Animal models show gut microbiota (bacteria, viruses, fungi, archaea and eukaryotes such as helminths) influence various aspects of physiology including brain function. Though data on their effect on human physiology is sparse, gut-associated pathologies and mental health issues such as depression () are strongly linked. Reverse also applies. For example, strong correlations between autism severity and gastrointestinal (GI) symptoms ( , ).
Physicians have for long recognized the link between ‘melancholia’ and constipation and other GI tract disturbances, and attempted to treat their symptoms with GI tract interventions (4). Though ideas such as autointoxication, the notion that psychiatric symptoms owed their genesis to GI tract disturbances (), faded over the 20th century, renewed research interest in gut-microbiota-brain link is helping move an idea that relied more on pseudoscience onto a firmer scientific footing.
Recently the term psychobiotic was coined for, ‘a live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness‘ (5). Could such outcomes be engineered reproducibly and if yes, exactly how do they work? Here the story gets much murkier because so far little can be stated unequivocally and even less claimed as a replicable therapeutic approach capable of manipulating human neuropsychiatric outcomes at will ().
This answer briefly explores
- Physical and neurochemical links between gut, gut bacteria and brain: Vagus nerve, Serotonin, other neurochemicals.
- Human studies on gut bacteria and brain: too few, poorly done, contradictory results.
- Antibiotics could affect brain function: Could harm (insomnia, mood alterations, psychosis, mania, depression, autism) or help (treatment-resistant depression, schizophrenia).
1. Physical & Neurochemical Links Between Gut, Gut Bacteria & Brain
Major nerve of the parasympathetic division of the autonomic nervous system, the vagus nerve physically connects the ~100 million neurons of the enteric (gut) nervous system to the base of the brain at the medulla () with projections into many other parts of the brain including the thalamus, hypothalamus, amygdala ( ). Gut inflammation and brain are theorized to connect via the vagus nerve, i.e., ( ).
- Enteric nerves could directly sense bacteria ( ).
- Vagus expresses receptors for many gastrointestinal hormones such as , which regulate food intake ( ), which may explain why blocking it can cause drastic weight loss ( , 13).
- is a procedure that increases parasympathetic tone. Its utility for and strengthens the link between gut-associated inflammation and brain function.
- Influencing brain states from appetite to circadian rhythms to moods, Serotonin is one of the clearest tangible links between gut microbiota and brain function. Major target of antidepressants, it’s also the most studied neurotransmitter in psychiatric illnesses. Rather than the brain, the in the gut are the body’s major source of serotonin ( ), and mouse gut microbiota were found to play a role in its synthesis ( ). Gut being abundant in both microbiota and serotonin, the latter in turn playing a major role in brain states, makes this a credible link though how serotonin, densely packed inside platelet granules, makes its way into the brain is still a mystery.
Bacteria As Source Of Other Neurochemicals
Many microbes can not only abundantly secrete neurochemicals such as Acetylcholine, Dopamine, Epinephrine, GABA, Norpeinephrine, Serotonin in culture () but also respond to them ( ). Sheer quantity of such neurochemicals suggests they may be of physiologic importance.
- For example, fermented foods such as Japanese funa-sushi (18) and Chinese paocai (19) use lactobacilli in their making and have millimolar levels of GABA in the final product.
- Bacteria that contaminate fish or shellfish products can secrete such large amounts of the neurotransmitter, histamine, testing is necessary to ensure levels don’t exceed government guidelines for food poisoning (20).
- Gut bacteria are also an important source of vitamins important for CNS ( ) function. For example, Lactobacillus reuteri, a normal human gut inhabitant, is a rich source of ( ), whose deficiency is implicated in in fetuses ( , ).
2. Human Studies On Gut Bacteria & Brain
Too many fundamentals yet lack answers. No consensus definition of what constitutes a healthy human gut microbiota. Gut bacteria alone are estimated to be >1000 species. Add how confounding variables such as age, diet, ethnicity, gender, location influence gut microbiota composition and the picture gets fuzzier rather than clearer. While proper understanding of gut microbiota-brain link requires an ecological approach, many studies assess gut microbiota-brain link in reductionist inbred rodent models whose results are hard if not impossible to extrapolate to human brain function.
- Often studies on effect of probiotics on brain function are poorly done, have few subjects and use questionnaires or scale-based assessments plagued by subjective bias.
- There are few RCT ( ).
- No wonder a 2015 systematic review found ‘very limited evidence for the efficacy of probiotic interventions in psychological outcomes‘ ( ) while a 2016 meta-analysis of RCTs could only provisionally conclude probiotics might improve CNS function but couldn’t rule out towards positive results ( ).
- No surprise that studies so far ( , , 28, , 30) comparing gut microbiota between MDD ( ) patients and healthy controls yield contradictory data.
- OTOH, a small study when well-designed and controlled can yield useful pointers for future studies. In one such ( ), healthy women were given fermented milk product with probiotic (n=12), non-fermented milk product (n=11), or nothing (n=13) twice daily for 4 weeks. The probiotics included Bifidobacterium animalis subsp lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, Lactobacillus lactis subsp lactis. fMRI ( ) suggested such probiotics might reduce stress responses and enhance cognition in healthy subjects.
3. Antibiotics Could Affect Brain Function
Do antibiotics influence neuropsychiatric symptoms? Since antibiotics wipe out gut bacteria, this offers another avenue to explore gut bacteria-brain link. Case-reports, epidemiological studies, clinical trials, a variety of such studies suggest antibiotics could either harm or help brain function, distinction depending on the antibiotic and kinds of bacteria it targets.
- One of the clearest examples is from case reports of antibiotics inducing insomnia, mood alteration (32), psychosis (33, 34, 35), even mania, antibiomania, especially in the elderly (36). Antibiotics most commonly implicated in these unusual behavior changes are clarithromycin, ciprofloxacin and ofloxacin.
- A retrospective medical records-based study (37) of 202974 patients with depression, 14570 with anxiety, 2690 with psychosis with 803961, 57862 and 10644 matched controls, respectively, concluded recurrent antibiotic Rx increased risk for depression and anxiety but not psychosis.
- Link between prior heavy antibiotic use and autism is quite strong (38, , ), especially use of trimethoprim/sulfamethoxazole ( ).
, a semi-synthetic , is usually used to treat acne and other skin conditions. It’s been suggested as a possibility for treatment-resistant depression ( ) and schizophrenia ( ).
- A small, open-label study found minocycline effective and well-tolerated in treatment-resistant depression (44).
- A pilot study by King’s College, London, is completed but no results posted yet ( , ).
- A couple of clinical trials are underway, one a phase II in Germany ( ) and another in Thailand/Australia ( ).
Thus, accumulating circumstantial data suggests gut microbiota influence human brain function but little of it is as yet tangible and reproducible.
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