The gut extends about 25 feet and is the largest interface between the environment and the human organism. While the entire human body is comprised of ~37 trillion host cells, at least 38 trillion microbes inhabit the colon alone. Despite our common sense knowledge that diet is a major key to health and longevity, research on how gut microbes are involved in human health and physiology has expanded exponentially in the past decade.
Out of over 22,000 PubMed search results that use the keywords ‘gut microbiota’, nearly 18,000 were published in the past 5 years (2014 or later). Clearly a booming area of research, gut microbial discoveries have been catalyzed by recent advances in epigenetics, immunology, neuroscience, and more.
Since May 2018, I have been conducting research in a neuroimmunology lab for my senior thesis. I am studying how certain metabolites produced by gut microbes may worsen or alleviate multiple sclerosis (MS) disease progression by studying a mouse model of MS called experimental autoimmune encephalomyelitis (EAE).
Outline
From gut to blood to brain
You can learn a lot about an organism from its poop: what it eats, what microbes inhabit its intestines, and its overall state of health. Serum collection tells us levels of circulating inflammatory cytokines. 16S bacterial rRNA sequencing of feces and serum enables us to determine which microbes are present in the gut, and whether enterotoxins (pathogenic bacterial products) may have entered the bloodstream. Antibody binding assays help quantify the levels of inflammation-associated protein biomarkers. Gut dysbiosis (discussed later) is suspected to contribute to MS, pointing to the impact of diet and gut microbes on immune and brain health.
MS is an autoimmune, neurodegenerative disease in which the T cells attack the myelin sheath of neurons of the central nervous system (CNS), lowering signal transmission. With an average age of onset of 34 years old (usual range: 20-50), MS is a is triggered by a combination of environmental and genetic factors. The strongest genetic risk factor associated with MS is a gene system called human leukocyte antigen (HLA), which encodes the major histocompatibility complex (MHC) proteins. These cell-surface proteins regulate the human immune response. Environmental risk factors for multiple sclerosis include vitamin D deficiency, Epstein-Barr Virus (EBV), smoking, high-fat diet, pathogenic intestinal microbes, and antibiotic treatment.
Development of the gut microbiome
Evidence of in utero colonization of gut microbes via the placenta remains controversial due to potential contamination. However, is well-known that maternal diet can have lasting effects on fetal immune and brain development. Gut microbes colonize the neonate during birth, and babies delivered by C-section have significantly different gut microbiomes than vaginally-delivered babies. Shortly after birth, skin contact with the mother and breastfeeding further shape the neonatal microbiome. Other postnatal factors that influence the gut microbiota include antibiotics, diet, and genetics. Babies have lower gut diversity and particularly high levels of Lactobacillus, which also happens to be the predominant gut bacteria in pregnant women. Once they switch to solid foods, babies’ gut microbiota starts to resemble that of adults’, stabilizing by age 3.
What are the roles of gut microbes?
Gut microbes play crucial roles in the body, influencing our growth, immunity, mood, and more:
1. Nutrition: Gut microbes help the host digest food.
2. Metabolism: They modify metabolites in the body, which can then act on different receptors and change gene expression.
3. Energy storage: They help the host store energy and affect energy balance.
4. Immunity: Gut microbes play a critical role in innate and adaptive immunity, and may partially explain the surge in autoimmune and inflammatory diseases in developed countries.
Innate: Gut microbes modulate and protect the intestinal barrier through mucosa lining the gut
Adaptive: Gut microbes promote the maturation of T cells towards anti-inflammatory (T regulatory cells) or pro-inflammatory (CD4+ T helper cells) phenotypes
5. Development and behavior: they produce important neurotransmitters such as GABA, norepinephrine, dopamine, serotonin, and melatonin.
6. Sensation and emotion: Gut microbes can influence sensations of nausea, bloating, and satiety; conditioned food aversion; and change our mood. Bidirectional communication between the gut and brain is mediated by the vagus nerve, which can be activated by gut microbes.
Gut microbe activity contributes to the happiness derived from food. Obviously, this reward response was useful to our ancestors’ survival, but in a modern context, food overindulgence leads to disease.
The gut-brain axis and how it breaks down
The breakdown of the blood-brain barrier is a major culprit for numerous neurodegenerative and inflammatory diseases, like Alzheimer’s, Parkinson’s, ALS, Huntington’s disease, and multiple sclerosis. Tight junctions are present in the gut lining as well as the blood-brain barrier. These tightly regulated, tiny gaps between cells protect against leaky gut by carefully vetting which substances can enter and exit the bloodstream via the gut or brain. Ideally, nutrients like glucose, as well as ions like potassium, sodium, or calcium that promote neurotransmission will be allowed through, while pathogens, enterotoxins, and bacterial lipopolysaccharide (LPS) will be prevented from exiting the gut, entering the bloodstream, and infiltrating the brain. In addition to tight junctions, the mucosal lining in the gut prevents bacteria from getting too close to the gut-blood barrier.
The standard, Western diet filled with processed food and high salt, sugar, and saturated fats is known to lead to heart disease, obesity, type 2 diabetes, and a range of chronic conditions. High mucus-creating foods include red meat, milk, cheese, soda, alcoholic beverages, bread, pasta, butter, and eggs. High mucus-creating foods trigger a feeding frenzy, allowing pathogenic gut microbes to overpopulate. Gut dysbiosis is the imbalance in the composition and function of gut microbiota, shifted towards more pathogenic than mutualistic bacteria. Ultimately, this can lead to degradation of the mucus lining and leaky gut. Americans that live in urban areas and eat a Western diet generally have a lower gut microbial diversity, leaving them more susceptible to malabsorption, metabolic disorders, inflammation, and autoimmunity. Since the 1940s, a lower prevalence of infectious disease has been accompanied by an increased prevalence of autoimmune diseases like allergies, lupus, rheumatoid arthritis, and MS.
Current gut-brain axis research and future directions
The major impact of gut microbes on human health, physiology, and behavior necessitates their study. Recent projects such as the NIH’s Human Microbiome Project aim to characterize the diverse species associated with different tissues and states of health, including type 2 diabetes and pregnancy. We are still learning more about how maternal gut microbes can influence fetal and postnatal development.
In the future, we can hope to see longitudinal studies that characterize the effects of particular dietary lifestyles on the microbiota (e.g. Mediterranean, Western, keto, paleo, pescatarian, vegetarian, vegan, etc.) We are also learning about the relationship between gut microbes and intermittent fasting, sleeping habits, and exercise. Host genetic analysis could provide even more information on whether certain diets are suited to people of different backgrounds or genetics, as “the healthy diet” isn’t as monolithic as it seems.
We are continually learning about how specific metabolites from food modulate health and disease–new papers are published daily. In the meantime, a whole, diversified, plant-based diet and regular moderate exercise may be our best bet at maximizing gut health and subsequently our immunity and neurological health.
Key takeaways
You are a super-organism; over 50% of cells in the human body are not human.
90% of the body’s serotonin is made in the gut.
Gut microbes influence nutrition, metabolism, energy storage, immunity, development, mood, behavior, and sensation.
Poor dietary choices can lead to breakdown of the blood-brain barrier, inflammation, and neurodegeneration.
Over a dozen chronic diseases are thought to start in the gut.