volunteers or patients with irritable bowel syndrome, performed with lactulose or fibre load, do not always
succeed in showing a direct correlation between these symptoms and colonic H2 production [10,11]. Our study supports the hypothesis that in patients who fail to absorb lactose, the intensity of abdominal symptoms such as bloating and fullness is directly correlated with the amount of H2 produced after a lactose load. This correlation is reinforced by the evidence that on reducing the colonic H2 load with rifaximin or lactose-free diet these symptoms are reduced as well. In patients with lactose intolerance, a diet without milk and dairy products when followed for long periods of time may induce reduction of calcium intake and ostheopenia [12,13]. The beneficial effect of dietary restriction is thought to be determined by the reduction of the substrate that should be fermented from the colonic bacteria [14]. Recently, various studies have proposed alternative treatment such as the daily intake of fresh yogurt with alive bacteria that improves lactose absorption and reduces H2 production [15]. Probiotics have also been shown to be effective in reducing symptoms in pa-
G. Cappello, L. Marzio / Digestive and Liver Disease 37 (2005) 316–319
tients with lactose intolerance [16]. A recent study has shown that Kefir, a fermented milk beverage that contains various bacteria cultures other than yogurt, improves lactose digestion and tolerance in adults with lactose maldigestion [17]. Rifaximin, a non-absorbable rifampycin derivative, has been shown to be highly effective against anaerobic bacteria [18] that produce large volume of hydrogen, carbon dioxide and methane via carbohydrate fermentation [19]. Di Stefano et al. [20] in patients with irritable bowel syndrome showed that the colonic production of H2 was increased in comparison to normal controls, and that rifaximin significantly reduces both the H2 production and the related symptoms. In patients with lactose intolerance, the study suggests that abdominal symptoms are linked to the presence of specific bacteria and it has been recently shown that there is a negative association between the presence of bacteria that are capable of hydrolysing lactose and intestinal symptoms [21]. On the basis of this study, it may be speculated that rifaximin reduces intestinal symptoms through a reduction of fermentative bacteria that produce H2 and a relative increase of those specific bacteria that are linked to hydrolyses of lactose. An increased prevalence of lactose intolerance has been shown in irritable bowel syndrome (IBS) with a high prevalence of abnormal lactulose breath test, suggesting bacterial overgrowth. Because symptoms of lactose intolerance result from bacterial fermentation, abnormal lactose breath test may be reflective of early presentation of lactose to bacteria or malabsorption or both. Indeed, in a recent study on patients with IBS, with symptoms suggestive for lactose malabsorption [22], a significant correlation was seen between the hydrogen production of lactose and lactulose breath test, suggesting the simultaneous presence in these patients of lactose intolerance and bacterial overgrowth. The beneficial effect of rifaximin shown in the present study may also reflect the presence of bacterial overgrowth in our patients as well. It must be noted however, that so far we have performed lactulose breath test in 10 patients with a positive lactose breath test and none of them was found with bacterial overgrowth. In conclusion, this study shows that 10 days of antibiotic therapy reduces the intestinal hydrogen production and symptoms in patients with lactose intolerance for about 30 days, suggesting that intestinal bacteria may be involved in the pathogenesis of this common clinical syndrome. Further studies with prolonged administration of rifaximin and longer follow up are necessary to determine its therapeutic value in lactose intolerance. Conflict of interest statement None declared.
References [1] De Vrese M, Sieber R, Stransky M. Lactose in human nutrition. Schweiz Med Wochenschr 1998;128:1393–400.
