Randomised Clinical Trial

Efficacy and Safety of the Live Biotherapeutic Product MRx1234 in Patients With Irritable Bowel Syndrome

Eamonn M. M. Quigley; Louise Markinson; Alex Stevenson; F. Peter Treasure; Brian E. Lacy


Aliment Pharmacol Ther. 2023;57(1):81-93. 

In This Article

Abstract and Introduction


Background: MRx1234 is a live biotherapeutic product that contains a strain of Blautia hydrogenotrophica. It is in development for the treatment of irritable bowel syndrome (IBS).

Aims: To assess the efficacy and safety of MRx1234 in patients with IBS with predominant constipation (IBS-C) or diarrhoea (IBS-D)

Methods: We conducted a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Patients aged 18–70 years in two parallel cohorts (IBS-C; IBS-D) were randomised (1:1) to MRx1234 or placebo for 8 weeks. The primary efficacy endpoint was overall responder rate—a composite of improved bowel habit (IBS-C: stool frequency; IBS-D: stool consistency) and abdominal pain intensity—for ≥50% of the treatment period in each cohort. Statistical testing was at a one-sided 0.10 significance level.

Results: Of 366 randomised patients (164 IBS-C; 202 IBS-D), 365 received any study medication (177 MRx1234, 188 placebo). Numerically, although not statistically significantly different, more patients who received MRx1234 than placebo were overall responders in the IBS-C (25.0% vs. 17.1%) and IBS-D (23.4% vs. 17.8%) cohorts. Similar results were observed in the additional combined cohort analysis (24.1% vs. 17.5%; p = 0.063). For the components of the primary endpoint, significantly more patients on MRx1234 than placebo reported improvement in bowel habit in the IBS-C, IBS-D and combined cohorts, while improvements in abdominal pain were observed in each cohort. The safety profile of MRx1234 was similar to placebo.

Conclusions: MRx1234 has the potential to become a novel, safe treatment option for patients with IBS-C or IBS-D, and for those who have mixed symptoms or transition between subtypes.

ClinicalTrials.gov: #NCT03721107.


Irritable bowel syndrome (IBS)—a chronic gastrointestinal disorder characterised by recurrent abdominal pain and alteration in stool frequency and/or form[1]—can have a significant impact on health-related quality of life.[2] Depending on the exact definition of IBS used, the worldwide prevalence of IBS among adults has been estimated to be approximately 4%–10%.[3–6]

The faecal microbiota of patients with IBS is significantly different to that of healthy individuals,[7] and has been associated with symptom severity.[8] It has been suggested that IBS may reflect, in part, a perturbation in interactions between the gut microbiome and the host's immune system based upon a disturbed microbiome and/or a dysfunctional host response.[9] Several other factors may contribute to pathophysiology, including dysregulation along the gut–brain axis and dysbiosis of intestinal microbiota.[10–13]

Recent British Society of Gastroenterology guidelines recommend that IBS should be initially managed with lifestyle and dietary advice (exercise, relaxation and probiotics), potentially followed by a dietician referral (with or without a low fermentable, oligo-, di- and monosaccharides and polyols [FODMAP] diet).[14] Recent American College of Gastroenterology guidelines also recommend a limited trial of a low FODMAP diet.[15] Further treatment options are based on the predominant symptoms. For IBS with predominant constipation (IBS-C), options include laxatives, secretagogues and 5-hydroxytryptamine 4 receptor agonists.[14,15] For IBS with predominant diarrhoea (IBS-D), options include loperamide, 5-hydroxytryptamine 3 receptor antagonists, eluxadoline and rifaximin.[14,15] There are limited options for IBS with mixed symptoms (IBS-M), including gut–brain neuromodulators and gut-directed psychotherapies.[14,15] As patients with IBS can transition between subtypes,[16,17] most commonly from IBS-D or IBS-C to IBS-M, it would be highly beneficial to have further treatment options that could be used for patients with mixed or alternating symptoms.

The United States (US) Food and Drug Administration (FDA) recently defined a potential new treatment option: live biotherapeutic products.[18] These contain live microorganisms but are distinct from probiotics in that they must be registered as medicinal products in the US and Europe, with associated higher pharmaceutical expectations.[19] MRx1234 (Blautix®; 4D Pharma PLC) is a live biotherapeutic product currently in development for the treatment of IBS. MRx1234 contains a strain of Blautia hydrogenotrophica, a Gram-positive anaerobic, non-sporulating coccobacillus. It is a hydrogen/carbon dioxide utilising acetogenic bacterium, which is a subdominant commensal in the human gastrointestinal tract.[20] Based on animal studies (data on file), potential mechanisms of action of include competition with sulphate-reducing bacteria, a reduction in the production of the gases hydrogen, H2S and methane and a normalisation of the gut microbiome. For example, IBS-C has been associated with increased methanogenesis resulting from intestinal colonisation with methanogens, while hydrogen sulphide (H2S) has been associated with diarrhoea. Indeed, sulphate-reducing bacteria such as Fusobacterium and Desulfovibrio spp. have been linked to IBS-D.[21] Therefore, the ability of B. hydrogenotrophica to reduce the production of H2S, methane and hydrogen gases (which H2S-producing bacteria and methanogens both utilise) could result in symptomatic benefits in both IBS-D and IBS-C.

In a phase 1 clinical study, MRx1234 was safe and well tolerated, and a dose of 1 × 1010 most probable number twice daily appreciably increased levels of MRx1234 and resulted in alterations to gut microbiota.[22]

The main objectives of the current phase 2 study were to assess the efficacy and safety of MRx1234 for 8 weeks in patients with IBS-C or IBS-D.