Modulation of the gut microbiota: a focus on treatments for irritable bowel syndrome

Figures & data

Table 1. Rome IV criteria for irritable bowel syndrome.

Recurrent abdominal pain, on average, ≥1 d/wk in the last 3 mo, associated with ≥2 of these 3 criteria:	Defecation related
	Change in stool frequency
	Change in stool form (appearance)
Symptoms present for the last 3 mo with onset ≥6 mo before diagnosis

Adapted and used with permission from Gastroenterology, vol 150, Lacy BE, et al. ‘Bowel disorders,’ pp 1393–1407, Copyright Elsevier (2016) [4].

Table 2. Proposed pathophysiologic factors in irritable bowel syndrome.

Proposed site of defect	Proposed defect or problem
Genetic^a	Abnormality in serotonin receptors Abnormality in sodium ion channels Altered bile acid metabolism Defect in protein involved in immune response
Central nervous system	Central nervous system processing of afferent gut signals Hormonal influences (e.g. estrogen, progesterone) Visceral hypersensitivity
Gastrointestinal	Altered motility Immune-mediated changes secondary to infection Increased levels of mast cells Increased intestinal permeability Diet (e.g. food sensitivity or intolerance) Changes in gut microbiota/microbiome (e.g. dysbiosis, antibiotic administration) Hormonal influences (e.g. estrogen, progesterone)
Psychological	Anxiety Depression Stress (e.g. coping) Somatization Posttraumatic stress disorder Abuse (e.g. early adverse life events, physical, verbal, or sexual)

^aMay be limited to select individuals.

Adapted and used with permission from Gastroenterol Clin N Am, vol 45, Harris LA, et al., Irritable bowel syndrome and female patients, pp 179–204, Copyright Elsevier (2016) [18].

Figure 1. Impact of gut microbiota in IBS. The potential role of gut microbiota in IBS symptoms and putative modulators of gut microbiota (e.g. diet, probiotics, antibiotics).

FODMAP: fermentable oligo-, di-, and monosaccharides and polyols; IBS: irritable bowel syndrome.

Table 3. Summary of clinical studies of VSL#3 in patients with IBS.

Study	Treatment	Outcomes
Wong et al. [89] R, DB, PBO-C Pts with IBS	VSL#3^a (n = 20) vs. PBO (n = 22) bid for 6 wk	IBS mean symptom scores (baseline vs. 6 wk):
		VSL#3: IBS-SSS: 224.5 vs. 158.0 Abdominal pain intensity: 18.8 vs. 15.0 Abdominal pain duration: 37.5 vs. 19 (P < 0.05) Abdominal distension intensity: 34.5 vs. 20 (P < 0.05) QOL: 63.8 vs. 52.5 BM satisfaction: 70.1 vs. 55.3 Frequency of defecation: 1.9 vs. 1.6 Stool type: 4.2 vs. 3.9	PBO: IBS-SSS: 226.4 vs. 183.5 Abdominal pain intensity: 27.7 vs. 21.8 Abdominal pain duration: 30.9 vs. 23.6 Abdominal distension intensity: 39.6 vs. 27.3 QOL: 59.6 vs. 50.2 BM satisfaction: 68.6 vs. 55.7 Frequency of defecation: 1.9 vs. 1.5 Stool type: 4.2 vs. 3.9
Michail et al. [87] R, DB, PBO-C Pts with IBS-D (Rome III)	VSL#3 (n = 15) vs. PBO (n = 9) for 8 wk	GSRS-IBS mean scores (baseline vs. 8 wk):
		VSL#3^b: Global: 2.8 vs. 1.5 Pain: 4.0 vs. 1.9 Bloating: 2.7 vs. 1.6 Constipation: 1.8 vs. 1.2 Diarrhea: 3.1 vs. 1.6 Satiety: 2.3 vs. 1.0	PBO: Global: 2.4 vs. 1.7 Pain: 3.0 vs. 2.0 Bloating: 1.6 vs. 1.5 Constipation: 2.2 vs. 1.5 Diarrhea: 3.1 vs. 1.8 Satiety: 1.8 vs. 1.5
Kim et al. [88] R, DB, PBO-C Pts with IBS (Rome II) with bloating	VSL#3 (n = 24) vs. PBO (n = 24) in yogurt for 4 or 8 wk (± 1 wk)^c	VAS mean symptom scores after 4 wk (VSL#3 vs. PBO): Bloating: 32.4 vs. 38.1 (P = 0.19) Pain: 23.7 vs. 27.4 (P = 0.22) Urgency: 20.1 vs. 23.0 (P = 0.28) Flatulence: 30.8 vs. 40.1 (P = 0.01) VAS mean symptom scores during entire treatment period (VSL#3 vs. PBO): Bloating: 31.3 vs. 38.5 (P = 0.11) Pain: 23.0 vs. 26.9 (P = 0.22) Urgency: 19.7 vs. 22.7 (P = 0.32) Flatulence: 29.7 vs. 39.5 (P = 0.01)
Kim et al. [90] R, DB, PBO-C Pts with IBS-D	VSL#3 (n = 12) vs. PBO (n = 13) bid for 8 wk	Percentage of responders (i.e. patients with “yes” answer to the weekly satisfactory relief question for ≥4 of 8 weekly assessments) did not differ between groups (33% vs. 38%, P > 0.9) GI transit: no significant differences in gastric emptying after 2 and 4 h (P = 0.41 and P = 0.86, respectively), colonic filling after 6 h (P = 0.62), or colonic transit after 24 and 48 h (P = 0.70 and P = 0.99) between groups

