Saturday, June 3, 2023
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Over the past few decades, medical researchers have begun to shine a light on a largely uncharted world of immense complexity and import residing in a place few suspected: the human gut. Although the centrality of our gastrointestinal (GI) tracts to our immune systems was well established, its myriad functions on a microbial level remained a mystery. When revolutionary genomic testing arrived to identify the microbial communities and their genes (the "microbiome") that populate the gut, it led to a dizzying number of studies indicating its prominent role in our overall health and propensity for various diseases. The gut microbiome has now been linked to an ever-increasing number of clinical fields beyond gastroenterology, including immunology, rheumatology, diabetes, and neurology. This slideshow explains how the microbiome went from an untestable hunch to a verified medical breakthrough, one deserving of both awe and healthy skepticism.
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Although people like to think of themselves as autonomous, when it comes to our bodies, we're fully colonized. Estimates of how many gut microbes humans play host to vary considerably, to as high as 400 trillion.[1] It was once thought that these organisms outnumber the cells that compose our own bodies by a factor of 10 to 1. However, this much-repeated figure was recently exposed as a factoid erroneously calculated in an earlier study and is likely closer to a ratio of 1.3:1 in the average human.[1] The sheer complexity of this hidden world is without question, though, and is one reason why the microbiome has come to be known as our "other genome." The microbiome is composed primarily of bacteria but also includes archaea, fungi, viruses, and protozoa.[2] It is populated by complex communities whose ability to function and survive often depends on the metabolic support from other organisms. The microbiome's delicate ecologic balance has given rise to the theory that modern hygienic practices (eg, overuse of antibiotics, improved sanitation) have actually weakened aspects of our health by reducing exposure to the bacteria on which we thrived for thousands of years.[3] Indeed, isolated hunter-gatherer tribes in South America have been shown to have considerably more diverse microbiomes than those from industrialized populations. In another ironic twist, the very same progress that may be hurting us has also given us the means to unravel the reasons why—and potentially intervene to correct it.
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More than two centuries after the "little animals" we now call bacteria were discovered, the first theories of the microbiome's role in maintaining health were put forth by Ilya Ilyich (Élie) Metchnikoff (1845-1916). A Russian scientist working in Louis Pasteur's laboratory, Metchnikoff would win a Nobel Prize in 1908 for helping to pioneer cellular and humoral immunology. Late in his life, Metchnikoff embarked on a personal quest to research possible methods of staving off senility and other markers of aging. Noticing that residents of certain sections of Eastern Europe who were relatively economically disadvantaged nonetheless experienced longer lives, he studied their diet and lifestyle choices. This led to his theory that aging-related illnesses were the result of phagocytes being transformed from protective to destructive via bacteria in the colon. He believed that regular consumption of lactic acid bacteria in fermented dairy would reverse this action and promote longevity, perhaps the first instance in which probiotics (the practice of introducing microorganisms for their health benefits) were specifically offered as a medical solution.[4,5]
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Metchnikoff's theories were untestable by earlier microbiologists, who were dependent on microbial species that could be easily grown in laboratories, thus ruling out the primarily anaerobic microbiota residing in the human gut. This began to change in the late 1950s, when germ-free mice made it possible to colonize specific human intestinal microbiota. In the late 20th century, the DNA analysis of microbes that could not be cultured changed everything. Aided by a sequencing technique using the 16S rRNA gene, which is relatively well conserved and present in a wide variety of bacterial organisms, real breakthroughs began to appear, including genome sequencing of the first microorganism and the first human fecal sample. Shortly thereafter, in the wake of the successful Human Genome Project, the early part of the 21st century saw no shortage of governmental support for research in this area, including the International Human Microbiome Consortium, the NIH's Human Microbiome Project, and the European Union's MetaHIT project. The microbiome was on its way to prominence.[5,6]
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In quick succession, multiple studies appeared in the middle of the 2000s that would reshape our concept of the gut microbiome's role in health and illness. One of the first crucial discoveries was of the microbiome's abundant variety, with a 2005 gene-sequencing study of feces and colonic site samples from healthy subjects noting that a majority of newly discovered microorganisms had little overlap from patient to patient and differed significantly based on sample location.[7] Further metagenomics research revealed, in the authors' words, that "humans are superorganisms whose metabolism represents an amalgamation of microbial and human attributes."[8] A comparative study then determined that lean and obese subjects had different groupings of microbes present in their gut, and that this profile changed upon weight loss on a low-calorie diet, giving tangible evidence of the value of even moderate interventions.[9] In these and other analyses, a revolutionary picture soon emerged of a microbiome composed of previously unknown organisms involved in a complex discourse with our own cells that, if understood and harnessed, could unlock new pathologic underpinnings and treatments.
