A randomized double-blind placebo-controlled trial showing rifaximin to improve constipation by reducing methane production and accelerating colon transit: A pilot study.

OBJECTIVE: Gut microbe-derived methane may slow colon transit causing chronic constipation (CC). Effect of rifaximin on breath methane and slow-transit CC was evaluated. METHOD: Bristol stool form, frequency, colon transit time (CTT), and breath methane were evaluated in 23 patients with CC (10 patients with constipation-predominant irritable bowel syndrome [IBS-C], 13 functional constipation, Rome III) and m-ethane production compared with 68 non-constipating IBS. Methane-producing CC (basal ≥ 10 PPM and/or post-lactulose rise by > 10 PPM) was randomized (double-blind) to rifaximin (400-mg thrice/day, 2-weeks) or placebo. Stool forms, frequency, breath methane, and CTT were recorded afterward. RESULTS: CC patients tended to be methane producer more often (13/23 [56.5%] vs. 25/68 [36.5%], p = 0.07) and had greater area under curve (AUC) for methane (2415 [435-23,580] vs. 1335 [0-6562.5], p = 0.02) than non-constipating IBS. Methane producers (8/13 [61.5%]) and 5/10 (50%) non-producers had abnormal CTT (marker retention: 36-h, 53 [0-60] vs. 19 [8-56], p = 0.06; 60-h, 16 [0-57] vs. 13 [3-56], p = 0.877). Six and 7/13 methane producers were randomized to rifaximin and placebo, respectively. Rifaximin reduced AUC for methane more (6697.5 [1777.5-23,580] vs. 2617.5 [562.5-19,867.5], p = 0.005) than placebo (3945 [2415-12,952.5] vs. 3720 [502.5-9210], p = 0.118) at 1 month. CTT normalized in 4/6 (66.7%) on rifaximin (36-h retention, 54 [44-57] vs. 36 [23-60], p = 0.05; 60-h, 45 [3-57] vs. 14 [11-51], p = 0.09) but none on placebo (p = 0.02) (36-h, 31 [0-60] vs. 25 [0-45], p = 0.078; 60-h, 6 [0-54] vs. 12 [0-28], p = 0.2). Weekly stool frequency (3 [1-9] and 7 [1-14], p = 0.05) and forms improved with rifaximin than placebo. CONCLUSION: Rifaximin improves CC by altering methane production and colon transit. TRIAL REGISTRATION: Clinical Trial Registry, India: REF/2012/01/003216 ᅟ ᅟ.

Irritable Bowel Syndrome, Particularly the Constipation-Predominant Form, Involves an Increase in Methanobrevibacter smithii, Which Is Associated with Higher Methane Production.

BACKGROUND/AIMS: Because Methanobrevibacter smithii produces methane, delaying gut transit, we evaluated M. smithii loads in irritable bowel syndrome (IBS) patients and healthy controls (HC). METHODS: Quantitative real-time polymerase chain reaction for M. smithii was performed on the feces of 47 IBS patients (Rome III) and 30 HC. On the lactulose hydrogen breath test (LHBT, done for 25 IBS patients), a fasting methane result ≥10 ppm using 10 g of lactulose defined methane-producers. RESULTS: Of 47, 20 had constipation (IBS-C), 20 had diarrhea (IBS-D) and seven were not sub-typed. The M. smithii copy number was higher among IBS patients than HC (Log105.4, interquartile range [IQR; 3.2 to 6.3] vs 1.9 [0.0 to 3.4], p<0.001), particularly among IBS-C compared to IBS-D patients (Log106.1 [5.5 to 6.6] vs 3.4 [0.6 to 5.7], p=0.001); the copy number negatively correlated with the stool frequency (R=-0.420, p=0.003). The M. smithii copy number was higher among methane-producers than nonproducers (Log106.4, IQR [5.7 to 7.4] vs 4.1 [1.8 to 5.8], p=0.001). Using a receiver operating characteristic curve, the best cutoff for M. smithii among methane producers was Log106.0 (sensitivity, 64%; specificity, 86%; area under curve [AUC], 0.896). The AUC for breath methane correlated with the M. smithii copy number among methane producers (r=0.74, p=0.008). Abdominal bloating was more common among methane producers (n=9/11 [82%] vs 5/14 [36%], p=0.021). CONCLUSIONS: Patients with IBS, particularly IBS-C, had higher copy numbers of M. smithii than HC. On LHBT, breath methane levels correlated with M. smithii loads.