bid: twice daily; BM: bowel movement; DB: double-blind; GI: gastrointestinal; GSRS-IBS: Gastrointestinal Symptom Rating Scale-irritable bowel syndrome; IBS: irritable bowel syndrome; IBS-D: irritable bowel syndrome with diarrhea; IBS-SSS: Irritable Bowel Syndrome-Symptom Severity Scale; PBO: placebo; PBO-C: placebo-controlled; pts: patients; QOL: quality of life; R: randomized; VAS: visual analog scale.

^aVSL Pharmaceuticals, Inc., Gaithersburg, MD, USA.

^bP value for between-group differences for VSL#3 vs. placebo were not significant.

^cDuration of treatment was amended from 8 wk to 4 wk after 17 patients completed 8 wk of treatment.

Table 4. Summary of clinical studies of multispecies probiotics in IBS.

Study and patients	Probiotic and dosing	Efficacy outcomes	Safety
Mezzasalma et al. [91] R, DB, PBO-C Pts with IBS-C (Rome III)	(1) Lactobacillus acidophilus (5 × 10^9 CFUs), L reuteri (5 × 10^9 CFUs), or (2) L plantarum (5 × 10^9 CFUs), L rhamnosus (5 × 10^9 CFUs), Bifidobacterium animalis ssp lactis (5 × 10^9 CFUs) Capsules administered once daily for 60 d	Probiotic (1) and (2) vs. PBO: Response (decrease from baseline ≥30% in symptoms for ≥50% of time) for 60 d: (1) 66–78% and (2) 78–90% vs. PBO, 6–36% (P < 0.001) Response during 30-d follow period: (1) 56–74% and (2) 76–82% vs. PBO, 10–40% (P < 0.001)	Not examined
Yoon et al. [92] R, DB, PBO-C Pts with IBS (Rome III)	LacClean Gold-S® (Cell Biotech, Co., Ltd., Gimpo, Korea) Bifidobacterium bifidum, B lactis, B longum, Lactobacillus acidophilus, L rhamnosus, and Streptococcus thermophilus 2 500-mg capsules (5 × 10^9 viable cells per capsule) daily for 4 wk	Probiotic vs. PBO: Overall adequate symptom relief: 74.4 vs. 61.9% of patients, respectively; P = 0.2 Mean change from baseline in IBS symptoms (VAS scores) at wk 4: Pain/discomfort: P = 0.4 Bloating/gas: P = 0.5 Constipation: P = 0.9 Diarrhea: P = 0.02	Not examined
Yoon et al. [93] R, DB, PBO-C Pts with IBS (Rome III criteria)	LacClean Gold-S 1 500-mg capsules (5 × 10^9 viable cells) bid for 4 wk	Probiotic vs. PBO: Primary end point Pts with global relief of IBS symptoms^a after 4 wk: 68.0 vs. 37.5%, respectively; P = 0.03 Secondary end points Mean % decrease from baseline in intensity of abdominal pain/discomfort and bloating^b at wk 4: 37.1 vs. 9.2 (P = 0.07), 28.7 vs. 17.8 (P = 0.4), 22.4 vs. 20.3 (P = 0.9), respectively % Change from baseline in mean number of weekly bowel movements at wk 4: –2.4 vs. 32.6 (P = 0.2) % Change in stool consistency (BSS) at wk 4: 0.5 vs. –3.3 (P = 0.7)	No AEs or SAEs in either group
Ki Cha et al. [94] R, DB, PBO-C Pts with IBS-D (Rome III criteria)	Duolac7 (Cell Biotech, Co, Ltd, Seoul, Korea) Lactobacillus acidophilus, L plantarum, L rhamnosus, Bifidobacterium breve, B lactis, B longum, and Streptococcus thermophilus 1 capsule (5 × 10^9 cells) bid for 8 wk	Probiotic vs. PBO: Primary end point Adequate relief of IBS symptoms ≥5 of 10 wk during tx and posttx periods: 48 vs. 12%, respectively; P = 0.01 Secondary end points Improvement from baseline in mean individual IBS symptom scores: 33.8 vs. 33.3% (P < 0.01 for both groups) Stool frequency: comparable between groups, and did not change significantly with tx Mean difference from baseline in stool consistency (BSS) at wk 8: 0.85 vs. 0.15, P = 0.04 Percentage change from baseline in overall IBS-QOL score at wk 8: 21.3% vs. 9.0%, P = 0.07	Probiotic: no AEs; PBO: 2 pts withdrew because of AEs (worsening abdominal pain, diarrhea)
