In March 2013, the Public Policy Polling group surveyed 1,247 American voters regarding their various beliefs. Among the question topics were ideas about who was really in charge of controlling our lives. The result indicated 28 percent believed there is a secret, elite authoritarian group conspiring to rule the world; 15 percent believed that the government adds mind-control technology to media broadcasts; and 4 percent believed there are shape-shifting, interplanetary aliens running the world. Of course, the emphasis was on who runs our show from the outside; what was not asked in the poll is who runs our show from the inside. Put another way, who exactly is running your superorganism? I wonder what percentage of those 1,247 voters suspect that microbes are affecting virtually all of their decisions.
Several researchers, including John Cryan at University College Cork and Carlo Maley at the University of California, San Francisco, have referred to the microbiome as our puppet masters. John Cryan’s colleagues at University College Cork point out that there are at least five puppet master strings or routes of communication between the gut microbes and brain: (1) immune signaling that also includes the hypothalamus-pituitary-adrenal (HPA) axis, (2) activation of the vagus nerve, (3) spinal pathways, (4) direct production of neurotransmitters by bacteria, and (5) microbial production of short-chain fatty acids. These routes provide not simply the transfer of information but also real change in our brain physiology and function.
We have known for some time that control of behavior can be circumvented by some parasites and pathogens. They can take control in a selfish way. An example most people know about is the case of the rabies virus, which causes its victims, including humans, to modify their behavior, become aggressive, and even bite. These actions help to spread the virus between animals and people through saliva. It is thought that the aggression is brought on by a severe reduction in serotonin levels. It is why you don’t take chances with animal bites, and why our diagnostic labs at Cornell do a great deal of testing for rabies in bats, dogs, foxes, skunks, and other warm-blooded animals. Stephen King made good narrative use of this virus in his rabid-dog novel-turned-movie titled Cujo—for older generations the Disney dog film Old Yeller covers the ground in a more tender way.
If pathogenic microbes can control our behavior, so can our microbial friends, and there are many more of them. The challenge is for us to determine exactly what is ultimately malicious and what is benevolent when it comes to a microbe’s intent.
The gut, with 70 percent of our immune system and thousands of microbial species, is critical to our health in a world filled with friends and foes. Following that fundamental requirement, the gut-brain axis is the next most significant connection since it colors how we feel about ourselves within our world. There is considerable stock placed in personal actions and responsibilities, as that is a key part of what holds societies together. However, the “personal” part of our personal responsibility involves a cast of thousands of different species.
The gut itself so affects neurological function and the brain that it has been called the “second brain.” Yet buried within the gut are our gut microbes, and in many ways, they are the puppet masters hiding behind the throne. Our microbes have been working with and on our ancestors for centuries. In fact, they have been working on our ancestors using epigenetic gene switches that very likely transferred down through generations of our predecessors, as described in Part One. The microbes developed strategies to mold us into the ideal co-partners, taking a very long view of this human behavioral project.
If a roof over their heads and three square meals are basic needs, then our microbes would prefer to stay home and simply send you out foraging with a type of grocery list. And they know how to do precisely that. Dark chocolate is rich in a variety of chemicals, including polyphenols. These are part of the same group of chemicals found in various fruits, red wine, and grapes and have been known for some time to play a role in preventing NCDs. Our gut microbes have to act on these chemicals for them to be really useful to us. Recently, researchers have pointed out that our gut microbes make these useful chemicals for us, and in turn the polyphenols affect the state of our gut microbes since they need these chemicals, too.
Our gut bacteria make the dark chocolate healthier for you as long as your calorie intake remains in check. There is evidence that people who crave chocolate have different microbes in their gut and different chocolate metabolites in their urine. It seems clear that your profile of gut microbes, your desire for certain foods, and the metabolites that you produce from that food all align. Exactly which signals from the gut microbes affect the relationship to cravings has yet to be determined among myriads of possibilities. Since the microbial by-products can drive our contrasting feelings of pleasure, euphoria, depression, anxiety, discomfort, and pain, that is the place to look. The take-home message from this area of work is that by changing your microbes, you have a better chance to change your eating behavior.