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[2] Vesa TH, Marteau P, Korpela R. Lactose intolerance. J Am Coll Nutr 2000;19:165S–75S. [3] Lisker R, Gonzalez B, Daltabuit M. Recessive inheritance of the adult type of intestinal lactase deficiency. Am J Hum Genet 1975;27:662–4. [4] Haderstorfer B, Psycholgin D, Whitehead WE, Schuster MM. Intestinal gas production from bacterial fermentation of undigested carbohydrate in irritable bowel syndrome. Am J Gastroenterol 1989;84:375–8. [5] Di Stefano M, Malservisi S, Veneto G, Ferrieri A, Corazza GR. Rifaximin versus chlortetracycline in the short-term treatment of small intestinal bacterial overgrowth. Aliment Pharmacol Ther 2000;14:551–6. [6] Kotler DP, Holt PR, Rosensweig NS. Modification of the breath hydrogen test: increased sensitivity for the detection of carbohydrate malabsorption. J Lab Clin Med 1982;100:789– 805. [7] Lasser RB, Bond JH, Levitt MD. The role of intestinal gas in functional abdominal pain. N Engl J Med 1975;293:524– 6. [8] Bennett A, Eley KG. Intestinal pH and propulsion: an explanation of diarrhoea in lactase deficiency and laxation by lactulose. J Pharm Pharmacol 1976;28:192–5. [9] Jouet P, Sabate JM, Coffin B, Bouhnik Y, Lemann M, Jian R, et al. Sugar intolerance: origin and mechanisms of symptoms? Dig Dis Sci 2002;47:886–93. [10] Levitt MD, Furne J, Olsson S. The relation of passage of gas an abdominal bloating to colonic gas production. Ann Intern Med 1996;124:422–4. [11] Bianchi M, Capurso L. Effects of guar gum, ispaghula and microcrystalline cellulose on abdominal symptoms, gastric emptying, orocaecal transit time and gas production in healthy volunteers. Dig Liver Dis 2002;34:129S–33S. [12] Vernia P, Ricciardi MR, Frandina C, Bilotta T, Frieri G. Lactose malabsorption and irritable bowel syndrome. Effects of a long term lactose free diet. Ital J Gastroenterol 1995;27:117–21. [13] Mainguet P, Faille I, Destrebecq L, Devgelaer JP, Nagant de Deuxchais C. Lactose intolerance, calcium intake, and ostepenia. Lancet 1991;338:1156–7. [14] King TS, Elia M, Hunter JO. Abnormal colonic fermentation in irritable bowel syndrome. Lancet 1998;352:921–9. [15] Rizkalla SW, Luo J, Kabir M, Chevalier A, Pacher N, Slama G. Chronic consumption of fresh but not heated yogurt improve breathhydrogen status and short-chain fatty acid profiles: a controlled study in healthy men with or without lactose maldigestion. Am J Clin Nutr 2000;72:1474–9. [16] De Vrese M, Stegelmann A, Richter B, Fenselau S, Laue C, Schrezenmeir J. Probiotics compensation for lactase insufficiency. Am J Clin Nutr 2001;73:421–9. [17] Hertzler SR, Clancy SM. Kefir improves lactose digestion and tolerance in adults with lactose maldigestion. J Am Diet Assoc 2003;103:582–7. [18] Lamanna A, Orsi A. In vitro activity of rifaximin and rifampicin against some anaerobic bacteria. Chemioterapia 1984;6:365–7. [19] Levitt MD, Bond JH. Volume, composition and source of intestinal gas. Gastroenterology 1970;59:921–9. [20] Di Stefano M, Strocchi A, Malservisi S, Veneto G, Ferrieri A, Corazza GR. Non absorbable antibiotics for managing intestinal gas production and gas-related symptoms. Aliment Pharmacol Ther 2000;14:1001–8. [21] Zhong Y, Priebe MG, Vonk RJ, Huang CY, Antoine JM, He T, et al. The role of colonic microbiota in lactose intolerance. Dig Dis Sci 2004;49:78–83. [22] Pimentel M, Kong Y, Park S. Breath testing to evaluate lactose intolerance in irritable bowel syndrome correlates with lactulose testing and may not reflect true lactose malabsorption. Am J Gastroenterol 2003;98:2700–4.