Because the GI system is the seat of the microbiome, diseases in this area understandably have been the most frequently associated with it. The link between Helicobacter pylori and GI diseases like peptic ulcer disease and gastric cancer is considered by some to be the most significant discovery yet to have arisen from this new field of research,[10] although it predates many of the advanced genomic sequencing methods now in use. There is a strong case for the role of the human intestinal microbiota in the development of colorectal cancer, not only via carcinogenic pathogens but also through the promotion of a chronic inflammatory environment.[11] The microbial underpinnings of inflammatory bowel disease (IBD) have been scrutinized heavily, with a substantial majority of genetic variants in this condition linked to heightened immune activation toward gut microbes.[12] Although it is not known whether alternations to the gut microbiome cause or are caused by nonalcoholic fatty liver disease, several interventional studies are also looking at whether dietary and lifestyle changes can positively affect the bacterial profiles of patients to produce clinical improvements.[13]
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The early adoption of fecal microbiota transplantation as an ad hoc, self-administered treatment by otherwise desperate patients, as well as its unavoidable sensational aspects, may have obscured its status as a life-changing treatment. There is no such confusion today, with patients with refractory Clostridium difficile infection commonly experiencing primary cure rates upwards of 90%.[14] Further refinement of how fecal specimens are transferred from patient to patient has also brought this treatment fully into the mainstream. The staggering results with C difficile infection led to its use in other GI disorders, most prominently IBD, where its value has been less certain. There is also concern over findings from animal studies, which showed that unwanted immunologic, behavioral, and metabolic phenotypes can be passed to recipients[10]; could this also prove true in humans? The American Gastroenterological Association announced in early August that, with financial support from the National Institutes of Health, it was launching the first national registry to track outcomes with fecal microbiota transplantation. They noted that the adoption of this treatment had outpaced its clinical study, and hope that such an effort would clarify the short- and long-term outcomes to be expected with its use.[15] Questions remain, but fecal transplantation is thus far the clearest translation of genomic microbiome research into demonstrable, real-world clinical benefit.
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The prolonged and elegant evolutionary process by which microbiomes have interacted with their human hosts to create efficient mucosal immune systems has slowly been illuminated with new testing methods.[16] Maintaining this symbiotic relationship is essential, as evidence suggests that the gut microbiome regulates not only the local intestinal immune system but also the host's adaptive immune responses.[5] It is therefore not surprising that non-GI autoimmune disorders like rheumatoid arthritis (RA) have also been linked to the gut microbiome. A study comparing the intestinal microbiota of patients with recent-onset RA and fibromyalgia observed substantial differences between the two, with the authors concluding that these results supported the microbiome's potential role in development of RA.[17] One theory holds that the microbiome may interact with predisposing genetic factors to trigger peripheral or axial arthritis.[18] The autoimmune disorder spondyloarthritis has also shown a common bacterial profile to another inflammatory disorder, IBD.[19] Early-stage research is looking at the efficacy of probiotic interventions for conditions such as these.
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The immunologic benefits of breast milk for newborns are widely known, yet the true complexity of its composition is coming more into focus. In comparisons with other mammals, scientists have noted that human mothers produce a much more varied number of complex sugars called oligosaccharides (more than 200 have been identified to date).[20] These sugars cannot be digested by babies but instead are more likely food for the microbiome, as they selectively provide nourishment to one bacterial subspecies that in turn produces adhesive proteins with immunoprotective and anti-inflammatory qualities.[20] A recent study showed that the microbiome of children who were exclusively breastfed differed significantly from those who were given formula and even from those who alternated between the two.
