Humans may be patients, poets, protestors, petermen and in the last resort politicians, but we are all self-reproducing bioreactors. We provide an environment for trillions of microbes, most of which cannot survive for long without the food, shelter and a place to breed that we provide. They inhabit us so thoroughly that not a single tissue in our body is sterile. They modify our health, personality, mood and behavior throughout life, they predict our death (1) and become our disassembly line after we die. The network of connections between our multicellular selves and our unicellular cousins is multi-dimensional and enormously complex, and the demarcation line where we stop and the bugs begin is rapidly disappearing. The microbiome is dead, long live the holobiome! (2)
But let’s stick to the old terms for a moment.
Our microbiome affects our development, character, mood and health, and we affect it via our diet, medications and mood states.
There is a vast and constantly shifting collaboration between us and our micro-passenger bacteria, between our bacteria, and between our bacteria and their micro-passengers, the phages. Everything is connected (ie 3, 4).
One clinically important aspect of this is the growing realization that when we take non-antibiotic drugs, they modulate our microbiome (ie 5), which in turn influences those drugs’ positive and negative effects. This is the exciting new science of pharmacomicrobiomics (6-10).
But it goes much further than pharmaceuticals. Behind the gut/brain trope, it has become obvious that bacterial species not only affect who we are – they affect who we think we are, individually and socially.
Some of the early research in this area focused on the neurotransmitter serotonin. About 90% of serotonin is synthesised not in the brain but in the gut, where it plays a role in immunity. In mice, Turicibacter and Clostridia bacteria send messages to the gut wall instructing it to boost serotonin synthesis by up to 50% (11); and there is some evidence that this serotonin may be transported to the brain via the vagus nerve (12).
This is not the whole story, however, and it may not necessarily be about serotonin at all, because vagal stimulation itself has anti-depressant effects (13); and so other scientists have focused on a different candidate gut / brain messenger, butyrate. This short chain fatty acid is produced by various gram-positive bacteria when they digest (or more properly ferment) prebiotic dietary fiber, and is a potent anti-inflammatory agent (ie 14-16).
Depression is strongly linked to inflammatory stress in the central nervous system (17, 18), and in clinical studies, higher numbers of butyrate-producing species in the gut are strongly linked to feelings of wellbeing (19).
As most butyrate is produced in the gut, it is not surprising that researchers find that the anti-inflammatory effects of butyrate are more pronounced in the gut than in other tissues (20). This is not, however, how things have to be – or how they used to be. Due to dietary change, and our increasing intakes of ultra-processed foods, our intakes of prebiotic fibers have fallen by an estimated 80-90% since the 19th century (21, 22). Butyrate production in today’s gut is probably therefore an order of magnitude lower today than it was in the pre-industrial era.
An outstanding team of scientists at Cork University believe that butyrate is indeed a potentially important element in the gut-brain axis (23): and others at the Universities of Beijing and Hiroshima have demonstrated significant anti-depressant activity in preclinical models with both butyrate itself (24) and the prebiotic fibers that produce butyrate in the gut (25).
Both serotonin and butyrate are part of the gut-brain connection, but there is more to it. Changes in the microbiome alter the synthesis of at least 8 gut peptides including neuropeptide Y, ghrelin and the ‘love hormone’ oxytocin, all of which act on multiple classes of receptors in the brain (26, 27). More on oxytocin later.
There may be multiple messengers, therefore, but the evidence linking neuroinflammation to depression is too pervasive to dismiss. And if you’re curious as to why inflammation should cause depression, it is probably because inflammation in the brain is linked, in evolutionary terms, to real or perceived danger signals (18, 28).
Neuroinflammation is a highly conserved response to adversity, and constitutes a survival strategy when an individual is faced with physical threat or injury. The perception of danger triggers the release of endogenous factors known as danger-associated molecular patterns (DAMP’s), which up-regulate pro-inflammatory cytokines in the brain. The cytokines then drive a suite of responses to injury or the threat of injury which include fatigue, psychomotor retardation, anhedonia and social and behavioral withdrawal. It is part of the fight/flight response, but geared towards flight; and like the fight/flight response, while it was pro-survival in primitive times, it can be triggered in the modern world by social defeat (29), or threats which may be merely symbolic or even imaginary. These all lead to brain inflammation, but now the responses of withdrawal, loss of resilience and depression may be largely or totally counter-productive.
There is evidence too that when faced with too many threats and/or defeats, the neuro-inflammatory machinery becomes permanently activated, as occurs in abused children (30); leading to damaged development and impaired cognition and data processing (31).
This has led researchers to investigate anti-inflammatory approaches to various brain disorders. One candidate compound, chosen on the basis of its low molecular weight and ability to enter the brain (and all physiological compartments), is molecular hydrogen. It is an intriguing new approach to depression, anxiety and PTSD (32), and has already been shown to increase resilience in animal models (33).
But there are other ways. The bidirectional relationships between diet, the gut microbiota, immunity and resilience, create the possibility of treating affective disorders with dietary tools (34). There is a body of evidence to support this. High intakes of fruit and vegetables have documented antidepressant activity (35) and have been shown to increase resilience (36-38). The omega 3 HUFA’s also have well documented anti-inflammatory and antidepressant effects.