Alimentary Tract
Rifaximin in patients with lactose intolerance G. Cappello, L. Marzio ∗ Department of Medicine and Ageing, G. d’Annunzio University, Chieti-Pescara, Italy Received 14 May 2004; accepted 1 December 2004 Available online 23 February 2005
Abstract Background. Abdominal symptoms linked to lactose malabsorption may be caused by metabolic activity of colonic bacteria. Rifaximin, a non-absorbable rifampycin derivative, is active against colonic bacteria, it may be useful in the treatment of lactose intolerance. Aim. The aim of this study has been to evaluate short-term rifaximin therapy in patients with lactose intolerance. Methods. Thirty-two patients with lactose intolerance diagnosed using the hydrogen lactose breath test were studied. Fourteen patients received rifaximin 800 mg/day for 10 days, 13 patients followed a diet without milk for 40 days and 5 patients received a placebo for 10 days. Total breath H2 excretion expressed as area under the curve, and the symptom score were evaluated in all patients at the start, and subsequently after 10 and 40 days. Results. In the 14 patients who received rifaximin for 10 days, area under the curve at day 10 and day 40 was statistically significantly lower than the one computed at basal (P < 0.01). Diet reduced area under the curve progressively reaching statistical significance at day 40, while the placebo did not change area under the curve throughout the study. The total symptom score significantly improved after rifaximin and diet. Conclusion. In patients with lactose intolerance, a 10-day therapy with rifaximin as well as 40-day diet without lactose reduces the area under the curve and the symptom score. © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: H2 breath test; Lactose intolerance; Rifaximin
1. Introduction Lactose is a disaccharide made up of glucose and galactose present in milk and other diary products. Before absorption, lactose is hydrolysed in the small intestine by a Bgalactosidase lactase–phloritzin hydrolase, generally called lactase, into glucose and galactose [1]. The prevalence of lactose maldigestion is in more than 50% of the population in South America, Africa, Asia and varies from 2% in northern Europe to about 70% in the south of Italy [2]. The lactase deficiency alone in rare cases is congenital [3]; in the greater part of the cases, instead, may be primary (i.e. genetic) or secondary to disease that damages the intestinal epithelium [2]. Lactase deficiency may be associated with ∗
Corresponding author. Fax: +39 085 4295 547. E-mail address: [email protected] (L. Marzio).
several symptoms such as abdominal distention and pain, bloating and diarrhoea, a phenomenon called lactose intolerance [1]. Symptoms are determined by the metabolic activity of the anaerobic bacteria of the colon that produce H2 through the fermentation of lactose that arrives at the proximal colon unchanged, through the fermentation of carbohydrates [4]. Lactase deficiency may be treated successfully with a specific diet without milk and derivatives, but several side effects, which include calcium deficiency, may arise after long-term application of this diet. A modification of colonic anaerobic bacteria with probiotics or antibiotics may be an alternative way of treatment. A recent study has shown that short-term treatment with rifaximin reduces the curve of excretion of H2 in patients with bacterial overgrowth [5], suggesting a potential beneficial effect in patients with lactose intolerance as well. The aim of this study has been therefore to evaluate whether or not rifaximin modifies breath H2 hydrogen
1590-8658/$30 © 2005 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2004.12.007
G. Cappello, L. Marzio / Digestive and Liver Disease 37 (2005) 316–319
production and improves symptoms in patients with lactose intolerance.
317
was obtained from all patients who fulfilled the inclusion criteria. 2.1. Statistical analysis
2. Patients and methods Patients with symptoms characterised by abdominal pain, diarrhoea and bloating with positive breath H2 test for lactose intolerance were selected. Exclusion criteria were the following: previous abdominal surgery, positive colonoscopy for organic pathologies, older than 80 and younger than 18, antibiotic therapy within the previous 2 months and a lactosefree diet for 30-days prior to the study. The patients enrolled filled in a questionnaire related to the intensity of the following symptoms: bloating, abdominal pain, abdominal distension and diarrhoea (loose stools with >3 defections/day). The symptoms score referred to the 5 days preceding each evaluation and were scored as: 0, absent; 1, mild (awareness of a symptom but easily tolerated); 2, moderate (interference with normal activities); 3, severe (incapacitating); and 4, very severe. The gas intestinal production was measured with hydrogen lactose breath test (Quintron Model 12i Microlyzer, SPECTRA2000, Rome, Italy). The breath samples were collected after 12 h fasting and every 30 min for 4 h after ingestion of 200 ml of fresh whole milk. Patients were considered positive for lactose intolerance if their H2 excretion increased over basal values by more than 20 parts per million (ppm) for two consecutive samples. Total excretion of H2 in the 4 h study was computed according to Kotler et al. [6], and has been expressed as area under the concentration–time curves (AUC, ppm, 4 h). Patients enrolled were randomly allocated into one of the following three groups: one group received rifaximin orally (400 mg before breakfast and supper) for 10 days, another group received placebo (before breakfast and supper) for 10 days and the third group followed a diet without lactose for 40 days. Patients on the lactose-free diet were instructed to avoid milk and the following foods that contain dairy products: industrial milk, cheese and cream cheese, powdered milk, bread, pasta and milk biscuits, cakes with custard, animal giblets, meatballs and meat cutlets, all smoked and canned meat and fish, packed meats with powdered milk and other milk derivatives, peas, dried beans, beets, mashed potatoes, mayonnaise and white sauce, chocolate, ice-cream, whipped cream, sweets and custards made with milk, pastry cream, candies, chewing gum, all drinks made with milk, all food containing casein and lactalbumin. Patients on rifaximin or placebo were instructed not to modify their diet followed before the study. The total excretion of H2 was evaluated before the therapy, at the conclusion of the therapy and 1 month after the end of the therapy. The AUC and symptom score were evaluated in all patients at the study start, and at 10 and 40 days subsequently. The protocol was approved by the ethical committee of G. d’Annunzio University and a written informed consent
All data are expressed as mean ± S.D. Mann–Whitney Utest, Wilcokson’s rank sum test and Fisher exact probability test were used to analyse the symptom score and AUC. The Spearman rank correlation coefficient and regression line were also calculated between the symptom score of each symptom and AUC computed at study start and at 10 and 40 days subsequently. P value less than 0.05 was considered significant.
