“All disease begins in the gut."
Hippocrates (460 BCE), Greek physician, father of Western Medicine
“Focusing on the role of our commensals (the microbiota) in addition to our traditional concerns about pathogens will lead to new understanding about the diagnosis, prevention, and treatment of infectious diseases.”
Martin Blaser, M.D., Henry Rutgers Chair of the Human Microbiome, Rutgers University
In the past several years, an incredible number of studies were published that dealt with the human microbiome—defined most simply as the microbes that share our bodily surfaces. Based on these studies, we now know that age-associated shifts in the human gut microbiome contribute to certain diseases including cardiovascular disease, cancer, obesity, diabetes, inflammatory, and neurodegenerative disorders. In this week’s Germ Gems post, I highlight some of the discoveries related to infectious diseases and to the aging process.
What is the human microbiome? A microbiome (from Ancient Greek mikrós for “small,” and bíos for “life”) refers to the community of microorganisms living together in any given habitat. The microbiome is not exclusive to humans; microbiomes are also found in other animals and even in plants.
Scientists recognized the human microbiome more than a century ago. In 2001, Nobel laureate Dr. Joshua Lederberg used the term "microbiome" to describe an “ecological system of commensal, symbiotic, and perhaps pathogenic microorganisms that reside in the human body.” Today, the term microbiome typically refers to a collection of microorganisms (bacteria, fungi, archaea, viruses, and protists) and their genomes found in a specific niche. (The term microbiota specifies the commensal or non-harmful microbes in a microbiome.)
Like other revolutions in human history, the precise origin of the revolution in biology called the “human microbiome” is unclear. But in December 2007, the National Institutes of Health launched the Human Microbiome Project (HMP), funding the project from 2007 through 2016. The project enabled a comprehensive characterization of microbiomes in five human niches or ecosystems (gut, oral cavity, lungs, skin, and vagina). The HMP’s mission was to define the roles of these microbiomes in human health and disease. This project fueled the “Microbiome Revolution.”
The microbiome and infectious diseases. Of the five human microbiomes, the gut has captured the most attention. It is home to 10x the number of microbes than cells in the entire human body, totaling roughly 100 trillion microbes representing as many as 5,000 different species and weighing approximately 2 kilograms (4.4 pounds). Commensal bacteria that colonize the lower gastrointestinal tract protect us against invasive, disease-causing pathogens. But antibiotics can disrupt the gut microbiome and cause disease.
The single most convincing evidence that disruption of the gut microbiome by antibiotics can result in serious infectious diseases is a bacterial infection of the colon called Clostridioides difficile colitis (or “C. diff”). The administration of antibiotics eliminates commensal bacteria that ordinarily prevent the bacterial pathogen C. difficile from gaining a foothold in the colon. Given the extensive use of antibiotics, each year in the U.S. there are approximately 500,000 C. difficile infections and 15,000 deaths.
A number of clinical and basic science research studies carried out this century provided the evidence needed for fecal microbiota transplantation (FMT—via colonoscopy, upper endoscopy, enema or oral capsule) to become a first-line therapy of recurrent C. diff infections. In my December 14, 2022 Germ Gems post, “Progress in Germ Warfare Treatment of C. diff Colitis,” however, I described the development of a commercial product containing a well characterized set of spores from a commensal bacterial species that could replace FMT as a treatment of C. diff. Treatment with this product only involves taking four pills twice a day for three days instead of undergoing FMT. On April 27, 2023, this product—SER-109 (Trade Name: Vowst) containing purified Firmicutes spores—became the first US Federal Drug Administration approved poop-based oral therapy.
An important principal that’s emerged in microbiome-based treatment is that “diversity matters.” This principal is strongly supported by a December 15, 2023 Science article, “Microbiome diversity protects against pathogens by nutrient blocking.” In this study using a germ-free mouse model, researchers found that colonization of the gastrointestinal tract of mice with a diverse population of commensal bacteria protected against invasive infections caused by Klebsiella pneumoniae and Salmonella typhimurium (two highly pathogenic bacteria in humans).
COVID-19 is another serious infectious disease in which the gut microbiome plays a role in pathogenesis. In a May 2, 2023 review article in Frontiers in Immunology, “The relationship between gut microbiota and COVID-19 progression: new insights into immunopathogenesis and treatment,” researchers suggest that an imbalanced gut microbiota can fuel COVID-19-related immune dysregulation. In a mouse model of SARS-CoV-2 infection, the virus was shown to induce severe gut microbiome injury or dysbiosis (an imbalance in the microbiota) characterized by the loss of microbiome diversity.
Perhaps even more important than SARS-CoV-2’s acute effects on the gut microbiome are the chronic consequences of SARS-CoV-2, that is, the development of Long COVID. (See “Gut Microbiota Dysbiosis Correlates With Long COVID-19 at One-Year After Discharge,” Journal of Korean Medical Science, 2023 April 17.) Given the vast number of patients suffering from Long COVID, and the lack of highly effective treatments, it seems likely we’ll soon see trials of FMT for Long COVID.
Gut microbiome and aging. The impact of gut dysbiosis on the aging process is another area of human microbiome biology that’s capturing increased attention. To understand the background for the growing interest in this topic, we need to turn to Elie Metchnikoff who in 1903 called for a new scientific discipline (that he named “gerontology”) to study and control senescence (aging). (Metchnikoff is recognized as the founder of longevity research. He received the Nobel Prize in Physiology or Medicine in 1908 for his groundbreaking research on cellular immunology.) In his classic text published in 1914, “The Prolongation of Life: Optimistic Studies,” Metchnikoff called for increased scientific efforts to ameliorate the degenerative aging process.
It’s now commonly known that aging increases the risk of many chronic diseases. The risk of developing many, if not most, infectious diseases is often attributed to an age-related impairment of the immune system, so-called immunosenescence. Less well appreciated is that most of these diseases are associated with an altered (often depleted) gut microbiome. Contemporary studies, however, have uniformly demonstrated that as we grow older we lose bacterial diversity in our gut. And, if we want to live longer, it’s suggested we need a diverse microbiome. For example, in a study in China, published in April 2023 in Nature Aging, “Longevity of centenarians is reflected by the gut microbiome with youth-associated signatures,” researchers reported that those living a hundred years or longer have gut microbial signatures like those of young people.
The future of the microbiome revolution. The December 1, 2023 supplemental issue of the journal Clinical Infectious Diseases was devoted to “The Microbiome and Human Health.” Dr. Martin Blaser, a pioneer in the field of modern-day microbiome research, co-authored its leading article, “The Microbiome and Infectious Diseases.” In it, the authors summarize the major developments of microbiome research in the past two decades pertaining to infectious diseases.
In today’s Germ Gems post, I’ve superficially highlighted discoveries that relate to infectious diseases and aging. In earlier posts, l have touched on topics where microbiome research is equally or even more exciting, for example, the fields of probiotics and the bidirectional interactions between the gut microbiome and the immune system and the nervous system.
In a December 19, 2023 article in Medscape Medical News, “Where Is the ‘Microbiome Revolution’ Headed Next?,” Dr. Blaser is cited as saying, “Yet the ‘microbiome revolution’ is just getting started.” I fully agree, and only wish I’d be around long enough to see more of its fruits mature into sorely needed treatments and prevention strategies.