The various bacteria in your gut are not simply innocent bystanders hoping you might accidentally choose to feed them over other microbes. They know how to biochemically influence you to choose their preferred food over others. A battle of signals rages inside you that eventually translates into a menu you only think you created. Instead, it reflects the balance of power among your microbes. There are three major phyla of gut bacteria: Actinobacteria (A), Bacteroidetes (B), and Firmicutes (F). It turns out that the ratio of B to F bacteria is much higher in lean individuals than in obese individuals. In fact, a high F-to-B ratio is pro-inflammatory and considered a biomarker for obesity. In general, a high-fiber diet is preferred by and facilitates the growth of B, and a high-fat diet is preferred by and facilitates the growth of F. Studies of children in different regions of the world indicate that those who eat a high-fiber, low-fat diet have a higher B-to-F ratio. But the phyla include many different bacteria, all with their own food preferences and needs. At a deeper level of comparison, gut bacteria within the three different phyla also have their own food preferences.
Preferred food sources differ as well depending upon what the bacteria can use as an energy source. For example, Prevotella bacteria, a genus within the B phylum, want to eat carbs, while Bifidobacterium bacteria, a genus in the A phylum, crave dietary fiber. Other minor microbial players in our gut (e.g., Akkermansia muciniphila and Roseburia species) have their own preferences and are weighing in as well. It is a balance-of-power issue. If you have eaten something for generations in your family, your microbes are likely to reflect that. You are synced up with your gut microbes’ long-standing energy sources. On the other hand, if you have a certain mix of microbes currently in your gut, they will be working hard to see that you eat precisely what they want.
Our gut microbes control much of our neurological and brain function because they produce a wide variety of neurotransmitters and neuromodulators in addition to affecting the production of those same neuroactive substances by our mammalian cells. These brain-affecting chemicals can reach the brain via either the enteric (or gut) nervous system or the portal circulation (a vein that runs from the gut to the liver). An ever-increasing list of neuroactive metabolites of gut microbes have been reported. These include:
serotonin (made by some Enterococcus species)
dopamine (a product of some Bacillus bacteria)
gamma-aminobutyric acid (GABA) (produced by some Lactobacillus and Bifidobacterium)
acetylcholine (produced by some Lactobacillus)
histamine (produced by some Lactobacillus)
norepinephrine (produced by some yeasts, Escherichia, and additional bacteria)
Serotonin is a neurotransmitter that regulates sleep, mood, and appetite and also affects certain cognitive functions such as learning and memory as well as cardiovascular function, bowel motility, ejaculatory latency, and bladder control. As a result regulation of serotonin is very important for our health, mood, and well-being—and the historic success of the drug Prozac and other selective serotonin reuptake inhibitors (SSRIs) illustrates the importance of appropriate balance of neurochemicals. What we had not realized is the extent to which our microbes control the balance of our neurochemicals. Much of the body’s serotonin is produced by specialized cells in the colon. It turns out that gut bacteria can control the gut’s production of serotonin via the metabolites that specific spore-forming gut bacteria produce. You might say that in controlling such central aspects of our core being, the microbes have us right where they want us. However, if we don’t like their influence at any given point, we now have the capacity to evict them and install new co-partners.
Accumulating evidence indicates that things like mood, anxiety, and depression are affected by microbes and their specific activities. Besides directly producing hormones and neurotransmitters, other metabolites of our gut microbes can epigenetically program our neurological system for behavioral characteristics. This programming can happen early in life and affect the rest of our lives. A team of University College Cork researchers recently showed precisely that. Germ-free animals lacking normal gut microbes have specifically altered gene expression in the amygdala that is connected to neurobehavior.
Germ-free mice lack the desire and/or capabilities of social cognition. They are antisocial. As John Cryan and his colleagues have hypothesized, social interactions, including a social collective mind, may have evolved for the primary purpose of permitting the exchange of microbes between individuals. Many authors have discussed what is called the collective consciousness: the hive mentality, shared values, and social mind of communities of people. However, it is clear that any future discussion of how collective consciousness and the unconscious operate will need to include our microbes.
