The Connection Between Gut and Brain
The gut microbiome has gained a lot of attention over recent years, accompanied by a growing body of evidence supporting its role in health and disease. The human gut microbiota consists of trillions of microbial cells and thousands of different bacterial species, whereas the gut microbiome encompasses the genes and functions of these species.
There are still a lot of mysteries when it come to the gut microbiome, but what we do know is that diet can have a profound influence on it - for the better and for the worse.
So, how does the ketogenic diet fare?
No one has explicitly studied this, nor would it ever be as simple as saying what the ketogenic diet does exactly to the microbiome, however, what’s been reported is that the diet can decrease the diversity of species. Different microbes feed off different food sources, so restricting carbohydrates to the extent of a ketogenic diet can starve off certain “carbohydrate-loving” species. This can eliminate the bacteria that thrive off refined carbohydrates, the ones associated with the production of harmful metabolites and promoting inflammation.
Additional findings in studies of ketogenic diets in both humans and animals have shown:
An increase in particular bacterial species that led to a decrease in the production of γ-glutamyl transpeptidase by the gut microbiome, which is an enzyme involved in the formation of glutamate. This has been implicated as a contributing factor to the diet’s anti-seizure effect by increasing the GABA to glutamate ratio.
An increase in certain species associated with improved insulin sensitivity and weight loss
Improvements in the Firmicutes to Bacteroides ratio, which is often impaired in Autism Spectrum Disorder (ASD), indicating a potential role for ketogenic therapies in ASD
Varied results (both increase and decrease) in the production of short chain fatty acids (SCFAs) which likely correlates to the amount of fiber in the diet used. SCFAs play a beneficial role in immunity, signaling molecules between the gut and host, and are a source of energy to our colonocytes
Varied results for the pro-inflammatory bacterial species: Desulfovibrio
Overall, from the small amount of research available, it appears that the ketogenic diet can improve the health of the gut microbiome which translates to the regulation of our immune system, anti-inflammatory properties, improved gut permeability, and the prevention of gastrointestinal disorders such as Crohn’s Disease.
Stay on the look-out for a blog post on ketonutrition.org covering this topic on a deeper level.
Evidence is starting to emerge supporting the efficacy of probiotics in the area of mental health (Foster et al., 2017). A psychobiotic was recently defined as a live organism that, when ingested in adequate amounts, produces a mental health benefit (Dinan & Cudmore, 2013). The gut microbiota has been implicated in a variety of stress-related conditions including anxiety, depression and irritable bowel syndrome. In the recent years, an increasing number of studies have reported that stress exposure early in life or in adulthood can change the organism’s microbiota composition, and that gut microflora can shape the organism’s stress responsiveness (Golubeva et al., 2015; De Palma et al., 2015; Bharwani et al., 2016).
In addition, Bifidobacterium and Enterococcus produce the neurotransmitter serotonin, an important biogenic amine involved in mood; and significantly lowered in the cases of depression. Desbonnet et al. (2008) found that consumption of probiotics increased plasma levels of serotonin’s precursor, tryptophan and decreased serotonin’s main metabolite 5-hydroxyindoleacetic acid (5-HIAA), similar to the antidepressant citalopram. Consumption of probiotics was also shown to increase expression of brain-derived neurotrophic factor (BDNF), a growth factor crucial for brain plasticity, memory, and neuronal health that is abnormally reduced in patients suffering from depression (Wallace & Milev, 2017).
Bacteria also produce short-chain fatty acid (SCFAs), such as butyric acid, propionic acid and acetic acid, which are able to stimulate sympathetic nervous system, and thus influence the memory and learning processes in the brain. The impact of gut bacteria on cognition was demonstrated in numerous laboratory animal model studies. In a study done by Neufeld et al. (2011), germ free animals have shown reduced anxiety like behaviour and increased hippocampal brain derived neurotrophic factor (a protein associated with neurogenesis). Furthermore, in rodent models, a specific strain of Bifidobacterium longum was found to alter cognition, as well as stress related behaviour and physiology; and a similar profile of effects was subsequently observed in humans who were given the same strain (Allen et al., 2016).
