A probiotic approach targeting the microbiota to improve Irritable Bowel Syndrome symptoms and associated low mood

Irritable bowel syndrome (IBS) is a common gastrointestinal condition, effecting an estimated 19 % of the UK population (NHS). IBS is associated with reduced quality of life and costs the healthcare system up to £2.07 billion per year (1). The cause of IBS is multifactorial, and the gut microbiota may have a role to play (2, 3) .

People with IBS have significantly fewer bacteria from the genera Lactobacillus and Bifidobacterium (2, 3), which protect the host against pathogens4, 5 and produce short chain fatty-acids (SCFA) that have been shown to improve gastrointestinal symptoms (6). There are also significant differences in microbiota composition between the sub-categories of IBS, (IBS-D (diarrhoea), IBS-C (constipation) and IBS-M (mixed)), whilst some microbial disparities in comparison to healthy controls are universal to all IBS types.

There is a bidirectional relationship between IBS and low mood (7 -9). Although not confirmed this relationship may be driven via the gut-brain axis, as both conditions share similarities in microbiota composition (10, 11). The microbiota is involved in the gut brain axis through a range of mechanisms, including neurotransmitter production pathways, such as Gamma-aminobutyric acid (GABA) and serotonin (12-15).

Additionally, those with low mood have been observed to have depleted SCFA levels (16, 17) and supplementing SCFAs to mice leads to significant improvements in depressive symptoms (18). Therefore, either altering the innate microbiota to produce more SCFA or introducing SCFA producing bacteria, may be a way to improve some low mood symptoms.

Probiotics have been researched for their efficacy in treating IBS with mixed outcomes (19, 20). More knowledge is needed to explore why some probiotics work and others do not. Furthermore, certain probiotic strains have been recorded to improve gastrointestinal symptoms (21-23). Whilst others have been observed to improve mood (24-26). A probiotic that combines strains with both functions could therefore support IBS sufferers by targeting gastrointestinal complaints and low mood.

This PhD would investigate whether IBS and low mood symptoms might be driven by the microbiota. The efficacy of specific probiotic combinations on improving microbiota composition, increasing SCFA production and optimising neurotransmitter production will be determined. Ultimately the ability of a selected probiotic combination in modulating symptoms of IBS and low mood will be determined.

This research would lead to enhanced understanding of mechanisms behind IBS/low mood symptoms and could lead to a cost effective, accessible, research backed option for those who want to supplement their usual methods of coping. Hypothesis Low mood experienced by IBS sufferers is linked to an altered gut microbiota.

A combination of probiotic strains will positively alter microbiota composition, this will increase the concentration of beneficial metabolites in the gut.

Intervention with an identified probiotic combination will alleviate IBS symptoms and bring participants' low mood levels closer to that of the general population. Objectives:

Mechanistically determine links between microbiota and gut brain metabolites in IBS using in vitro models of the gut with faecal bacteria from IBS sufferers, exploring the microbial community and metabolite production

Add probiotics to in vitro models to Identify a combination that positively influences bacterial composition and metabolite profile in the faeces of participants with IBS-D and IBS-C.

Conduct a randomised placebo-controlled feasibility study to assess the ability of a probiotic combination to alleviate symptoms of low mood and IBS in human participants.

Determine potential benefits of intervention by assessing the microbial community (sequencing), selected metabolites and neurotransmitters (NMR and LC/MS) and markers of inflammation (ELISAs).