Engineering the Microbiome to Cure Disease

Residing within the human gut are trillions of bacteria and other microorganisms that can impact a variety of chronic human ailments, including obesity, type 2 diabetes, atherosclerosis, cancer, non-alcoholic fatty liver disease and inflammatory bowel 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.

The lack of engraftment severely limits the use of LBTs for chronic conditions for curative effect or to study specific functions in the gut microbiome,” said Amir Zarrinpar, MD, PhD, assistant professor of medicine at UC San Diego School of Medicine and a gastroenterologist at UC San Diego Health. “Published human trials using engineered LBTs have demonstrated safety, but still need to demonstrate reversal of disease. We believe this may be due to problems with colonization.

In a proof-of-concept study, published in the August 4, 2022, online issue of Cell , Zarrinpar and colleagues at University of California San Diego School of Medicine 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. Using this method, the group found they can provide long-term therapy in a mouse model of type 2 diabetes.


How to Reverse Age-related Brain Deterioration

Research from APC Microbiome Ireland (APCSFI Research Centre at University College Cork (UCC) published in the journal Nature Aging introduces a novel approach to reverse aspects of aging-related deterioration in the brain and cognitive function via the microbes in the gut.

As our population ages one of the key global challenges is to develop strategies to maintain healthy brain function. This ground-breaking research opens up a potentially new therapeutic avenues in the form of microbial-based interventions to slow down brain aging and associated cognitive problems. The work was carried out by researchers in the Brain-Gut-Microbiota lab in APC led by Prof John F. Cryan, Vice President for Research & Innovation, University College Cork as well as a Principal Investigator at APC Microbiome Ireland an SFI Research Centre, based in in University College Cork and Teagasc Moorepark.

There is a growing appreciation of the importance of the microbes in the gut on all aspects of physiology and medicine. In this latest mouse study the authors show that by transplanting microbes from young into old animals they could rejuvenate aspects of brain and immune function.

Prof John F. Cryan, says “Previous research published by the APC and other groups internationally has shown that the gut microbiome plays a key role in aging and the aging process. This new research is a potential game changer , as we have established that the microbiome can be harnessed to reverse age-related brain deterioration. We also see evidence of improved learning ability and cognitive function”.

Although very exciting Cryan cautions that “it is still early days and much more work is needed to see how these findings could be translated in humans”.

APC Director Prof Paul Ross stated that “This research of Prof. Cryan and colleagues further demonstrates the importance of the gut microbiome in many aspects of health, and particularly across the brain/gut axis where brain functioning can be positively influenced. The study opens up possibilities in the future to modulate gut microbiota as a therapeutic target to influence brain health”.

The study was led by co-first authors Dr Marcus Boehme along with PhD student Katherine E. Guzzetta, and Dr Thomaz Bastiaanssen.


How To Strengthen Your Immune System

There’s another reason to celebrate the gut microbiome—a healthy gut might actually be able to save lives. According to scientists at the Lawson Health Research Institute, all it takes to strengthen your immune system is to improve your gut health, a process that we know is as easy as increasing your ingestion of probiotics and dietary fiber. How’s that for functional food?

These Lawson Health Research Institute scientists are implementing a preliminary study that would discover whether a fecal transplant of a healthy microbiome can help patients with melanoma become more receptive to immunotherapy treatments. During immunotherapy treatments, patients take certain drugs to stimulate their immune systems in order to attack tumors in their bodies. A fecal transplant, according to these researchers, would make their immune systems more receptive to the drugs and, in turn, could help more people successfully fight their cancer.

We know that some people’s immune systems don’t respond well, and it seems to be associated with the microbes within your gut,” Michael Silverman, M.D., a Lawson associate scientist, said in a video filmed by the research institute. “The goal is to give people healthy microbes to replenish the microbes in their gut so that their immune system responds optimally, and they’re able to control the tumor.”