This provides a new view on what can happen when infants and children receive broad-spectrum antibiotic treatment, thereby depleting their microbiome. There are both early postnatal brain function effects as well as later effects seen during critical windows of childhood development, all of which are controlled by microbiome status. John Cryan and his colleagues performed that experiment in mice, looking at behavioral effects. They found that antibiotic-induced alteration of the microbiome after weaning (during later infancy) led to changes in the adult microbiome profile and also resulted in cognitive deficits. In fact, besides their later-life cognitive deficits, germ-free mice have eerily similar social interaction profiles to those of autistic children. These findings of the neurological importance of the early-life microbiome suggest that any procedure causing a depletion of a baby’s or infant’s microbiome could have a lifelong, adverse impact on brain function.
Imbalance in our microbes can also injure the brain via inflammation. Our microbes are a source of both pro-inflammatory and anti-inflammatory signals. But when the balance is shifted inappropriately, as with overgrowth of some bacteria in the gut, the ramifications can be dramatic. Pro-inflammatory signals can increase gut permeability as well as the levels of both systemic and central-nervous-system inflammation. The resident macrophages in the brain, microglia cells, are primary responders to many of these bacterial signals. When inappropriately activated, these cells can promote neurodegeneration and destruction. Depression, mental illness, and neurodegeneration are very difficult to correct until and unless the gut microbial signaling that created the inappropriate neuroinflammation is reversed. Much of the effort to date has been to focus on the site of the inflammatory damage (e.g., brain, gut lining) rather than on the source of the problem, imbalance in the gut microbes. There is encouraging human evidence that shifting the balance of gut bacteria using probiotics can reduce systemic inflammation.
We need to rethink mental health from the viewpoint of what is best for the superorganism.
As this is a self-care chapter, I will discuss how you can use the idea of master-controller microbes to improve your health. What was the bestselling prescription drug in the United States in 2014? According to WebMD it was Abilify at $7.2 billion in sales between July 2013 and June 2014. Abilify, generically known as aripiprazole, is an antipsychotic drug that works by changing the chemistry of the brain, primarily by dampening the signal produced by dopamine receptors. It is used to treat depression, schizophrenia, bipolar disorder, and behavioral issues in children. One of the side effects is elevated risk of suicide in the young. But in the era of the microbiome, now that we are armed with the knowledge that our gut microbes are the master controllers of our brain, heavy-duty prescription drugs are no longer the only option. Change your microbes; change your life.
Our brain is similar to the immune system in one important way: They both need a balanced, healthy microbiome to develop and function well. The prevalence and toll of neurological diseases and disorders is staggering. In a recent study of twenty countries, the incidence of neurological deaths has risen significantly between 1990 and 2010 compared with deaths due to cancer or circulatory disease. For example, cancer deaths in the United States fell by double digits over the twenty-year span, while neurological deaths rose by double digits. As the researchers have pointed out, the specific increase in neurological deaths over those of other categories may be due to differences in the effectiveness of treatments. That would be all the more reason to examine the value of manipulating the microbiome to protect the brain and neurological system better.
The high percentage of deaths from neurological disorders is particularly evident in the United States. It is presently estimated that one in three seniors in the US dies of Alzheimer’s or another dementia. However, death is not the only meaningful measure when it comes to the human toll from the neurological part of our broader NCD epidemic. Perhaps an even more alarming concern and related indicator of our problem is the recent explosion in mental illness and behavioral conditions in children. Based on recent estimates, one in forty-five children now has autism spectrum disorder, and up to 20 percent have a mental illness for which care costs $247 billion each year. Given that the upcoming generation is challenged with serious NCD issues for which many need continual care, and that the aging baby boomer population is developing their own set of NCD issues for which they will need continual care, exactly who will be left as the caretakers when we reach the tipping point? Continuing the path of ineffective, patchwork solutions for this NCD epidemic is no longer an option.
