Your Microbiome and You: What Clinicians Need to Know

The Microbiome: One Big Block Party
The human body as a singular entity is anything but. Millions upon millions of microbes live inside and on the surface of each person, with some estimates suggesting that microbes outnumber human cells on the order of 10 to 1. This has given rise to the idea of referring to a human as a "metaorganism" that possesses a metagenome far larger than that which our own chromosomes encode.

In a sense, then, each person is made up of multiple ecosystems. Each individual's microbiome is composed of a diverse collection of microbial species that interact with each other and with their human host cells, contributing to and being affected by every normal and abnormal physiologic process that occurs in daily life.

How these trillions of microbes affect human health and disease -- and vice versa -- is still mostly a mystery and has become an intense area of study across nearly all medical disciplines.

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When Microbes Go Bad
Through the Human Microbiome Project and other efforts, researchers are looking at microbes in 4 major body habitats -- nasal/oral cavities, skin, gut, and the urogenital area -- to identify, classify, and categorize variations in the microbiota of individuals and across populations.^[1] But linking these data to human health and disease is more challenging.

The normal symbiotic relationship between human and microbe is a function of homeostasis between us and our microbial counterpart and microbial diversity and stability. Accordingly, disruptions in homeostasis have been linked to a range of beneficial and pathologic physiologic processes and have been implicated in direct effects such as bacterial vaginosis, endocarditis, and inflammatory bowel disease, as well as indirect effects such as drug metabolism, the generation of pro- and anticancer compounds, and the development of autoimmunity.

But do alterations in an individual's microbiome cause disease, reflect an underlying disease process, or both? And what might this mean for clinical practice?

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From the Microbiomial Bench to the Bedside
The practical application of research on the microbiome ultimately leads us to 2 key questions:

Can we predict disease by monitoring changes in the microbiome? If we had standardized measures for microbial species and could link variations to the onset of disease, could we use this information in the same way we use changes in blood pressure to measure risk for cardiovascular disease? Although detailed knowledge of microbiome composition and its functional significance may be out of reach, can we define surrogate markers of health and disease risk using microbiome readouts?

Can we prevent disease by manipulating the microbiome? If we could link the presence of specific communities of microbes with healthy outcomes, could we introduce these beneficial communities in the same way we introduce vitamins and minerals to combat deficiency? In this approach, probiotics, prebiotics, dietary interventions, narrow-spectrum antibiotics, and fecal microbiome transplantation are all viable options.

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The Gut Microbiome: Going to the Source
Microbes in the GI system are an obvious target for research. Breakdown of the intestinal wall and the presence of proinflammatory factors have long been linked to ulcers, inflammatory bowel disease, and chronic liver disease. But microbes in the gut also play key roles in energy metabolism, and disease can ensue when they go awry. This relationship has been explored in the development of nonalcoholic fatty liver disease (NAFLD). Clinically, intake of fructose has been shown to increase lipid synthesis, impair insulin sensitivity, and increase visceral adiposity, which predispose patients to NAFLD.^[2] On the microbial level, the presence of this sugar alters the gut microbiome, which allows for overharvesting of sugars and fat, increased gut permeability, inflammation, and liver injury.^[3]

Tantalizing research suggests that altering bacterial species in the gut can influence metabolic rate,^[4] making the combination approach of clinical interventions through diet and exercise plus microbiome-targeting therapy an attractive approach for further study.

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Tiny Microbes Drive Big Changes in Diabetes and Obesity
The link between the microbiome, obesity, and diabetes is thought to hinge on a leaky gut and chronic low-grade inflammation. A high-fat diet alters the microbiota, leading to increased calorie absorption. Reduced gut barrier function may provide microbes with access to the gut epithelium, initiating a cascade of immune responses and a chronic inflammatory state. The combination of dysregulated metabolism and inflammation promotes obesity and related metabolic disorders.^[5] Modulating gut microbiota can reduce inflammation and improve insulin signaling. The effects on gut microbiota after bariatric surgery contribute to resolution of diabetes, suggesting that manipulating the gut microbiome may play a role in combating obesity.^[6,7] A leaky gut has also been implicated in type 1 diabetes, where altered microbiota and disruptions in the immune system converge to promote autoimmune islet cell destruction.^[8] The links between gut microbiota and type 1 diabetes are still being explored, but this could prove a novel route to preventing or stopping it earlier.^[9]

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The Chicken/Egg Conundrum in Cancer
Colon cancer illustrates the chicken-or-the-egg conundrum when considering the link between the microbiome and disease. Alterations in intestinal microbes and elevated access to the gut epithelium lead to chronic inflammation, while microbes generate procarcinogenic compounds such as heterocyclic amines derived from the metabolism of a high-protein diet. Both promote colon cancer growth. But cancer growth, in turn, alters intestinal microbial species.^[10,11] Which comes first? This question has broad implications considering the well-established roles of genetic and environmental changes in cancer. If microbes promote disease, might they only do so in those with preexisting risk factors? Preclinical data with prostate cancer suggest so,^[12] and this approach also fits with what we know about microbial influence on progression to hepatocellular carcinoma in chronic liver disease.^[13] This complex interplay between genes, environment, and the microbiome opens a whole new avenue of research into oncogenesis.