3. Results Sixteen patients were included in the rifaximin group, 16 in the diet group and 8 in the placebo group. Two patients in the group of rifaximin and three in the group of diet and placebo, respectively, did not return to control, therefore they were excluded from the study. The following data are referred to the patients who completed the study. Fourteen patients (12 F, 2 M, mean age 41 ± 16 years) received rifaximin, 13 patients (10 F, 3 M, mean age 46 ± 21 years) diet without lactose and 5 patients (2 F, 3 M, mean age 46 ± 16 years) received placebo. The 14 patients who received rifaximin at the end of therapy showed an AUC that was statistically significantly lower than the one computed before therapy (Table 1). Forty days from the beginning of therapy, although increased in comparison to the one computed after 10 days, AUC was still significantly lower than the one computed at basal (Table 1). Diet reduced AUC progressively with a statistical significance 40 days from start, while placebo did not change the AUC throughout the study (Table 1). Intensity of each symptom significantly improved with rifaximin and diet at day 10 and day 40 from the start of study (Table 2). In the placebo group, the basal score of distension and pain was clearly less than the one of the group of rifaximin and diet. This difference however was not statistically significant. The symptom score in patients who received placebo did not change throughout the study (Table 2). A statistically significant correlation was found between the score of bloating, distension, diarrhoea but not pain and AUC computed at each step of the study (basal, 10 and 40 days). Since each patient was tested three times, a total of 96 AUC after lactose load and 96 scores for each symptom were collected (Fig. 1). Table 1 AUC in 14 patients treated with rifaximin, 13 with diet and 5 with placebo
Rifaximin Diet Placebo ∗
Basal
10 days
40 days
5955 ± 3132 6099 ± 4207 6068 ± 2116
1639 ± 1302*
3343 ± 2624* 2374 ± 1987* 6058 ± 2109 n.s.
5597 ± 5508 n.s. 6982 ± 2746 n.s.
P < 0.01 vs. before therapy, n.s. vs. before therapy.
318
G. Cappello, L. Marzio / Digestive and Liver Disease 37 (2005) 316–319
Table 2 Symptoms intensity in 14 patients treated with rifaximin 800 mg for 10 days, 13 with lactose-free diet for 40 days and 5 with placebo for 10 days Rifaximin Basal Distension Pain Bloating Diarrhoea ∗
2.4 2.0 2.5 1.3
± ± ± ±
Diet 10 days
1.1 1.1 1 1.7
1.4 ± 0.9*
0.6 ± 0.7* 1.6 ± 0.9* 0.4
40 days 1.5 1 1.6 0.2
± ± 1.2* ± 0.9* ± 0.6* 1.2*
Basal 1.8 ± 1.6 1.3 ± 1.0 2.5 ± 1.1 2.2
Placebo 10 days 1.2 0.7 1.9 1.0
± ± 1.0* ± 1.3* ± 0.9* 1.4*
40 days 1.5 0.5 1.8 0.7
± ± 0.7* ± 1.2* ± 1.1* 1.1*
Basal 1.6 1.0 2.8 1.3
± ± ± ±
10 days 1.3 1.4 1.0 1.7
1.5 1.0 2.7 1.4
± ± ± ±
1.0 1.4 0.5 0.9
40 days 1.7 0.7 2.7 1.0
± ± ± ±
1.7 0.9 1.2 0.9
P < 0.05 vs. before therapy, n.s. vs. before therapy.
