Dysbiosis
Figure 1: Therapeutic approaches for dysbiosis. Areas with yellow highlight indicate target(s) not explored by existing companies. Company logo is followed by description of their approach, stage of development, and disease(s) they target.
Dysbiosis describes imbalance in gut microbiome that can lead to adverse health effects. It recently emerged as a new hallmark of aging due to observed associations between age-related changes in the gut microbiome and pathological conditions such as cardiovascular diseases and frailty. Dysbiosis is interconnected with other supra-cellular hallmarks, as it can drive inflammaging and immunosenescence, and vice versa.
There are general trends in age-related changes of the gut microbiome, such as a depletion of core taxa like Bacteroides. At the same time, there is also significant variation in the gut microbiome depending on different regions and conditions. For instance, elderly controls from North America and Europe exhibit higher variation in gut microbiomes compared to region-matched young/middle-aged controls, but no such differences are observed in Chinese populations (Ghosh et al. 2020). There are also clear distinctions in microbiome signatures between elders living in the community versus those in nursing homes (Haran and McCormick 2020).
Even though the age-related changes in the gut microbiome remain incompletely understood, animal experiments suggest that it can be modulated to improve longevity. There are four different strategies to target dysbiosis.
Adding microbes
1.1. Fecal microbiota transplant (FMT)
Fecal microbiota transplantation (FMT) is a process in which fecal matter from a healthy donor is transferred into another individual. The donor's fecal material is processed to remove solids, resulting in a liquid suspension of bacterial cells, which is then administered to the recipient through various methods, such as colonoscopy, enema, or pill. Primarily used to treat recurrent C. difficile infections caused by excessive gut bacteria growth following heavy antibiotic use, FMT also shows potential in targeting aging. Studies have demonstrated that FMT from young to old mice improves brain health, neuroimmunity, and ovarian function (Boehme et al. 2021, Xu et al. 2022).
As an experimental procedure, FMT faces logistical, regulatory, and reimbursement challenges, prompting biotech companies like Seres and Finch to work on standardizing it through microbiome drugs. Seres’s SER-109, an oral formulation of purified Firmicutes spores, has recently been approved by the FDA for preventing recurrent C. diff infections.
Other companies are also exploring FMT-inspired therapeutics for inflammatory conditions like inflammatory bowel disease (IBD) and graft vs host disease (GvHD). However, no one is currently leveraging this approach for aging-related diseases. Considering the preclinical evidence supporting FMT's potential in improving healthspan, this area represents an underexplored opportunity.
1.2. Adding beneficial microbes
An alternative approach to FMT is to add beneficial individual strains of gut microbes. For example, transplantation of Akkermansia muciniphila extends lifespan in progeroid mice (Bárcena et al. 2019). Similarly, Lactobacillus plantarum GKM3 promotes longevity, memory retention, and reduces brain oxidative stress in progeroid mice (Lin et al. 2021).
Petri Bio is currently pursuing this approach by developing engineered microbes for aging-related metabolic disorders.
2. Adding metabolites
Gut microbes produce metabolites that can regulate various biological processes. Instead of directly administering the microbes to patients, their metabolites can be used to develop small molecules or biologics using traditional drug development methods.
Certain metabolites have shown beneficial effects on healthspan and lifespan in animal models. For example, urolithin A, a metabolite generated from ellagic acid via its metabolism by gut bacteria, improves cognitive deficits in mouse models of Alzheimer’s disease and extends lifespan in normal aging mice (Ballesteros-Álvarez et al. 2022).
Similar to FMT, companies, such as Enterome and Second Genome, are using this approach to develop therapeutics for IBD and adjuvant for immuno-oncology, but none is doing this for age-related diseases. Incorporating beneficial microbe metabolites, such as urolithin A, for aging reveals a promising avenue to explore.
3. Modulating microbes
Gut bacteria can generate a mix of beneficial and harmful molecules. Another approach to address dysbiosis involves modulating these microbes to reduce the production of detrimental molecules, particularly those that increase with aging.
Specific gut-derived metabolites are found in higher concentrations in aged individuals and have been identified as risk factors for age-related diseases (Hasavci and Blank 2022). Trimethylamine (TMA), in particular, is a precursor of TMAO, which is found to be elevated in aged individuals and associated with cardiovascular diseases, Alzheimer's, and cancer. Zehna Therapeutics is a company that develops inhibitors of selected gut microbial pathways linked with such harmful metabolites. Their lead compound is an inhibitor of the gut microbial enzyme CutC, which converts dietary choline to TMAO, as a potential treatment for chronic kidney diseases.
4. Enhancing intestinal barrier
Dysbiosis-induced gut barrier dysfunction and inflammation contribute to the overall aging process. Intestinal alkaline phosphatase (IAP) is a vital gut enzyme involved in promoting gut health through its anti-inflammatory properties, preservation of gut barrier function, and maintenance of microbiota balance. IAP supplementation has been shown to extend the lifespan of mice, decrease age-related gut permeability and systemic inflammation, and reduce frailty (Kühn et al. 2020).
At present, no companies are pursuing this approach, making IAP a compelling target to explore.