A proof-of-concept study showing antibiotics to be more effective in irritable bowel syndrome with than without small-intestinal bacterial overgrowth: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Antibiotics relieve symptoms in half of the unselected patients with irritable bowel syndrome (IBS); however, their efficacy if selected according to small-intestinal bacterial overgrowth (SIBO) is unknown. AIMS: The aim of this study was to evaluate (a) symptom resolution among IBS patients with or without SIBO on norfloxacin treatment, and (b) its efficacy in obtaining negative SIBO test results as compared with placebo. METHOD: Eighty IBS patients (Rome III) were evaluated for SIBO by gut aspirate culture. Patients with (≥10 CFU/ml) and those without SIBO were separately randomized (computer-generated stratified) to 800 mg/day norfloxacin for 10 days or placebo. Global symptom score (blindly), Rome III criteria, aspirate culture, and glucose hydrogen breath test (GHBT) were assessed before and 1 month after treatment, and patients were followed up for 6 months. RESULTS: Although norfloxacin was more effective at reducing the symptom score at 1 month among patients with compared with those without SIBO [15/80, 19% on culture, four on GHBT too; 6.5 (2-13) vs. 2 (0-10), P=0.01; 8.5 (2-16) vs. 5 (0-12), P<0.001] but not placebo, the scores were comparable at 6 months [3 (1-10) vs. 9 (5-19), P=NS]. Symptoms more often resolved to turn Rome III negative in SIBO patients treated with norfloxacin compared with placebo at 1 month (7/8, 87.5 vs. 0/7, P=0.004); of the other 65 patients, 8/32 (25%) treated with norfloxacin but none of the 33 treated with placebo turned Rome III negative. Patients without SIBO and a colony count of 10-10 CFU/ml responded more than those with a colony count less than 10 CFU/ml. Overall, 15/40 (37.5%) patients responded to norfloxacin. At 6 months, 2/8 (25%) with and 5/32 (15.6%) without SIBO remained Rome III negative following norfloxacin. All 4/8 consenting patients treated with norfloxacin became SIBO negative (two each by culture+GHBT and GHBT alone), but 0/7 patients treated with placebo became SIBO negative. CONCLUSION: Norfloxacin is superior to placebo in relieving symptoms of SIBO-associated IBS.

Fructose malabsorption is not uncommon among patients with irritable bowel syndrome in India: a case-control study.

BACKGROUND: Fructose malabsorption (FM) is reported in 38 % to 75 % patients with irritable bowel syndrome (IBS). Most of these studies, however, had limitations due to use of variable dose of fructose, small sample size, and lack of control population. Moreover, there is no study on this issue from India. Hence, in this prospective study, we evaluated the frequency of FM on an adequately powered sample of patients with IBS and healthy controls (HC) from India. METHODS: Ninety-seven patients with IBS (diagnosed using Rome III criteria) and 41 healthy controls were evaluated for FM by fructose hydrogen breath test (FHBT) using 25 g fructose. Persistent rise (at least two readings) in breath hydrogen 20 parts per million (PPM) above basal was considered diagnostic of FM. RESULTS: Patients and controls were comparable in age (37 years [21-66] vs. 33 years [15-56]; p = 0.1) and gender (76/97 [78.4 %] vs. 29/41 [70.7 %] male; p = 0.3). Of 70 patients reporting data on Bristol's stool forms, 10 (14 %), 43 (61 %), and 17 (25 %) had constipation, diarrhea predominant and unclassified IBS (Asian classification), respectively. Patients with IBS more often had FM than controls on FHBT (14/97 [14.4 %] vs. 1/41 [2.4 %]; p = 0.04). Patients with FM more often had diarrhea-predominant IBS than those without FM (10/11 [91 %] vs. 33/59 [56 %]; p = 0.02). CONCLUSION: Though FM was not very common among Indian patients with IBS, it was higher among them than controls. Patients with FM more often had diarrhea-predominant IBS.

