Towards Lasting Engineering of the Gut Microbiome

The gut microbiome is important in long-term health. At a guess, its influence on health may be on a par with, say, the state of physical fitness exhibited by an individual. The relative sizes of microbial populations change over a lifetime, and in detrimental ways. Inflammatory microbes and those producing harmful metabolites increase in number, while useful metabolite production declines. This occurs for a range of reasons, easy enough to list, but hard to put in an order of relative importance. For example, the intestinal mucosal barrier declines in effectiveness; the immune system becomes less capable of suppressing problematic microbial populations; diet tends to change with age; and so forth.

At present the only definitively lasting way to beneficially alter the gut microbiome is fecal microbiota transplantation, such as from a young individual to an old individual. Methods such as probiotics can produce benefits, but do not last very long, and are also far from a complete solution. Can more be done to apply fine degrees of control to the composition and function of the gut microbiome without full transplantation of a new microbiome? In the research materials below, researchers suggest an intriguing approach based on engineering native microbes. At the end of the day, however, that full reset via fecal microbiota transplantation may just be the best approach to an aging microbiome, and not just because it can be implemented now.

Engineering the Microbiome to Potentially Cure Disease

Numerous diseases are associated with imbalance or dysfunction in gut microbiome. Even in diseases that don't involve the microbiome, gut microflora provide an important point of access that allows modification of many physiological systems. Modifying to remedy, perhaps even cure these conditions, has generated substantial interest, leading to the development of live bacterial therapeutics (LBTs). One idea behind LBTs is to engineer bacterial hosts, or chassis, to produce therapeutics able to repair or restore healthy microbial function and diversity.

Existing efforts have primarily focused on using probiotic bacterial strains from the Bacteroides or Lactobacillus families or Escherichia coli that have been used for decades in the lab. However, these efforts have largely fallen short because engineered bacteria introduced into the gut generally do not survive what is fundamentally a hostile environment. The inability to engraft or even survive in the gut requires frequent re-administration of these bacterial strains and often produces inconsistent effects or no effect at all. The phenomenon is perhaps most apparent in individuals who take probiotics, where these beneficial bacteria are unable to compete with the individual's native microorganisms and largely disappear quickly.

In a proof-of-concept study, researchers report overcoming that hurdle by employing native bacteria in mice as the chassis for delivering transgenes capable of inducing persistent and potentially even curative therapeutic changes in the gut and reversing disease pathologies. The research team showed that they can take a strain of E. coli native to the host and engineer it to express transgenes that affect its physiology, such as blood glucose levels. The modified native bacteria were then reintroduced into the mouse's gut. After a single treatment, the engineered native bacteria engrafted throughout the gut for the lifetime of the treated mice, retained functionality and induced improved blood glucose response for months. The researchers also demonstrated that similar bacterial engineering can be done in human native E. coli.

Intestinal transgene delivery with native E. coli chassis allows persistent physiological changes

Live bacterial therapeutics (LBTs) could reverse diseases by engrafting in the gut and providing persistent beneficial functions in the host. However, attempts to functionally manipulate the gut microbiome of conventionally raised (CR) hosts have been unsuccessful because engineered microbial organisms (i.e., chassis) have difficulty in colonizing the hostile luminal environment.

In this proof-of-concept study, we use native bacteria as chassis for transgene delivery to impact CR host physiology. Native Escherichia coli bacteria isolated from the stool cultures of CR mice were modified to express functional genes. The reintroduction of these strains induces perpetual engraftment in the intestine. In addition, engineered native E. coli can induce functional changes that affect physiology of and reverse pathology in CR hosts months after administration. Thus, using native bacteria as chassis to "knock in" specific functions allows mechanistic studies of specific microbial activities in the microbiome of CR hosts and enables LBT with curative intent.

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