Fig. 1. Spearman correlation coefficient and regression line between AUC after lactose load and symptoms score of the 5 days preceding the test in 14 patients treated with rifaximin, 5 with placebo and 13 with lactose-free diet evaluated at basal, after 10 and 40 days from the beginning of the study for a total of 96 evaluations.
4. Discussion This study shows that in patients with lactose intolerance, abdominal symptoms such as fullness, bloating and diarrhoea and not pain are correlated with the amount of colonic gas production. It is also shown that a 10-day therapy with rifaximin at 800 mg/day reduces symptoms score and normalises the breath H2 hydrogen curve in patients with lactose intolerance. The pathogenesis of abdominal distension and pain in patients with lactose intolerance is not fully understood. While pain seems to be more related with intestinal motility and perception rather than increased colonic gas volumes [7], diarrhoea may be due to an osmotic effect of the excess of acidic products of fermentation formed in the colon by various bacteria [8]. Bloating and fullness and flatulence seem to be generated by events occurring in the colon [9], however studies on healthy volunteers or patients with irritable bowel syndrome, performed with lactulose or fibre load, do not always
succeed in showing a direct correlation between these symptoms and colonic H2 production [10,11]. Our study supports the hypothesis that in patients who fail to absorb lactose, the intensity of abdominal symptoms such as bloating and fullness is directly correlated with the amount of H2 produced after a lactose load. This correlation is reinforced by the evidence that on reducing the colonic H2 load with rifaximin or lactose-free diet these symptoms are reduced as well. In patients with lactose intolerance, a diet without milk and dairy products when followed for long periods of time may induce reduction of calcium intake and ostheopenia [12,13]. The beneficial effect of dietary restriction is thought to be determined by the reduction of the substrate that should be fermented from the colonic bacteria [14]. Recently, various studies have proposed alternative treatment such as the daily intake of fresh yogurt with alive bacteria that improves lactose absorption and reduces H2 production [15]. Probiotics have also been shown to be effective in reducing symptoms in pa-
G. Cappello, L. Marzio / Digestive and Liver Disease 37 (2005) 316–319
tients with lactose intolerance [16]. A recent study has shown that Kefir, a fermented milk beverage that contains various bacteria cultures other than yogurt, improves lactose digestion and tolerance in adults with lactose maldigestion [17]. Rifaximin, a non-absorbable rifampycin derivative, has been shown to be highly effective against anaerobic bacteria [18] that produce large volume of hydrogen, carbon dioxide and methane via carbohydrate fermentation [19]. Di Stefano et al. [20] in patients with irritable bowel syndrome showed that the colonic production of H2 was increased in comparison to normal controls, and that rifaximin significantly reduces both the H2 production and the related symptoms. In patients with lactose intolerance, the study suggests that abdominal symptoms are linked to the presence of specific bacteria and it has been recently shown that there is a negative association between the presence of bacteria that are capable of hydrolysing lactose and intestinal symptoms [21]. On the basis of this study, it may be speculated that rifaximin reduces intestinal symptoms through a reduction of fermentative bacteria that produce H2 and a relative increase of those specific bacteria that are linked to hydrolyses of lactose. An increased prevalence of lactose intolerance has been shown in irritable bowel syndrome (IBS) with a high prevalence of abnormal lactulose breath test, suggesting bacterial overgrowth. Because symptoms of lactose intolerance result from bacterial fermentation, abnormal lactose breath test may be reflective of early presentation of lactose to bacteria or malabsorption or both. Indeed, in a recent study on patients with IBS, with symptoms suggestive for lactose malabsorption [22], a significant correlation was seen between the hydrogen production of lactose and lactulose breath test, suggesting the simultaneous presence in these patients of lactose intolerance and bacterial overgrowth. The beneficial effect of rifaximin shown in the present study may also reflect the presence of bacterial overgrowth in our patients as well. It must be noted however, that so far we have performed lactulose breath test in 10 patients with a positive lactose breath test and none of them was found with bacterial overgrowth. In conclusion, this study shows that 10 days of antibiotic therapy reduces the intestinal hydrogen production and symptoms in patients with lactose intolerance for about 30 days, suggesting that intestinal bacteria may be involved in the pathogenesis of this common clinical syndrome. Further studies with prolonged administration of rifaximin and longer follow up are necessary to determine its therapeutic value in lactose intolerance. Conflict of interest statement None declared.
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