Jeffrey S. Buguliskis Ph.D. Technical Editor Genetic Engineering & Biotechnology News

Microbiome Focus Could Lead to the Development of New Immunotherapies and Neurological Drugs

As humans, we often like to think of ourselves as unique. Much of our existence throughout written antiquity has been dotted by various cultures placing humankind at the center of the known universe—with top philosophical minds reveling in the exceptionalism of Homo sapiens over all other organisms inhabiting this planet. However, as is often the case, the pragmatic nature of science grounds the haughty opinions we fabricate about ourselves and names like Copernicus, Darwin, Watson, and Crick become intertwined with the lexicon that is used to describe just how small humans are in the universe and our interconnections with so many species, current and past. 

Even in our modern, technological advanced times, we still like to think of ourselves as autonomous and well with our control. Yet, again in recent decades science has impressed upon our fragile egocentric minds that there are literally billions of microorganisms living on and within our bodies exerting an enormous, if not imperceptible, amount of influence on all of our systems. These communities—composed primarily of bacteria—outnumber all of the cells of the human body and work symbiotically with our systems, like a harmonious Lilliputian army hell-bent on keeping Gulliver running in tip-top shape.

Yet, as is often the case during various times in our lives, our biological systems run amok—caused from either the relatively benign like an infection from a microbial pathogen, not unlike those that constitute our microbiomes, or from our cells turning against the collective and branching out on their own accord. It has come to the attention of many scientists in recent years that many of these biological perturbations have a link to the microbiome, either directly or indirectly. Even seemingly distant and somewhat disconnected systems such as the brain and the lumen of the intestinal tract have become inextricably linked to disorders like multiple sclerosis, Alzheimer’s disease, autism, and mood disorders.

“I believe that during the early (prenatal to adolescence) phase of human development when both gut microbiome and brain circuits are being programmed…that gut microbiota may play a role in increasing the risk for autism spectrum disorders, ingestive behavior, depression, and anxiety,” explained Emeran Mayer, M.D., Ph.D., director of the UCLA Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress and author of “The Mind-Gut Connection: How the Hidden Conversation Within Our Bodies Impacts Our Mood, Our Choices, and Our Overall Health,” which outlines the microbiome’s impact on neurodevelopment and general neurological health. 

Guts and Bolts

As with all areas of science, the terminology is a critical and descriptive means of classifying organisms. Nobel Prize winning microbiologist Joshua Lederberg coined the term microbiota in 2001 to describe a population of microbes that reside within a particular ecological niche. Simultaneously, Dr. Lederberg and his colleagues fashioned the term microbiome to refer to the collective genes of the microbes within that niche. In the omic dominating sciences of today, these terms are often used interchangeably without overwhelming reproach. 

Interestingly, the microbiota that lines the entirety of the human gastrointestinal (GI) tract comprises approximately 1,014 microbes with a collective biomass around two kilograms. The approximate ratio of microbial cells that make up the microbiota to eukaryotic cells of the human body is still in contention, with estimates ranging as high as ten times greater, to more recent reports placing the value closer to 1.5 times larger. As for the microbiome, the bacteria of the gut alone originate from over 1,000 different species and encode more than three million genes, far exceeding that of the human genome by 150-fold.

A range of physical and biochemical barriers exist to differentiate regions of the gut microbiota, with the spatial distribution of microbes increasing in diversity from the stomach through to the colon. The physiological influences on the homeostatic ecosystem of the microbiome are too numerous to dissect here, however, the interaction between the human immune system and microbiome has become of great interest to a vast number of investigators—especially in light of relatively recent successes with new immunotherapy treatments. 

Sphere of Influence

In many ways, the symbiosis between the microbiome and the immune system seems counterintuitive as immune cells have evolved to seek out and destroy organisms that are closely related to those of the gut microbiota. However, a few million years of co-evolution has allowed the immune cells to recognize friend from foe rapidly, and the two systems have even come to depend on each other for maintaining overall wellness. When working harmoniously, we hardly know that these two biological schemes exist. Though, slight perturbations of the microbiota can have a profound consequence on the effectiveness of the immune system. One well-known example comes from the activation of TH17 cells (T helper cells) within the small intestine from segmented filamentous bacteria (SFB) that has been shown to lead to autoimmune arthritis in mouse models.