Min et al. [95] R, DB, C Pts with IBS (Rome III criteria)	Streptococcus thermophilus (≥3 × 10^9 CFUs/bottle), Lactobacillus acidophilus (≥1 × 10^9 CFUs/bottle), Bifidobacterium animalis spp lactis Bb-12 (≥1 × 10^11 CFUs/bottle), Bifidobacterium enhancer, and acacia dietary fiber (Namyang Dairy Products Co. Ltd., Seoul, South Korea) 1 150-mL bottle bid for 8 wk	Probiotic-enriched yogurt (n = 58) vs. standard yogurt (n = 59): Satisfaction with bowel habit and overall IBS symptoms improved significantly from baseline with probiotic vs. standard yogurt at wk 8 (P = 0.01 and P < 0.001, respectively)	No significant AEs reported
Sondergaard et al. [96] R, DB, PBO-C Pts with IBS	Cultura (Arla Foods, Denmark) milk fermented with Lactobacillus bulgaricus and Streptococcus thermophilus and containing ≥5 × 10^7 CFUs/mL each of L paracasei ssp paracasei F19, L acidophilus La5, and Bifidobacterium lactis Bb12; 500 mL/d for 8 wk	Probiotic (n = 27) vs. PBO (n = 25): Primary end points Adequate relief of IBS symptoms at each wk of tx phase (wk 1–8), and at the end of the follow-up phase (wk 16): no significant difference between groups Total mean IBS-SSS score during study: no significant difference between groups Secondary end points Individual mean VAS scores of the IBS-SSS (abdominal pain, abdominal distension, overall satisfaction with bowel habits, and impact of IBS on overall QOL): symptoms decreased over time, but no significant difference between groups	No SAEs reported
Ringel-Kulka et al. [97] R, DB, PBO-C Pts with non-constipation IBS, functional diarrhea, or functional bloating (Rome III)	Lactobacillus acidophilus NCFM and Bifidobacterium animalis spp lactis Bi-07 1 pill containing 1 × 10^11 CFUs bid for 8 wk	Probiotic (n = 31) vs. PBO (n = 29) Primary end points Global relief of GI symptoms^c and satisfaction with treatment^d improved from baseline in both groups, but did not differ significantly between groups Secondary end points Abdominal pain improved from baseline to wk 8 (probiotic, 3.3 vs. 2.5, P = 0.03; PBO, 3.7 vs. 2.5, P = 0.01), but did not differ significantly between groups Bloating improved significantly at wk 4 vs. PBO (score at wk 4, 4.1 vs. 6.2; P = 0.009) and numerically at week 8 (score at wk 8, 4.3 vs. 5.8; P = 0.06) IBS-QOL improved from baseline in both groups, but did not differ significantly between groups	No differences in AEs between groups AEs included cold symptoms, fatigue, abdominal pain, and sinus infection
