White Paper by Wei (Adelyn) Tsai
Reviewed by: Greg Hollenbeck, Thia Hanania
Foods that influence live bacteria in the gut are called probiotics. Probiotics confer beneficial health effects and affect mood and have been coined psychobiotics (Cheng et al., 2019). One type of psychobiotics is fermented dairy products. Different fermented dairy products have been found to have various beneficial effects on the brain, such as protecting against neurotoxicity and oxidative stress and improving learning and memory (Kim et al., 2016).
Kefir is a traditional fermented dairy beverage originating from the Caucasus mountains. It is produced from adding a kefir grain to milk. Kefir grain and the eventual milk products consist of a variety of bacteria, fungal, and yeast populations (Bourrie et al., 2016) that generate kefir’s probiotic and possibly psychobiotic properties. The most common bacterial genera found in kefir are Lactobacillus, Lactococcus, Streptococcus, and Leuconostoc. Moreover, kefir can alter gut microbiome composition and gut microbial activity including a strain of bacteria Bifidobacterium (Hamet et al., 2016; Serafini et al., 2014).
It is now well understood that gastrointestinal bacteria affect the central nervous system and the host’s behaviors via bidirectional communication through the microbiota-gut-brain axis. Multiple pathways are involved in this bidirectional communication (Fig.1) (Cryan & Dinan, 2012).
Fig.1 Microbiota-gut-brain axis. The hypothalamus-pituitary-adrenal axis regulates the secretion of cortisol, which affects immune cells and triggers cytokines release. Cortisol can also change epithelial permeability and in turn alter the gut microbiome. Additionally, the vagus nerve, the major nerve of the parasympathetic system, and tryptophan metabolism also influence gut microbiota. Conversely, gut microbiota and probiotics also affect the brain functions, by altering the microbial composition, activating the immune system that communicates with the central nervous system, or producing metabolites such as short-chain fatty acids that have neuroactive properties. Gut bacteria also can affect tryptophan metabolism and generate neurotransmitters and neuromodulators. It is also known now that bacteria produce metabolites such as short-chain fatty acids from dietary fibers that have neuroactive properties (Cryan & Dinan, 2012).
Importantly, women who drank fermented milk containing probiotics Bifidobacterium animalis subsp. lactis, Streptococcus thermophiles, Lactobacillus bulgaricus, and Lactococcus lactis subsp. Lactis had reduced brain responses to an emotional task containing negative emotional faces, while there were no effects in the control group drinking non-fermented milk (Tillisch et al., 2013). These results suggested that these four probiotics strains, of which the latter three are also contained in kefir (Bourrie et al., 2016), could influence the human brain to process negative stimuli. In healthy human volunteers, a probiotic formulation composed of Lactobacillus and Bifidobacterium reduced psychological distress (Messaoudi et al., 2011). Probiotics composed of the bacteria found in kefir have also been found to have beneficial effects in neurodegenerative diseases. Alzheimer’s disease patients taking 200ml/d probiotic milk containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum (2 × 109 CFU/g for each), all of which have been found in kefir (Bourrie et al., 2016), for 12 weeks showed improved cognition (Akbari et al., 2016). In clinical trials, Parkinson’s disease patients consumed a probiotic supplement containing Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum (2 × 109 CFU/g for each), again all of which have been found in kefir, for 12 weeks. Patients receiving the supplement showed improved movement. Moreover, probiotics also conferred antioxidant and anti-inflammatory benefits measured by reduced oxidative stress markers and neuroinflammatory cytokines and increased antioxidants in patients’ blood samples (Borzabadi et al., 2018; Tamtaji et al., 2019). With all these clinical studies, it is conceivable that kefir could also be a useful psychobiotics.
Studies in mice consuming kefir provide insights into the mechanisms underlying the psychobiotic properties of kefir. van de Wouw et al provided evidence that kefir could modulate the microbiota-gut-brain axis in mice. As mentioned above, probiotics affect tryptophan metabolism. Tryptophan is the precursor of the neurotransmitter serotonin (Ruddick et al., 2006), and in this study, they found that kefir was able to impact colonic serotonergic signaling. It was also found that kefir alters gut microbiome composition which was linked to increased γ-aminobutyric acid (GABA) levels. GABA is the main brain inhibitory neurotransmitter and is associated with anxiety and depression. They also found that kefir could influence inflammation by suppressing the peripheral immune system (Van De Wouw et al., 2020). All these changes indicated kefir is possible to affect neuropsychological conditions via the microbiota-gut-brain axis. Kefir was also demonstrated to produce antihypertensive effects in rats, partly through protection against neuroinflammation in brain cardioregulatory nuclei by reducing neuroinflammatory cytokines and abolishing microglial activation (de Almeida Silva et al., 2020). Since hypertension is a leading cause of cerebrovascular diseases (Bansal et al., 1999), based on these results, it is warranted to examine the effects of kefir in cerebrovascular diseases in the future. Furthermore, in a rat model of spinal cord ischemia/reperfusion, kefir reduced neuronal degeneration and oxidative stress, providing more evidence for kefir as a neuroprotective agent (Guven et al., 2015).
