Patients with inflammatory diseases involving peripheral organs or tissues commonly experience altered brain function giving rise to symptoms that adversely affect their quality of life (QOL) (D’Mello and Swain, 2014). How peripheral inflammation leads to remote changes in brain function remains unclear and, as a result, there are limited therapeutic options available clinically to address this issue. A number of general pathways have been described that link systemic inflammation to changes occurring in the brain, which in turn give rise to altered behavior (Dantzer et al., 2014).
These pathways traditionally have included signaling via neural pathways (mainly vagal nerve afferents) and immune signaling (mainly via circulating cytokines, which either enter the brain directly or activate cerebral endothelium; Capuron and Miller, 2011). Recently, we described a novel peripheral signaling pathway occurring in the setting of liver inflammation, which involves increased peripheral TNF-α production driving increased microglial activation, followed by monocyte recruitment into brain vasculature and brain parenchyma, which in turn drives the development of sickness behaviors (D’Mello et al., 2013).
The beneficial effect of probiotic consumption on behavior and brain function is now becoming increasingly appreciated in a variety of inflammatory diseases. Specifically, probiotic administration improves QOL in patients with irritable bowel syndrome (O’Mahony et al., 2005) and was associated with significant improvements in cognitive function and the restoration of impaired hippocampal long-term potentiation in a model of diabetes (Davari et al., 2013).
Potential peripheral pathways that link probiotic ingestion to changes in brain function have primarily focused on the role of vagal afferent nerve signaling and changes in cerebral levels of neuromodulators such as brain-derived neurotrophic factor (Bercik et al., 2010).
We now define an alternate signaling pathway established in the setting of liver inflammation, which links probiotic consumption to changes within the brain and alterations in behavior.
In patients with inflammatory disease and in animal models of systemic inflammation, probiotic ingestion has been previously shown by others to reduce circulating TNF-α levels (Loguercio et al., 2005; Dhiman et al., 2014; Sánchez et al., 2015; Vaghef-Mehrabany et al., 2014). In addition, probiotic treatment-induced reductions in circulating TNF-α levels were associated with improved neuropsychiatric outcomes, as seen in patients with chronic liver disease (Dhiman et al., 2014).
Our current findings in BDL mice parallel these clinical observations and are consistent with our previous studies demonstrating a critical role for elevated levels of TNF-α in the circulation of BDL mice driving sickness behavior development (D’Mello et al., 2009; D’Mello et al., 2013).
TNF-α-associated sickness behaviors in BDL mice are linked directly to cerebral microglial activation and recruitment of monocytes into the brain vasculature and brain parenchyma (D’Mello et al., 2009; D’Mello et al., 2013).
Observations of increased leukocyte recruitment to brain vasculature in a model of inflammatory bowel disease (D’Mello et al., 2009) was noted.
Our current findings are consistent with a role of probiotic ingestion in disrupting this signaling pathway in BDL mice.
TNF-α blockade using etanercept in probiotic-treated BDL mice did not further improve sickness behavior development, microglial activation, or cerebral monocyte infiltration in probiotic-treated BDL mice, consistent with the probiotic effects in BDL mice being TNF-α related. Interestingly, although probiotic treatment reduced circulating TNF-α levels in BDL mice to sham levels, sickness behavior development was not completely abrogated by probiotic treatment.
This finding suggests that alternative signaling pathways must also exist in BDL mice to cause sickness behaviors, possibly those driven by vagal afferent signaling to the brain (Capuron and Miller, 2011).
Changes in cross-talk among the intestinal epithelium, the intestinal immune system, and gut microbes has increasingly been recognized for its capacity to modulate systemic immunity (Belkaid and Naik, 2013). As a result, probiotics have been administered in an attempt to beneficially alter systemic immunity.
Consistent with this paradigm, administration of Bifidobacterium infantis to patients with irritable bowel syndrome was associated with an improvement in symptoms and a normalization of the IL-10 to IL-12 cytokine ratio in peripheral blood mononuclear cells (O’Mahony et al., 2005).
Probiotic treatment has been shown to reduce circulating levels of systemic proinflammatory biomarkers, including TNF-α levels, in patients with a range of systemic inflammatory conditions including psoriasis (Groeger et al., 2013), rheumatoid arthritis (Vaghef-Mehrabany et al., 2014), chronic fatigue syndrome, and liver disease (Loguercio et al., 2005; Dhiman et al., 2014); all findings replicated in our study.
Probiotic administration has been reported previously to induce increased intestinal production of the cytokine G-CSF (Martins et al., 2009). In our current study, consistent with this previous report, we found a striking increase in plasma G-CSF levels in probiotic-treated BDL mice compared with placebo-treated BDL and sham mice.
