Person-specific Assessment of Probiotics Responsiveness

Background and Unmet Need

Probiotics are the third most commonly consumed dietary supplement after vitamin and mineral preparations.
Claimed rationales for probiotics consumption by healthy individuals vary from alleviation of gastrointestinal (GI) symptoms, ‘fortification’ of the immune system and protection against infectious diseases, prevention of weight gain, mental and behavioral augmentation, and promotion of wellbeing.
However, despite the popularity of probiotic products, their efficacy remains controversial, with only a few controlled clinical studies pointing to beneficial outcomes, while others failing to establish sustained modulation of the microbiome or objective physiological consequences.
Several major challenges limit a comprehensive assessment of probiotics' effects on the mammalian host. The first stems from significant inter-individual human microbiome variability, mediated by factors such as age, diet, antibiotic usage, consumption of food supplements, underlying medical conditions, and disturbances to circadian activity. A second limitation stems from universal reliance on stool microbiome assessment, as a surrogate marker of probiotics' impact on the host and its microbiome. However, multiple studies have shown that stool microbiome assessment cannot distinguish between probiotic-permissive and resistant individuals.
These findings highlight the need for the development of better predictive models to infer gut microbiome mucosal composition and function.

The Solution

The teams of Profs. Elinav and Segal have developed a method of assessing whether a candidate subject is suitable for probiotic treatment.

Technology Essence

The teams of Profs. Elinav and Segal have developed a method of assessing whether a subject is suitable for probiotic treatment by analyzing specific metabolites in the subject’s feces. By comparing the gut microbiome signature of the candidate to that of control known to be responsive to probiotic treatment the teams can assess the effectiveness of probiotic treatment. Individuals that are found suitable are treated with antibiotics and subsequently supplemented with an oral probiotic. Individuals that are predicted to be resistant to oral probiotic treatment can otherwise be treated using an autologous fecal transplant.
Probiotics transiently colonize the human gut mucosa in highly individualized patterns, thereby differentially impacting the indigenous microbiome and host gene-expression profile, a trait which is predictable by baseline host and microbiome features, but not by stool shedding.

Advantages and Applications

A novel method of assessing whether a candidate subject is suitable for probiotic treatment by analyzing an individual's microbiome signature.
Potential individualized probiotic treatment.
A potential method to predict the signature of a microbiome of a GI location of a subject, by analyzing either mRNA, polypeptides, carbohydrates or metabolites in a subject’s feces.

Development Status

To assess whether stool microbiome represents an accurate marker of upper and lower GI mucosal and luminal microbiome configuration, the teams of Prof. Elinav and Prof. Segal performed the MUSPIC1 (MUcosal Search for
Probiotic Impact and Colonization 1) study in a cohort of 25 healthy human adults at different biogeographical regions (e.g. Upper intestinal (GUI), Lower intestinal (LGI), etc.). They found only a weak correlation between fecal microbiome composition and the microbiome population of the different intestinal regions.
To test the individualized response to probiotics, the teams conducted a placebo-controlled trial, in which 15 healthy volunteers received either an identical 11-strain probiotics preparation or a cellulose placebo bi-daily for 4 weeks. By analyzing both stool samples and direct samples taken by colonoscopy the joint team found probiotic colonization only occurred in four individuals of the group. Importantly, stool analysis could not distinguish between responsive and unresponsive individuals to probiotic treatment.
To elucidate which factors determine an individual's susceptibility to microbiome colonization the team tested mice conventionalized with microbiomes taken from the human cohort. They found that the microbiome of humans susceptible to microbiome colonization also made the mice susceptible. The team also noted changes in gene expression related to immune pathways of the GI tract. These changes were different between resistant and permissive individuals. This research has been published in the prestigious scientific journal Cell.
Relevant Publications: Zmora et al., 2018, Cell; Suez et al., 2018, Cell