Kefir also modulates host behaviors. In the study done by van de Wouw et al, mice consuming kefir had increased reward-seeking behavior. A feature of depression is decreased reward-seeking behavior, suggesting that kefir might be able to ameliorate some aspects of depression. However, they did not find kefir to influence depressive-like behaviors. The authors proposed that the changes in gut microbiota function and peripheral immunity contribute to the behaviors observed (Van De Wouw et al., 2020). Kefir also affects cognitive functions. Noori et al found that kefir offered anti-depression and anxiolytic effects in rats with depression and anxiety induced by nicotine withdrawal. Kefir also improved learning and memory impairment as a result of nicotine withdrawal. The authors argue that the ability of kefir to modulate tryptophan metabolism and affect serotonergic signaling produced the observed results, since serotonin levels are linked to mood regulation (anxiety and depression) and improvement of learning and memory (Noori et al., 2014).
In humans, kefir improved sleep disturbances, depression, and quality of life in postmenopausal women (Özcan et al., 2019). In Alzheimer’s disease patients, kefir helped improve cognitive deficits by reducing systemic inflammation, oxidative stress, and blood cell damage (Fig.2) (Ton et al., 2020). For the first study, postmenopausal women consumed unsweetened 500ml kefir milk daily while in the second study Alzheimer’s disease patients consumed 2 mL/kg/daily of unsweetened pasteurized milk containing 4% kefir grains for 90 days. No side effects were reported in these two studies, suggesting the dosage used and the duration of consumption could be effective. Still, more studies on the percentage of kefir in milk needed and the duration of consumption as well as the safety should be conducted.
Fig.2 Effects of cognition of Kefir in Alzheimer’s disease patients. In Alzheimer’s disease patients, kefir was able to decrease proinflammatory (interleukin-8 (IL-8), IL-12, and tumor necrosis factor-alpha (TNF-α)) levels and the ratio of proinflammatory cytokines to anti-inflammatory (IL-10) cytokines, suggesting lower systemic inflammation. Oxidative markers including reactive oxygen species (ROS) and advanced oxidation protein products (AOPP) decreased while nitrous oxide (NO) level increased after kefir consumption, indicating reduced oxidative stress, which ameliorated mitochondrial damage as measured by reduced membrane potential. Neuronal damage was also reduced as demonstrated by lower DNA fragmentation and cleaved poly [ADP-ribose] polymerase 1 (PARP-1), a hallmark of apoptosis. Increased p53 under lower ROS and increased cell cycle arrest prevent the proliferation of damaged cells, enhancing cell survival. Therefore, kefir supplementation mitigated neurodegeneration progress in AD through cytoprotective, antiapoptotic, and anti-inflammatory actions, all of which improve cognitive functions (Ton et al., 2020).
In conclusion, kefir can be an effective probiotic affecting neurological and cognitive functions via the microbiota-gut-brain axis. Mechanistic studies showed that kefir modulates the immune system, oxidative stress, synthesis of neurotransmitters, neuronal cells’ health and damage. All these actions produce the important psychobiotic properties of kefir that influence behaviors in both mice and humans.
References
Akbari, E., Asemi, Z., Kakhaki, R. D., Bahmani, F., Kouchaki, E., Tamtaji, O. R., Hamidi, G. A., & Salami, M. (2016). Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: A randomized, double-blind and controlled trial. Frontiers in Aging Neuroscience, 8(NOV). https://doi.org/10.3389/fnagi.2016.00256
Bansal, B. C., Agarwal, A. K., & Rewari, B. B. (1999). Hypertension and cerebrovascular disease. Journal of the Indian Medical Association, 97(6), 226–232. http://www.ncbi.nlm.nih.gov/pubmed/10645696
Borzabadi, S., Oryan, S., Eidi, A., Aghadavod, E., Kakhaki, R. D., Tamtaji, O. R., Taghizadeh, M., & Asemi, Z. (2018). The effects of probiotic supplementation on gene expression related to inflammation, insulin and lipid in patients with Parkinson’s disease: A randomized, double-blind, placebo-controlled trial. Archives of Iranian Medicine, 21(7), 289–295.