Simrén et al. [98] R, DB, PBO-C Pts with IBS (Rome II criteria)	Cultura (Arla Foods, Denmark; milk fermented with Lactobacillus bulgaricus and Streptococcus thermophilus and containing ≥5 × 10^7 CFUs/mL each of L paracasei ssp paracasei F19, L acidophilus La5, and Bifidobacterium lactis Bb12); 400 mL/d for 8 wk	Probiotic (n = 37) vs. PBO (n = 37) Primary end point Adequate relief of IBS-related symptoms ≥50% of wk of tx phase achieved by 38 and 27% of pts, respectively (P = 0.3) Secondary end points Overall IBS-SSS score decreased from baseline during 8 wk tx phase in both groups (P = 0.2 vs. control) Pain frequency, pain severity, bloating severity, satisfaction with bowel habits, and interference with daily life improved from baseline in both groups, but did not differ significantly between groups HAD scale score did not decrease significantly from baseline with probiotic, but did with PBO (P = 0.001 vs. baseline) at wk 8 IBS-QOL subscale scores for physical and social functioning improved significantly from baseline for probiotic at wk 8, but no significant differences between groups	No AEs reported
Williams et al. [99] R, DB, PBO-C Pts with IBS by self-report (Rome II criteria)	LAB4 multistrain probiotic (Cultech Ltd., Port Talbot, UK) Lactobacillus acidophilus CUL60 and CUL21, Bifidobacterium lactis CUL34, and B bifidum CUL20 1 capsule (2.5 × 10^10 CFUs) daily for 8 wk	Probiotic (n = 28) vs. PBO (n = 28) Primary end point Overall IBS-SSS score improved significantly from baseline to wk 8 and 10 with probiotic (P < 0.0001 for both time points) and PBO (P < 0.0001 and P = 0.0005, respectively) Secondary end points Improvement in IBS-SSS individual scores from baseline to wk 8 and 10: Abdominal distension/bloating: probiotic (P < 0.0001 and P = 0.008, respectively); PBO (P = 0.003 and P = 0.13) Satisfaction with bowel habit: probiotic and PBO (P < 0.0001 for both time points) Number of d with pain: probiotic (P < 0.0001 for both time points); PBO (P = 0.0004 and P = 0.01) QOL: probiotic (P < 0.0001 for both time points); PBO (P < 0.0001 and P = 0.0001) Abdominal pain: probiotic (P < 0.0001 and P = 0.0008); PBO (P = 0.0009 and P = 0.01)	Probiotic: flatulence (3.6%)
Kajander et al. [100] R, DB, PBO-C Pts with IBS (Rome II criteria)	Probiotic milk-based drink (Valio Ltd., Helsinki, Finland) Lactobacillus rhamnosus GG, L rhamnosus Lc705, P freudenreichii ssp shermanii JS, and B animalis ssp lactis Bb12 1 1.2-dL drink daily containing 1 × 10^7 CFUs/mL each probiotic strain for 20 wk	Probiotic (n = 43) vs. PBO (n = 43) Primary end point Weekly composite IBS symptom score (including abdominal pain, distension, flatulence, and rumbling) decreased from baseline to wk 20 with probiotic and PBO (37% vs. 9% reduction, respectively; P = 0.008) Secondary end points Distension improved significantly with probiotic vs. PBO at wk 20 (36% vs. 10% reduction; P = 0.02) Abdominal pain decreased at wk 20 with probiotic; but difference vs. PBO was not significant (38% vs. 0%; P = 0.052) Flatulence and rumbling decreased in both groups at wk 20, but differences between groups were not significant (P = 0.11 and P = 0.09, respectively) Frequency of soft stools (58% vs. 53%), hard stools (16% vs. 15%), and diarrhea (27% vs. 32%) comparable between groups at wk 20	AEs reported by 23.3 and 34.9% of pts receiving probiotic or PBO, respectively