Small intestinal bacterial overgrowth is common both among patients with alcoholic and idiopathic chronic pancreatitis.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is known to occur in patients with chronic pancreatitis, particularly of alcoholic etiology. There are, however, scanty data on frequency of SIBO in patients with chronic idiopathic pancreatitis and factors associated with its occurrence. METHODS: 68 patients with chronic pancreatitis and 74 age and gender-matched healthy subjects (HS) were evaluated for SIBO using glucose hydrogen breath test (GHBT). Persistent rise in breath hydrogen 12 ppm above basal (at least two recordings) was diagnostic of SIBO. RESULT: SIBO was diagnosed more often among patients with chronic pancreatitis than controls (10/68 [14.7%] vs. 1/74 controls [1.3%]; p = 0.003). Of 68 patients, 22 (32.3%) had alcoholic and 46 (67.6%) had idiopathic chronic pancreatitis. SIBO was as commonly detected among patients with alcoholic as idiopathic pancreatitis (3/22 [13.6%] vs. 7/46 [15.2%]; p = 0.86). Age, gender, body mass index (BMI), steatorrhoea, pain, analgesic use, pancreatic calcifications and use of pancreatic enzyme supplements had no relationship with the presence of SIBO. Diabetes mellitus tended to be commoner among patients with chronic pancreatitis with than without SIBO (6/10 [60%] vs. 18/58 [31%]; p = 0.07). CONCLUSION: SIBO was commoner among patients with chronic pancreatitis, both alcoholic and idiopathic, than HS. Though presence of SIBO among patients with chronic pancreatitis tended to be commoner among those with diabetes mellitus, there was no relationship with age, gender, BMI, steatorrhoea, pain, analgesic use, pancreatic calcifications and use of pancreatic enzyme supplements.

Breath tests in the diagnosis of small intestinal bacterial overgrowth in patients with irritable bowel syndrome in comparison with quantitative upper gut aspirate culture.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is reported in 4-78% patients with irritable bowel syndrome (IBS). This wide range of percentages might be because of the different techniques and criteria used to define the condition. We studied the utility of early (breath hydrogen increase 20 ppm above basal within 90 min) and double peaks on lactulose and glucose hydrogen breath tests (LHBT and GHBT, respectively) to diagnose SIBO (gold standard: upper gut aspirate culture). We also studied the clinical parameters that are associated with SIBO among them. METHODS: Overall, 80 patients with IBS (Rome 3) were evaluated for SIBO using aspirate culture, GHBT, and LHBT (with methane). RESULTS: A total of 15/80 (19%) patients had SIBO (≥ 10 CFU/ml) on culture compared with 0/10 historical controls; 4/15 (27%) with and none of 65 without SIBO had positive GHBT (sensitivity 27%, specificity 100%). None of 15 with and one of 65 without SIBO had double peaks on LHBT (sensitivity 0%, specificity 98%); 5/15 (33%) with and 23/65 (35%) without SIBO had an early peak on LHBT (sensitivity 33%, specificity 65%); and 2/15 (13.3%) with and 26/63 (41.3%) without SIBO had high methane on LHBT (sensitivity 13.3%, specificity 58.7%). Patients with SIBO on culture more often had diarrhea [6/15 (40%) vs. 8/65 (12.3%), P=0.011], higher weekly stool frequency [21 (3-28) vs. 14 (4-49), P=0.003], and looser forms [Bristol 5-6, 11/15 (73.3%) vs. 33/65 (50.8%), P=0.116]. CONCLUSION: On the basis of culture, 19% patients with IBS had SIBO. The specificity of GHBT was 100%, but the sensitivity of this test and the diagnostic performances of LHBT and breath methane were all very poor. SIBO was more common in IBS patients with diarrhea than in patients with other bowel habits.

Tropical sprue in 2014: the new face of an old disease.