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Although the research is still preliminary, considerable attention has been given lately to the possible role of the microbiome in the treatment of both type 1 and type 2 diabetes. One study of infants from the United States, Germany, Sweden, and Finland, who were non-autoimmune but at high risk for type 2 diabetes, reported vastly different microbiomes based on location.[21] This finding was mirrored by another study that sequenced the fecal metagenome of European women with normal, impaired, or diabetic glucose control; researchers found that they could create a model that can positively identify type 2 diabetes.[22] They then applied this to a cohort of similar Chinese women and observed that the markers for type 2 diabetes differed in this group. Although recent data show that select microbial targets may prove valuable in addressing insulin resistance,[23] these other studies are reminders that when looking at trillions of suspect bacteria varying greatly by location, it may be difficult to develop specific interventions with global reach.
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One of the most interesting findings in recent years has been the role of the microbiome in mental health and neurologic conditions. The microbiome can communicate with the brain indirectly (eg, hormonally or using the immune system) or directly (eg, through neurotransmitters in the gut that signal through the vagus nerve), and has been linked to several neurologic conditions. Autism spectrum disorders have a potential association with changes in the gut microbiome as well and may account for the occurrence of GI disorders in such patients.[24] The inflammatory-state changes noted in schizophrenia, major depressive disorder, and bipolar disorder similarly indicate a possible role of dysbiosis in their development.[25] This connection between the gut and the brain has also inspired surprising new treatments for psychological and neurologic conditions. Healthy participants without current mood disorders who were given probiotics were shown to experience reduced rumination and aggressive thoughts.[26] Probiotics were also observed to decrease stress in those about to undergo laryngeal cancer surgery.[27] Although conducted at the murine level, a just-released study observed that long-term, broad-spectrum antibiotics decreased the plaques that contribute to Alzheimer disease, showing just how wide the range is for the therapeutic concepts currently being tested in neurogastroenterology.[28]
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It is important to note that the overwhelming attention given to the microbiome has not been without its critics. A 2014 review in the journal Nature[29] succinctly noted the general concerns: "The hype surrounding microbiome research is dangerous, for individuals who might make ill-informed decisions, and for the scientific enterprise, which needs to develop better experimental methods to generate hypotheses and evaluate conclusions." The article's author also referenced the companies that, similar to those conducting individual human genetic testing, offer to provide a microbial portrait using fecal samples, with concern about the varying and imprecise results that can come from such an analysis. The push to try fecal transplantation in extraintestinal disorders, where it may not have efficacy (eg, Alzheimer disease), was also held out for criticism. The research community must consider the age-old question of whether correlation is being confused with causation, and whether the tools pivotal to this research, such as germ-free mice, truly reflect the real-world diversity of the human microbiome.
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Skepticism does not seem to have afflicted the investment community. A 2014 article in Nature News[30] noted that $500 million worth of microbial research had been conducted in the preceding 6 years, with much more expected to follow. Just this past spring, the White House Office of Science and Technology Policy, in collaboration with federal agencies and private-sector stakeholders, announced a new National Microbiome Initiative.[31] It will fund interdisciplinary research, new technologies, and additional workers across a variety of government agencies. The initiative was supplemented with contributions from such organizations as the Bill and Melinda Gates Foundation, whose $100 million represents the majority of the overall $121 million commitment. When factoring in the untold amounts being spent on less-sophisticated and relatively untested probiotic foods and supplements that we find in any grocery store or pharmacy, it appears that the microbiome has staked a claim right in the heart of the American economy.
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While clinicians await more proven therapeutic options and hope for something as simple and effective as fecal transplantation, there are steps they can take today to positively affect their patients' microbiomes. These begin with dietary and lifestyle recommendations, which, although in line with previous advice, now come with a robust new set of data to back up their utility. Established strategies with evidence for improving gut health include shifting patients toward diets using simple sugars and fiber-rich foods,[32,33] combating glucose intolerance by avoiding artificial sweeteners,[34] and promoting immunity and intestinal stem cell health with established sleep patterns.[35]
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If the microbiome was a largely undiscovered territory toward the end of the 20th century, it is now one that is awash with pioneers seeking answers to some of our most pressing concerns. Our work on the "forgotten organ" has revealed some fascinating insights thus far, but there is promise for even more important revelations, which will draw even more researchers looking to produce crucial interventions, as well as healthcare companies hoping to convert that work into healthy returns on investment.
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