Development and Validation of a Novel Microbiome-Based Biomarker of Post-antibiotic Dysbiosis and Subsequent Restoration

Abstract

Background: The human gut microbiota are important to health and wellness, and disrupted microbiota homeostasis, or “dysbiosis,” can cause or contribute to many gastrointestinal disease states. Dysbiosis can be caused by many factors, most notably antibiotic treatment. To correct dysbiosis and restore healthier microbiota, several investigational microbiota-based live biotherapeutic products (LBPs) are in formal clinical development. To better guide and refine LBP development and to better understand and manage the risks of antibiotic administration, biomarkers that distinguish post-antibiotic dysbiosis from healthy microbiota are needed. Here we report the development of a prototype Microbiome Health Index for post-Antibiotic dysbiosis (MHI-A).Methods: MHI-A was developed and validated using longitudinal gut microbiome data from participants in clinical trials of RBX2660 and RBX7455 – investigational LBPs in development for reducing recurrent Clostridioides difficile infections (rCDI). The MHI-A algorithm relates the relative abundances of microbiome taxonomic classes that changed the most after RBX2660 or RBX7455 treatment, that strongly correlated with clinical response, and that reflect biological mechanisms believed important to rCDI. The diagnostic utility of MHI-A was reinforced using publicly available microbiome data from healthy or antibiotic-treated populations.Results: MHI-A has high accuracy to distinguish post-antibiotic dysbiosis from healthy microbiota. MHI-A values were consistent across multiple healthy populations and were significantly shifted by antibiotic treatments known to alter microbiota compositions, shifted less by microbiota-sparing antibiotics. Clinical response to RBX2660 and RBX7455 correlated with a shift of MHI-A from dysbiotic to healthy values.Conclusion: MHI-A is a promising biomarker of post-antibiotic dysbiosis and subsequent restoration. MHI-A may be useful for rank-ordering the microbiota-disrupting effects of antibiotics and as a pharmacodynamic measure of microbiota restoration.

HUMAN FECAL BILE ACID ANALYSIS AFTER INVESTIGATIONAL MICROBIOTA-BASED LIVE BIOTHERAPEUTIC DELIVERY FOR RECURRENT CLOSTRIDIOIDES DIFFICILE INFECTION

“…The emergence of LCA and DCA and other 7-dehyroxylated derivatives (12-KLCA, DHLCA, isoLCA, 3-KDCA) starting on day 7 post-baseline revealed that commensals with 7-dehydroxylating activity were being restored over time in rCDI patients after RBX2660 treatment. Consistent with this, the restoration of secondary BAs post-baseline coincided with a shift to a healthier MHI-A in the same cohort(8,11). Notably, a healthier MHI-A is partially defined by increased relative operational taxonomic units (OTUs) from the Clostridia class, which is known to harbor critical commensals that express 7-dehydroxylating genes(3–5).…”

“…The copyright holder for this preprint this version posted September 1, 2022. ; https://doi.org/10.1101/2022.08.30.22278604 doi: medRxiv preprint diversity (7)(8)(9)(10). The analysis conducted on samples from these trials also led to the development of the Microbiome Health Index (MHI-A)-a microbiome-based biomarker of antibiotic-induced dysbiosis and restoration (11). RBX2660 treatment is associated with a significant shift of MHI-A to levels associated with those observed in healthy subjects (11).…”

“…In several clinical trials, RBX2660 reduced CDI recurrence and normalized trial participants' microbiota composition and diversity (7)(8)(9)(10). The analysis conducted on samples from these trials also led to the development of the Microbiome Health Index (MHI-A)-a microbiome-based biomarker of antibiotic-induced dysbiosis and restoration (11). RBX2660 treatment is associated with a significant shift of MHI-A to levels associated with those observed in healthy subjects (11).…”

Gut microbiome health and dysbiosis: A clinical primer

“…Another, called the Microbiome Health Index (MHI), considers bacterial distributions within the Firmicutes, Bacteroidetes, and Proteobacteria phyla. MHI, evaluated after antibiotic exposure, is measured by the relative abundances of bacteria belonging to the Clostridia (Firmicutes phylum) and Bacteroidia (Bacteroidetes phylum) classes, given their associations with healthy functions, compared with the abundances of Bacilli (Firmicutes phylum) and Gammaproteobacteria (Proteobacteria phylum), given their association with pathogenesis 24 …”

The role of the gut microbiome in colonization resistance and recurrent Clostridioides difficile infection

“… 16 , 17 Broadly, studies demonstrate that a healthy gut microbiota is dominated by a diversity of members from the Bacteroidetes and Firmicutes phyla, with a lower abundance of Proteobacteria and Actinobacteria. 16 , 18 Genera such as Lactobacillus , Bacillus , Clostridium , and Ruminococcus within the Firmicutes phylum and Bacteroides and Prevotella within the Bacteroidetes phylum are frequently associated with good health. 16 , 19 Because interindividual variation in the types of genera and species in the human gut occurs, 19 – 21 providing a specific definition of what constitutes a healthy microbiota is complicated.…”