Tropical sprue (TS), once known to be a common cause of malabsorption syndrome (MAS) in India and other tropical countries, is believed to be uncommon currently in spite of contrary evidence. Several recent studies from India showed TS to be the commonest cause of sporadic MAS in Indian adults. TS is diagnosed in patients presenting with suggestive clinical presentation, which cannot be explained by another cause of MAS and investigations revealing malabsorption of two unrelated substances, abnormal small-intestinal mucosal histology, which responds to treatment with antibiotics such as tetracycline and folic acid. There is substantial overlap between TS and postinfectious irritable bowel syndrome. There have been several advances in epidemiology, pathogenesis, and diagnosis of TS, hitherto an enigmatic condition.

Irritable bowel syndrome and small intestinal bacterial overgrowth: meaningful association or unnecessary hype.

Irritable bowel syndrome (IBS) is a common condition characterized by abdominal pain or discomfort, bloating, and altered stool form and passage. Small intestinal bacterial overgrowth (SIBO) is a condition in which there is overgrowth of bacteria in small bowel in excess of 105 colony forming units per milliliter on culture of the upper gut aspirate. Frequency of SIBO varied from 4%-78% among patients with IBS and from 1%-40% among controls. Higher frequency in some studies might be due to fallacious criteria [post-lactulose breath-hydrogen rise 20 PPM above basal within 90 min (early-peak)]. Glucose hydrogen breath test (GHBT) has a low sensitivity to diagnose SIBO. Hence, studies based on GHBT might have under-estimated frequency of SIBO. Therefore, it is important to analyze these studies carefully to evaluate whether the reported association between IBS and SIBO is over or under-projected. This review evaluates studies on association between SIBO and IBS, discordance between different studies, their strength and weakness including methodological issues and evidence on therapeutic manipulation of gut flora on symptoms of IBS.

Frequency and factors associated with increased small intestinal permeability in patients with portal hypertension.

AIM: Cirrhosis with portal hypertension (PHT) may be associated with increased small intestinal permeability (SIP), predisposing to malnutrition and bacterial translocation causing septicaemia, endotoxaemia and spontaneous bacterial peritonitis. However, data on SIP in extrahepatic portal venous obstruction (EHPVO), in which PHT occurs without hepatic dysfunction, are scanty. Such studies would help to know the effect of PHT on SIP independent of hepatic dysfunction; hence, we undertook this study. METHODS: A total of 96 patients with PHT (cirrhosis 71, EHPVO 25) underwent evaluation of SIP using urinary lactulose/mannitol excretion ratio over 6 hours after oral administration of 15 mL (10 g) lactulose and 5 g mannitol using 1H-NMR spectroscopy by a method described by us previously. RESULTS: Gender of patients with EHPVO and cirrhosis was comparable but patients with EHPVO were younger in age. The causes of cirrhosis were cryptogenic (n = 22), alcohol (n = 20), post-viral (n = 21) and others (n = 8). Twenty-seven (38%) patients with cirrhosis had ascites. Abnormal SIP was detected in 47 (49%) patients (40/71,56% with cirrhosis vs. 7/25, 28% with EHPVO, p = 0.01). Patients with cirrhosis had a higher urinary lactulose/mannitol excretion ratio than those with EHPVO (0.09, range 0-0.87 mmol vs. 0.05, 0-0.19 mmol; p = 0.008). Patients with abnormal SIP had a higher Child score, and more often had cirrhosis than EHPVO, ascites and deranged liver function. On multivariate analysis, presence of cirrhosis, ascites, high serum bilirubin level and prothrombin time were associated with abnormal SIP. CONCLUSIONS: Cirrhosis was associated with abnormal SIP, which was related to liver dysfunction. However, SIP was normal in patients with EHPVO.

Slow transit constipation associated with excess methane production and its improvement following rifaximin therapy: a case report.

Constipation, a common problem in gastroenterology practice, may result from slow colonic transit. Therapeutic options for slow transit constipations are limited. Excessive methane production by the methanogenic gut flora, which is more often found in patients with constipation, slows colonic transit. Thus, reduction in methane production with antibiotic treatment directed against methanogenic flora of the gut may accelerate colonic transit resulting in improvement in constipation. However, there is not much data to prove this hypothesis. We, therefore, report a patient with slow transit constipation associated with high methane production both in fasting state and after ingestion of glucose, whose constipation improved after treatment with non-absorbable antibiotic, rifaximin, which reduced breath methane values.