With the latest success of immunotherapy drugs for a variety of oncology patients, researchers have turned their focus toward methods that may positively influence outcomes of the administered therapies. Previous work has shown that even classical chemotherapeutic compounds, like cyclophosphamide, are affected by depletions of the microbiome due to the recent exposure of the patient to antibiotics, compromising the drug regimen. Moreover, data has begun to pile up suggesting that fluctuation in the microbial diversity within the gut influence new checkpoint blockade drugs such as anti-PD-L1 and anti-CTLA-4 immunotherapies.

In a recent study published in Science—“Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota”—investigators found that the antitumor activity of Ipilimumab, a fully human monoclonal antibody directed against CTLA-4, a key negative regulator of T-cell activation, was dependent on a distinct species of Bacteroides bacteria (B. thetaiotamicron or B. fragilis). This study found that tumors in antibiotic or germ-free mice did not respond to CTLA-4 blockade treatment, but could be overcome through the exogenous addition of Bacteroides. This is one of the numerous examples of the immunostimulatory effects of microbiota on various cancer therapies.

To Touch the Mind, Go With Your Gut

While in many respects the brain is still an enigma, recent investigations into neuro- developmental and chemical pathways have forced scientists to reevaluate many long-held hypotheses concerning cognitive growth and the onset of neurological disorders. Researchers now deem it critical to include the influence of the microbiome in a comprehensive outlook of neurology.

Dr. Mayer believes that gut microbes, along with the metabolites they form from our diets, have a significant impact on the brain, stating that “such effects could play a role in increasing the risk for neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease in genetically vulnerable individuals. I believe both animal and human research should focus on these two general areas.”

With respect to the microbiome-neurology connection, Dr. Mayer stated that he feels “in the next five years there are likely to be significant breakthroughs in our understanding of the etiology of autism spectrum disorders, Parkinson’s disease, autoimmune disorders, and metabolic disorders.”

Unfortunately, microbiome research is not always straightforward and suffers from an issue that can haunt scientists for a lifetime of laboratory and clinical investigation—causality. Though many studies have established links between the gut microbiome and the brain, it can sometimes be difficult to determine if the observed differences are the cause, consequence, or phenomenology. A growing body of data from gnotobiotic (germ-free) animals has shown how gut microbiota can alter brain physiology and neurochemistry. However, research done in humans is limited and the data more convoluted. 

“The biggest challenge is the difficulty in studying [these links] in humans with their tremendous genetic and environmental heterogeneity, and the cost of performing long-term longitudinal studies,” Dr. Mayer stated.

Yet, strong mechanistic evidence is beginning to emerge that should firmly establish the microbiomes interactions with the brain and what the importance will be for both disease and daily metabolic functions.

No Guts, No Glory

As with most scientific endeavors, future success is tied to technological advances and nonlinear thinking. Scientists often have ideas that can’t be fully realized as the technology to analyze their hypothesis either doesn’t exist or is prohibitively expensive to employ in any useful fashion. Developments for next-generation sequencing platforms have begun to provide genomic researchers with data that continues to push many scientific fields forward, and microbiome research is at the forefront.

Dr. Mayer believes that the breakthroughs we have seen for next-gen sequencing, as well as the rapidly declining costs, will allow researchers to “see similar advances and cost reductions in metabolomics profiling, metagenomic shotgun sequencing, and multi-omics data analysis approaches, such as machine-learning approaches.  There will also be advances in molecular imaging techniques of local microbial communities, of regional sampling techniques throughout the GI tract with wireless capsules.”

If “mind, body, and soul” is the mantra for Eastern meditative philosophies, then “mind, gut, and immunity” may just become the intonation of microbiome research as we continue to discover the immense interconnections these systems have on one another and the entire human body.


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