If microbes affect our behavior and cognition, and we can reshape our microbiome and its metabolism using probiotic and prebiotic supplementation or FMT treatments (by working in concert with health professionals), then we have the potential to change and improve our cognition and behavior significantly. For anyone facing these diseases and conditions, either personally or within their families, this is a sea change in terms of both hope and opportunity. If you don’t like your current mental state, there are emerging strategies for shifting the balance of functions in the brain that are alternatives to lifelong, side-effect-producing, heavy-duty medications.
There is research supporting this type of new approach, although it is important to note that not just the species of probiotic bacteria matters but also the specific strain since genes, metabolites, and physiological effects can differ between strains. One useful, newly emerging probiotic is Bifidobacterium longum strain 1714, which has an antianxiety action in mice. Additionally, a recent human trial involving probiotics and college undergraduate students found that daily supplementation with the probiotic bacteria Bifidobacterium bifidum R0071 resulted in a higher percentage of healthy days among academically stressed students. Finally, a psychiatric study in humans concluded that consumption of fermented foods containing probiotics was associated with reduced social anxiety. A recent study compared the mental health and HPA effects among workers in the petrochemical industry who for six weeks ingested yogurt with probiotic bacteria, an encapsulated mix of several probiotic bacteria, or standard yogurt as a control. Both types of probiotic supplements significantly improved both general and mental health among those workers who consumed them compared with controls.
There is evidence that supplementing with certain prebiotics can boost resiliency to stress by acting through the gut microbiota–brain axis. In a stressed-mouse model, a team of researchers at Ohio State University looked at the impact of dietary supplementation with two different, slightly modified lactose sugars that are normally found in human milk. The two types of human milk oligosaccharides are indigestible by our mammalian cells, pass through the small intestine unabsorbed, and then get used by microbes in our colon to make a variety of needed metabolites. These specific specialized sugars from breast milk are known to support the growth of friendly co-partner bacteria such as Bifidobacterium longum. In this study, male mice were given either of the two prebiotics for two weeks prior to a social-disruptor stressor where the younger male mice were confronted with a “foreign,” aggressive male mouse. The prebiotic supplementation led to greater maturation level of brain neurons, a stabilized gut microbiome after the social stress exposure, and a lack of anxiety in poststress behavioral testing. These results support the value of nurturing brain-friendly gut microbes via supplementation with useful prebiotics. They also reaffirm the value of breast-feeding whenever possible for neurological benefit.
A study in humans of two prebiotics yielded encouraging results similar to what has been found with rodents. Work-related stress can elevate cortisol levels and also reduce work effectiveness because anxiety makes attention and focus difficult. When researchers compared a prebiotic galacto-oligosaccharide preparation versus a second prebiotic and controls, they found that people taking the galacto-oligosaccharide preparation had both a reduction in neuroendocrine stress response and anxiety-related changes in attention and focus. There is the real possibility that prebiotic intake may provide a useful route to reducing anxiety and improving work performance by disconnecting us from constant fight-or-flight responses.
Prebiotics, like oligosaccharides found in breast milk, can be useful for infants, with manufacturers increasingly adding them to some infant formulas. These prebiotics include galacto-oligosaccharide, fructo-oligosaccharide, polydextrose, and various combinations of these. Positive effects have been reported with the supplemented formulas. For example, formula supplemented with galacto-oligosaccharides enhanced the growth of Bifidobacterium and Lactobacillus bacteria, inhibited the growth of Clostridium, and reduced the prevalence of colic. These prebiotics can also lead to an increased production of a variety of neurotransmitters and neuromodulators working between the gut microbiota and the hippocampus.
Putting all of this together, there is real promise for probiotics and prebiotics to increase our resiliency throughout our physiological systems, including the brain and neurological system. They can produce combined effects across the immune, neurological, and endocrine systems and help buffer us against the ravages of stress regardless of the type and origin. We perform better in terms of brainpower, focus, and memory, and we are less likely to see major HPA fluctuations in response to the stress that hammers our immune defenses and opens us to more disease.