Plant foods are complex combinations of chemical compounds, and the most interesting candidates in this context are polyphenols and prebiotic fibers. Scientists generally want to know which compound has which effect, but it may be that these two types of nutrient work conjointly. The polyphenols undoubtedly increase resilience (39), but we do not know whether they act directly in the brain or indirectly, at least in part, via the microbiome (40).
Based on experience with patients, I recommend both prebiotics and polyphenols as part of a treatment program for affective disorders, with omega 3 HUFA’s on the side. This is not new; in 19th century England, the prison system emphasized use of a healthy diet (rich in polyphenols and prebiotic fibers) to improve prisoners’ health, behavior and rehabilitation (41).
The microbiome affects our thinking and our moods, but it goes deeper than that. It influences how we develop. It molds our personalities, our sociability, our responses to fear and pain and our proneness to brain disease; and may be as or more important in these respects than our genetic makeup (42-47).
For example, as we age we generally become more conservative and more risk-averse. Some of this is due to growing awareness of the impermanence of life and the painful accumulation of experience – with, perhaps, a little wisdom. But our single cell collaborators play a role here too. As the decades pass our microbiome changes in a way that creates a greater degree of neuroinflammation. This tends to make us more risk-averse because it amplifies responses to DAMP’s, and by reducing neuroplasticity, makes it more difficult to learn – so we become more fixed in our thinking (48). Fascinatingly, by changing the microbiome, these age-related changes in the brain and the associated changes in behavior can be reversed; in mice, at least (48).
So what is the take-home message?
There is pervasive evidence that the ageing process has accelerated within the last generation, due to dietary and lifestyle changes (49). A significant part of this is due to dysbiosis (50), which has become prevalent due to the removal of prebiotic fibers from today’s ultra-processed foods (51, 52).
Hedge accordingly, but if you are experiencing accelerated ageing, have psychological problems or believe that you have dysbiosis, I do not recommend probiotics. There is clinical evidence that some probiotic species, if consumed regularly, reduce activity in the brain in areas related to emotion and pain and may have anxiolytic and anti-depressant activity (53). However, a more detailed analysis suggests that while probiotic supplements may improve cognitive functions associated with dysbiosis, they can be counter-productive when added to a normal microbiome (54) or a microbiome depleted by antibiotics (55).
Probiotics can also cause dysbiosis directly, with small bowel malcolonization and excess production of D-lactic acid leading to significant cognitive impairment. Previously known to occur in subjects with short bowel syndrome and/or carbohydrate malabsorption, this has now been documented in normal subjects also (56).
Prebiotics present better treatment options, because here one is not introducing novel species of microbes into the body but amplifying the probiotic species already in situ. Additionally, by adding prebiotics we are merely restoring what the multinational food companies have irresponsibly removed from our diet.
How will you feel?
Personal experience may convince because of its intimacy, but has relatively little value because our personal experiences are so limited. Nonetheless, people often tell me they never felt depressed or anxious until they started having problems with their gut; and conversely, once their dysbiosis was resolved, they felt more stable. I have never been particularly depressed or anxious, but after starting to use a blended prebiotic I noticed significant changes. People who plank gain improved physical strength, balance, groundedness, posture and flexibility. I would describe what I experienced, personally, as the psychological equivalent. But the personal is the political, as second wave feminists never tired of telling us in the ‘70’s, and these gut feelings are very relevant to today’s incivility.
Germ-free mice display increased depression / anxiety and autistic behavior, and are less sociable. Without microbes (and you could think of this as our intrinsic or default mode), we are more anti-social, less cooperative. One attractive theory suggests that our microbes found ways to make us more social so that they could spread more easily. In this sense they contributed to human social behaviors and the development and maintenance of human society (57).
We are not germ-free, but our microbiomes have changed radically. Human diet (and shape) has shifted over the last century, with huge increases in ultra-processed foods, fats and oils, and obesity. Maternal obesity during pregnancy increases the risk of neurodevelopmental disorders, including autism spectrum disorders, in the offspring. More specifically, pre-clinical work has shown that a maternal high fat, low fiber diet changes the infant microbiome in ways that degrade the infants’ social behavior and ability to learn social cues. Even more specifically, these offspring had fewer oxytocinergic neurons in their hypothalamus, indicating that they were less able to love (58). Amazingly, however, restoring a healthy microbiome returned most brain functions to normal.
I believe that dietary shift has created a generation of humans less able to sustain or receive love. They suffer from reduced motivation, lower impulse control and are less informed by any sense of civic responsibility. At the same time they are more anxious, more depressed, more selfish and more polarized, and therefore more susceptible to the corrosive politics of identity. When combined with the corruption of crony capitalism, wide-spread environmental erosion and the slo-mo collapse of obsolescent 19th century social institutions, this begins to look like the beginning of the collapse of Western civilization.
Some say the youth of today lack moral fiber, but it may be that what they really lack is prebiotic fiber. It is certainly easier to restore.
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