Conclusion
Understanding how the brain and the gut microbiota interact at a functional level is likely to remain one of the great scientific challenges of the 21st century. Moreover, the emerging concept of a microbiome-brain-gut axis through which probiotics demonstrate positive influence on brain development, emotions and cognitive function suggests that modulation of the gut microflora could be an effective strategy for developing novel therapeutics for complex mental health disorders.
ketone bodies, molecules produced by the breakdown of fat, help the intestine to maintain a large pool of adult stem cells, which are crucial for keeping the intestinal lining healthy.
https://www.sciencedaily.com/releases/2019/08/190822113401.htm
Links between gut microbes and depression strengthened.
Links between the central nervous system and the trillions of bacteria in the gut — the microbiota — are now a major focus of research, public interest and press coverage. But how does this ‘gut–brain axis’ work? The mechanisms by which microorganisms shape aspects of brain functioning such as memory and social behaviour, and how they might contribute to conditions such as depression and neurodegenerative disease, are tenuous and often controversial.
Researchers know that the gut microbiota can produce or stimulate the production of neurotransmitters and neuroactive compounds, such as serotonin, GABA and dopamine, and that these compounds can modulate bacterial growth. The challenge now is to find out whether, and how, these microbe-derived molecules can interact with the human central nervous system, and whether that alters a person’s behaviour or risk of disease. At least now, answering these questions is a wise pursuit, not a wild one.
The role of gut microbiota in tryptophan metabolism:
Tryptophan (Trp) is an essential amino acid and a precursor of several metabolites involved in key physiological processes. Metabolic pathways leading to serotonin (5-hydroxytryptamine) and other metabolites from Trp are under the direct or indirect control of the microbiota.
A new review led by Prof. Harry Sokol, a gastroenterologist and researcher from the French National Institute for Agricultural Research (INRA) and the French Medical Research Institute (INSERM), clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions, based on the pathogenesis of human diseases and potential new treatments.
Dr. Sokol corresponded with GMFH editors about the significance of the work.
Approximately 95% of Serotonin (5-HT) is produced by gut mucosal enterochromaffin (EC) cells. Serotonin [5-hydroxytryptamine (5-HT)] is a biogenic amine which acts as a neurotransmitter within the CNS and ENS. In the gut, 5-HT is involved in the regulation of GI secretion, motility (smooth muscle contraction and relaxation), and pain perception, whereas in the brain 5-HT is implicated in regulating mood and cognition. Gut microbiota regulates 5-HT biosynthesis in the gut by increasing the levels of tryptophan, a well-known precursor for serotonin production.
Why did you conduct the review? What gap in the impact of the gut microbiota on host physiology is this review filling?
There have been several studies pointing to the role of the gut microbiota in many diseases associated with western life style. In parallel, many data also show the role of Trp metabolites in the same diseases. We know that the gut microbiota has a major impact on the tryptophan metabolism in the gut. In this paper, we reviewed the data linking the gut microbiota to the tryptophan metabolism in health and disease and generated new concepts regarding the interactions between the different pathways and the therapeutic potential of intervention on the gut microbiota to modulate them.
Which pathways are involved in the intestinal Trp metabolism and how do they affect host physiology in terms of clinical relevance?
Trp metabolism follows three major pathways in the gastrointestinal tract: (i) the direct transformation by the gut microbiota of Trp into several molecules, including ligands of the aryl hydrocarbon receptor (AhR); (ii) the kynurenine pathway in both immune and epithelial cells via indoleamine 2,3-dioxygenase 1 (IDO1); and (iii) the serotonin production pathway in enterochromaffin cells via Trp hydroxylase 1 (TpH1). The metabolites of these three pathways have major effects on the host and notably on immunity and metabolism (all 3 pathways), intestinal barrier (AhR pathway particularly), and intestinal transit (serotonin pathway).