Bourrie, B. C. T., Willing, B. P., & Cotter, P. D. (2016). The microbiota and health promoting characteristics of the fermented beverage kefir. Frontiers in Microbiology, 7(MAY), 1–17. https://doi.org/10.3389/fmicb.2016.00647
Cheng, L. H., Liu, Y. W., Wu, C. C., Wang, S., & Tsai, Y. C. (2019). Psychobiotics in mental health, neurodegenerative and neurodevelopmental disorders. Journal of Food and Drug Analysis, 27(3), 632–648. https://doi.org/10.1016/j.jfda.2019.01.002
Cryan, J. F., & Dinan, T. G. (2012). Mind-altering microorganisms: The impact of the gut microbiota on brain and behaviour. Nature Reviews Neuroscience, 13(10), 701–712. https://doi.org/10.1038/nrn3346
de Almeida Silva, M., Mowry, F. E., Peaden, S. C., Andrade, T. U., & Biancardi, V. C. (2020). Kefir ameliorates hypertension via gut–brain mechanisms in spontaneously hypertensive rats. The Journal of Nutritional Biochemistry, 77, 108318. https://doi.org/10.1016/j.jnutbio.2019.108318
Guven, M., Akman, T., Yener, A. U., Sehitoglu, M. H., Yuksel, Y., & Cosar, M. (2015). The neuroprotective effect of kefir on spinal cord ischemia/reperfusion injury in rats. Journal of Korean Neurosurgical Society, 57(5), 335–341. https://doi.org/10.3340/jkns.2015.57.5.335
Hamet, M. F., Medrano, M., Pérez, P. F., & Abraham, A. G. (2016). Oral administration of kefiran exerts a bifidogenic effect on BALB/c mice intestinal microbiota. Beneficial Microbes, 7(2), 237–246. https://doi.org/10.3920/BM2015.0103
Kim, B., Hong, V. M., Yang, J., Hyun, H., Im, J. J., Hwang, J., Yoon, S., & Kim, J. E. (2016). A Review of Fermented Foods with Beneficial Effects on Brain and Cognitive Function. Preventive Nutrition and Food Science, 21(4), 297–309. https://doi.org/10.3746/pnf.2016.21.4.297
Messaoudi, M., Lalonde, R., Violle, N., Javelot, H., Desor, D., Nejdi, A., Bisson, J. F., Rougeot, C., Pichelin, M., Cazaubiel, M., & Cazaubiel, J. M. (2011). Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. British Journal of Nutrition, 105(5), 755–764. https://doi.org/10.1017/S0007114510004319
Noori, N., Bangash, M., Motaghinejad, M., Hosseini, P., & Noudoost, B. (2014). Kefir protective effects against nicotine cessation-induced anxiety and cognition impairments in rats. Advanced Biomedical Research, 3(1), 251. https://doi.org/10.4103/2277-9175.146377
Özcan, H., Oskay, Ü., & Bodur, A. F. (2019). Effects of Kefir on Quality of Life and Sleep Disturbances in Postmenopausal Women. Holistic Nursing Practice, 33(4), 207–213. https://doi.org/10.1097/HNP.0000000000000310
Ruddick, J. P., Evans, A. K., Nutt, D. J., Lightman, S. L., Rook, G. A. W., & Lowry, C. A. (2006). Tryptophan metabolism in the central nervous system: medical implications. Expert Reviews in Molecular Medicine, 8(20), 1–27. https://doi.org/10.1017/S1462399406000068
Serafini, F., Turroni, F., Ruas-Madiedo, P., Lugli, G. A., Milani, C., Duranti, S., Zamboni, N., Bottacini, F., van Sinderen, D., Margolles, A., & Ventura, M. (2014). Kefir fermented milk and kefiran promote growth of Bifidobacterium bifidum PRL2010 and modulate its gene expression. International Journal of Food Microbiology, 178, 50–59. https://doi.org/10.1016/j.ijfoodmicro.2014.02.024
Tamtaji, O. R., Taghizadeh, M., Daneshvar Kakhaki, R., Kouchaki, E., Bahmani, F., Borzabadi, S., Oryan, S., Mafi, A., & Asemi, Z. (2019). Clinical and metabolic response to probiotic administration in people with Parkinson’s disease: A randomized, double-blind, placebo-controlled trial. Clinical Nutrition, 38(3), 1031–1035. https://doi.org/10.1016/j.clnu.2018.05.018
Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B., Guyonnet, D., Legrain-Raspaud, S., Trotin, B., Naliboff, B., & Mayer, E. A. (2013). Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology, 144(7), 1394-1401.e4. https://doi.org/10.1053/j.gastro.2013.02.043
Ton, A. M. M., Campagnaro, B. P., Alves, G. A., Aires, R., Côco, L. Z., Arpini, C. M., Guerra E Oliveira, T., Campos-Toimil, M., Meyrelles, S. S., Pereira, T. M. C., & Vasquez, E. C. (2020). Oxidative Stress and Dementia in Alzheimer’s Patients: Effects of Synbiotic Supplementation. Oxidative Medicine and Cellular Longevity, 2020. https://doi.org/10.1155/2020/2638703
Van De Wouw, M., Walsh, A. M., Crispie, F., Van Leuven, L., Lyte, J. M., Boehme, M., Clarke, G., Dinan, T. G., Cotter, P. D., & Cryan, J. F. (2020). Distinct actions of the fermented beverage kefir on host behaviour, immunity and microbiome gut-brain modules in the mouse. Microbiome, 8(1), 1–20. https://doi.org/10.1186/s40168-020-00846-5