AE: adverse event; bid: twice daily; BSS: Bristol Stool Scale; C: controlled; CFU: colony-forming unit; DB: double-blind; GI: gastrointestinal; HAD: Hospital Anxiety and Depression; IBS: irritable bowel syndrome; IBS-C: irritable bowel syndrome with constipation; IBS-D: irritable bowel syndrome with diarrhea; IBS-QOL: irritable bowel syndrome quality of life; IBS-SSS, Irritable Bowel Syndrome-Symptom Severity Scale; PBO: placebo; PBO-C: placebo-controlled; posttx: posttreatment; pts: patients; QOL, quality of life; R: randomized; SAE serious adverse event; tx: treatment; VAS: visual analog scale.

^aAssessed by ‘yes’ or ‘no’ response to the question: ‘Compared with your health before treatment started, have overall IBS symptoms improved during the past 7 days?’

^bWorst symptoms over previous 24 h on numeric scale ranging from 0 to 10.

^cChange in patient’s bowel symptoms scored on a 7-point scale ranging from ‘substantially worse’ to ‘substantially improved.’

^dEvaluated using satisfaction survey.

Table 5. Summary of clinical studies of synbiotics in IBS.

Study design	Patients	Treatment(s)	Efficacy outcomes	Safety
Andriulli et al. [63] R, DB, C, MC	IBS (Rome II criteria) IBS-C: n = 17 IBS-D: n = 47 IBS-M: n = 203	Synbiotic (Flortec, Bracco Co, Milan, Italy; Lactobacillus paracasei B21060 [5 × 10^9 CFUs]; n = 132) vs. prebiotic (synbiotic without probiotic; n = 135) bid for 12 wk 2-wk run-in phase, followed by 12-wk tx phase	Synbiotic vs. prebiotic: Percentage of pts with no or mild pain: wk 4, 54% vs. 57.4%, respectively; wk 8, 60.9% vs. 53.9%; wk 12, 53.9% vs. 53.4% (P = NS for all comparisons) Percentage of pts with self-reported improvement in well-being: wk 4, 60.7% vs. 61.7%, respectively; wk 8, 69.2% vs. 63.5%; wk 12, 63.3% vs. 60.9% (P = NS for all comparisons) Pts with IBS-D: decrease in mean daily bowel movements from baseline to wk 12: synbiotic, 3.59 vs. 2.41; prebiotic, 3.4 vs. 2.95 (between-group difference at wk 12, P = 0.05)	Frequency of AEs did not differ between groups AEs led to study discontinuation in 3.8 and 3.0% of pts receiving synbiotic (i.e. diarrhea, abdominal discomfort, vomiting) vs. prebiotic (i.e. abdominal pain, skin rash), respectively
Bittner et al. [101] OL	IBS (Rome II criteria; n = 22 completed)	Synbiotic (Prescript-Assist™, Safer Medical Inc., Fort Benton, MT; 29 soil-based microorganisms [probiotic] and leonardite [prebiotic]) 550 mg bid for 2 wk 1-y extension period consisted of 3 groups: (1) unsupported remission: no further tx for ≥52 wk (n = 6); (2) maintenance remission: synbiotic 550 mg bid for 12 to 20 wk, then decreased synbiotic use (e.g. synbiotic 550 mg every 2–3 d; n = 6); (3) episodic tx: synbiotic use when mild IBS symptoms perceived to occur (n = 10) Follow-up phase up to ~60 wk	Remission of IBS at 52 wk follow up: 81.5–100% (dependent on whether pts lost to follow up included in analysis)	No AEs reported up to ~60 wk follow up
Bittner et al. [102] R, DB, PBO-C	IBS (Rome II criteria; n = 25 completed)	Synbiotic (Prescript-Assist) 500 mg bid (n = 12) vs. PBO (n = 13) for 2 wk	3 IBS subsyndromic factors (i.e. general ill feelings/nausea, indigestion/flatulence, and colitis) significantly decreased from baseline with synbiotic vs. PBO (P < 0.05)	Not evaluated
Colecchia et al. [103] OL, MC	IBS-C (Rome II criteria; n = 636 completed)	Zir Fos® (Alfa Wasserman, Alanno Scalo, Pescara, Italy; Bifidobacterium longum W11 [probiotic], Fos Actilight [prebiotic]) 3 g daily for ≥36 d	For bloating or abdominal pain, compared with baseline, the frequency of moderate to severe symptoms was significantly decreased at 1 mo after tx (bloating, 62.9% vs. 9.6%, respectively, P < 0.0001; abdominal pain, 38.8% vs. 4.1%, P < 0.0001) Stool frequency significantly increased from baseline to 1 mo after tx (2.9 vs. 4.1 times/wk, respectively; P < 0.001)	Only AE reported was mild diarrhea, experienced by 6 pts (0.9%)

AE: adverse event; bid: twice daily; C: controlled; CFU: colony-forming unit; DB: double-blind; IBS: irritable bowel syndrome; IBS-C: constipation-predominant irritable bowel syndrome; IBS-D: diarrhea-predominant irritable bowel syndrome; IBS-M: mixed/alternating irritable bowel syndrome; MC: multicenter; NS: not significant; OL: open-label; PBO: placebo; PBO-C: placebo-controlled; pts: patients; R: randomized; tx: treatment.

Figure 2. Patients achieving adequate relief of global irritable bowel syndrome (IBS) symptoms^a and adequate relief of bloating^b during ≥2 of the first 4 weeks posttreatment (combined population from two phase 3 trials).

^aYes response to the following question, which was asked weekly: ‘In regard to all your symptoms of IBS, as compared with the way you felt before you started the study medication, have you, in the past 7 days, had adequate relief of your IBS symptoms?’ ^bYes response to the following question, which was asked weekly: ‘In regard to your symptoms of bloating, as compared with the way you felt before you started study medication, have you, in the past 7 days, had adequate relief of your IBS symptom of bloating?’ Data from Pimentel M et al. N Engl J Med 2011;364:22–32 [109].

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