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Microbes, Atherogenesis, and You
A high-fat diet/low-exercise lifestyle leading to cardiovascular (CV) disease may be only part of the story. Metabolites of specific foods generated by intestinal microbes have been implicated in atherogenesis, underscoring that what you eat is at least as important as how much you eat. The metabolite TMAO is produced by intestinal microbes after ingestion of phosphatidylcholine and L-carnitine from foods such as eggs, beef, liver, and pork. TMAO can promote atherogenesis by inhibiting cholesterol transport out of the body, and plasma levels are markers for major CV events independent of risk factors.^[14,15]

Yet, the microbiome's effects on atherosclerosis are not limited to the after-effects of digestion. Bacterial species from the oral and gut microbiota have been found in atherosclerotic plaques, and certain species found in the blood have been linked to a higher risk for CV events.^[16] The next step is to determine whether manipulating microbial species can affect the development and progression of atherosclerosis and CV disease.

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Is Using Microbes to Combat Infections Counterintuitive?
Infectious disease can be seen as simply an extreme imbalance between microbe and human. Although it may seem counterintuitive to use bugs to fight bugs, introducing "healthy" bacterial species can restore balance and health. The most well-known strategy is the use of fecal transplant to treat refractory C difficile infection,^[17] and the use of probiotics to prevent C difficile infection.^[18]

But the microbiome may also hold the key to combating antibiotic resistance, particularly multidrug-resistant organisms. Efforts in this area are focusing on increasing colonization resistance (the ability of the microbiota to resist colonization with a new organism) and resilience (the ability of the microbiota to recover from alterations in its composition).^[19] Resilience following antibiotic treatment may be a highly personalized trait, and studies in pharmacomicrobiomics^[20] (how microbiome compositional and functional variations affect drug action, fate, and toxicity) will offer new insight into how to treat infectious diseases more effectively.

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More Than Just Skin-Deep
The skin is teeming with microbes, and alterations in colonization and/or barrier protections have been linked to dermatologic disorders. The classic example is atopic dermatitis, in which Staphylococcus aureus is commonly cultured during disease flares. Research shows that the overabundance of S aureus reflects an imbalance in normal skin microbiota, with dramatic reductions in microbial diversity seen during disease flares and restored diversity seen after treatment.^[21] In theory, if microbial populations were tracked, earlier antimicrobial therapy could be initiated and the disease course could be modified. An imbalance in microbial species has also been seen in psoriatic plaques vs normal skin in patients with psoriasis and normal skin in nonpsoriatic patients. Of note, species that are thought to have immunomodulatory effects and serve in a protective role were underrepresented.^[22] This suggests that loss of protective microbes may be as important as increased pathogenic microbes, and that restoring balance in the skin microbiota may be a therapeutic goal.

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A Joint Approach to Immune Dysregulation
Multiple preclinical studies support the hypothesis of a "gut-joint axis" in which alterations in gut microbial species trigger an arthritis-like disease in the presence of an underlying systemic autoimmunity.^[23] Recent research pointing to an overabundance of a single species in new-onset untreated rheumatoid arthritis -- but not in chronic arthritis -- further supports this notion.^[24] This suggests that combining insight from studies on genetics, immune regulation, and microbial colonization might lead to a new way to prevent or slow the development of clinical disease.

A link between genetics and alterations in the microbiome has also been suggested in relation to ankylosing spondylitis. Here, researchers have theorized that HLA-B27 influences the composition of microbial species in the gut, and that HLA-B27-shaped flora activate clinical disease.^[25] Whether the microbiome can be targeted to prevent disease remains unknown, but further study of how known genetic susceptibilities interact with the microbiome is certainly welcome.

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This Is Your Brain on Microbes
The "gut-brain axis," in which signals from the brain influence GI function through decreased or increased innervation, is well understood. On the flipside, research has shown that alterations in the gut microbiome can influence behavioral responses, including learning, memory, and stress response. Preclinical studies suggest that a shift in the normal balance of gut microbial species can decrease levels of the neurotrophic factor BDNF, leading to impaired memory and increased anxiety-like behaviors.^[26] These responses were attenuated in settings of underlying stress, which in turn promoted increased gut permeability and intestinal inflammation, clearly illustrating the bidirectional nature of the gut-brain axis.

The gut-brain axis has been implicated in proinflammatory immune responses in the central nervous system that underlie diseases such as multiple sclerosis.^[27] This fits with what we know about interactions between the microbiome and the immune system and widens the potential clinical applications for this avenue of research.

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Where Do We Go From Here?
In considering what we know about the effects of the microbiome on health and disease, 3 key areas of research emerge:

• Better understanding of what constitutes "normal." Attempts to measure changes in microbial species and their effects on physiologic processes can progress only so far if we don't know how to distinguish between microbial homeostasis and dysbiosis.
• Better understanding of how manipulating an individual's microbiota affects health and disease. This is the holy grail of microbiome research, but until we know the effects of antibiotics, probiotics, and prebiotics, we won't make much progress in influencing microbial colonization for beneficial effects.
• Better understanding of how we can use this information in clinical practice. Over the years, we've seen successes and failures in therapeutically targeting microbes to restore health and stave off disease. As more preclinical research demonstrates the merits of this approach across all disciplines, we'll need to increase our focus on translating this research for patient care.

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