In which diseases is Trp metabolism perturbed and to what extent could Trp metabolites be used as biomarkers for specific diseases and conditions?
Currently, it is clearly demonstrated that Trp metabolism is perturbed in intestinal diseases (such as inflammatory bowel disease and irritable bowel syndrome), but also in some non-intestinal diseases such as neuropsychiatric conditions and metabolic diseases.
What strategies can be used for modulating the gut microbiota to restore the perturbed Trp equilibrium?
There is nothing currently available. However, if the microorganisms involved in Trp metabolism control are identified, it will open up the possibility of using them as next generation probiotics. For example, we identified a Lactobacilus reuterii strain with a strong and natural ability to produce AhR agonists from Trp metabolism. In mice with dysbiotic microbiota, this strain exhibits anti-inflammatory effects in colitis models.
Reference:
Agus A, Planchais J, Sokol H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe. 2018; 23(6):716-24. doi: 10.1016/j.chom.2018.05.003.
Influence of Tryptophan and Serotonin on Mood and Cognition with a Possible Role of the Gut-Brain Axis
Lactobacillus reuteri
grounded in evolution
Research has shown that Lactobacillus reuteri is a species of bacteria that has developed a mutualistic relationship with its specific host over millions of years. In other words, throughout evolution certain strains of Lactobacillus reuteri have made their home in the specific environment that is found in the human gut. In some of us they still reside there today, while most others have insufficient levels. For some probiotic strains, a relatively low amount of bacteria is needed, while other strains require a larger amount.
The epithelial lining covers our gastrointestinal tract and works like a skin on the inside of our bodies. The main task of our ”inner skin” is to differentiate between what should be absorbed and what should not be let into our bodies. Biopsies have shown that Lactobacillus reuteri is temporarily binding to our epithelial lining. However, since the cells in our epithelial lining is replaced every fourth day, the majority of L. reuteri cells are also washed away within a week or so. Since L. reutericolonization is transient, every day intake is recommended to ensure adequate and stable levels ofL. reuteri in the gastrointestinal tract.
Reference:
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Bharwani, A., Mian, M.F., Foster, J.A. et al. (2016). Structural and functional consequences of chronic psychosocial stress on the microbiome and host.Psychoneuroendocrinology. 63 (16), 217-227.
Chang, J.Y., Talley, N.J. (2011). An update on irritable bowel syndrome: from diagnosis to emerging therapies. Curr. Opin. Gastroenterol. 27 (1), 72-78.
De Palma, G., Blennerhassett, P., Lu, J. et al. (2015). Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat. Commun. 6 (15), 673-735.
Desbonnet, L., Clarke, G., Shanahan, F. et al. (2013). Microbiota is essential for social development in the mouse. Molecular Psychiatry. 19 (13), 146-148.
Desbonnet, L., Garrett, L., Clarke, G. et al. (2008). The probiotic Bifidobacteria infantis: an assessment of potential antidepressant properties in the rat. J Psychiatr Res. 43 (2), 164–174.
Dinan, T., Cudmore, S. (2013). Probiotics for Mental Health and Wellbeing. Atlantia Food Clinical Trials. 3 (13), 10-23.
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Hayland, N.P., Quigley, E.M. et al. (2014). Microbiota-host interactions in irritable bowel syndrome: epithelial barrier, immune regulation and brain-gut interactions. World Journal of Gastroenterology. 20 (14), 8859-8866.
Jefferey, I.B., Ohman, L. et al. (2012). An irritable bowel syndrome subtype defined by species specific alterations in faecal microbiota. Gut. 61 (12), 997-1006.
Nagel, R., Traub, R.J. et al. (2016). Comparison of faecal microbiota in Blastocystis- positive and Blastocystis-negative irritable bowel syndrome patients. Microbiome 4 (16), 44-47.
Wallace, J.K., Milev, R. (2017). The effects of probiotics on depressive symptoms in humans: a systematic review. Annals of General Psychiatry. 7 (17), 16-18.