G-CSF can affect a wide variety of biological functions that are potentially relevant to our current experimental observations in probiotic-treated BDL mice. Specifically, G-CSF significantly attenuates monocyte/macrophage production of TNF-α (Nishiki et al., 2004).
G-CSF can mediate a reduction in cerebral inflammation (Nishiki et al., 2004). In BDL mice, monocyte/macrophage production of TNF-α is significantly enhanced compared with sham controls (Kerfoot et al., 2006; D’Mello et al., 2009). Therefore, increased plasma G-CSF levels in BDL mice treated with probiotic3 may contribute to the reduced circulating TNF-α levels observed in these mice and warrants future investigation.
Together, our data define a novel pathway whereby probiotic ingestion prevents peripheral inflammation-associated increases in circulating TNF-α levels, cerebral microglial activation, and recruitment of activated monocytes into the brain, ultimately attenuating BDL-associated sickness behavior development. Therefore, probiotic therapy may have a therapeutic role in regulating peripheral inflammation-associated brain dysfunction and behavioral alterations that often significantly affect patient quality of life (QOL).
Stress and Inflammation
During the last five years, it has been established that pro-inflammatory cytokines induce not only symptoms of sickness, but also true major depressive disorders in physically ill patients with no previous history of mental disorders. Some of the mechanisms that might be responsible for inflammation-mediated sickness and depression have now been elucidated. These findings suggest that the brain–cytokine system, which is in essence a diffuse system, is the unsuspected conductor of the ensemble of neuronal circuits and neurotrans-mitters that organize physiological and pathological behaviour. In this Review we discuss how the brain engenders sickness behaviour in response to peripheral infections. We then review the evidence that pro-inflammatory cytokines can also trigger the development of depression in vulnerable individuals, and the possible underlying mechanisms. Finally, we discuss how these actions of cytokines in the brain might have a role in at least part of the increased prevalence of depression in people with physical illness.
Probiotic Foods to Add to Your Diet
1. Yogurt
One of the best probiotic foods is live-cultured yogurt, especially handmade. Look for brands made from goat’s milk and infused with extra forms of probiotics like lactobacillus or acidophilus. Goat’s milk is a rich source of proteins, vitamins, and minerals while having better digestibility and lower allergenicity than cow’s milk.[1] Goat milk yogurt is particularly high in probiotics like thermophillus, bifudus, and bulgaricus, and can be infused with extra forms of probiotics like lactobacillus or acidophilus.
Be sure to read the ingredients list, as not all yogurt is made equally. Many popular brands are filled with high fructose corn syrup, artificial sweeteners, and artificial flavors and are way too close to being a nutritional equivalent of sugary, fatty ice cream.
2. Kefir
Similar to yogurt, this fermented dairy product is a unique combination of goat’s milk and fermented kefir grains. High in lactobacilli and bifidus bacteria, kefir is also rich in antioxidants. Look for a good, organic version at your local health food shop.
Similar to yogurt, this fermented dairy product is a unique combination of goat’s milk and fermented kefir grains. High in lactobacilli and bifidus bacteria, kefir is also rich in antioxidants.[2] Look for a good, organic version at your local health food shop.
3. Sauerkraut
Made from fermented cabbage (and sometimes other vegetables), sauerkraut is not only extremely rich in healthy live cultures, but might also help with reducing allergy symptoms. Sauerkraut is also rich in vitamins A, B, C, and K.[3]
4. Dark Chocolate
Chocolate itself doesn’t contain probiotics, but it was found to be a very effective carrier for probiotics. Chocolate helps them survive the extreme pHs of the digestive tract to make it to the colon.[4] Because of this protective ability probiotics can be added to high-quality dark chocolate. This is only one of the many health benefits of chocolate.
5. Microalgae
This refers to super-food ocean-based plants such as spirulina, chlorella, and blue-green algae. While not a probiotic itself, microalgae can act as a prebiotic, which means that it feeds and nourishes the probiotics already in your gut. These prebiotic foods have been shown to increase beneficial bacteria and improve gastrointestinal health.[5] They also offer the most amount of energetic return, per ounce, for the human system.
6. Miso Soup
Miso is one the mainstays of traditional Japanese medicine and is commonly used in macrobiotic cooking as a digestive regulator. Made from fermented rye, beans, rice or barley, adding a tablespoon of miso to some hot water makes an excellent, quick, probiotic-rich soup, full of lactobacilli and bifidus bacteria.[6]
Beyond its important live cultures, miso is extremely nutrient-dense and believed to help neutralize the effects of environmental pollution, alkalinize the body and stop the effects of carcinogens in the system.[7]
7. Pickles
Believe it or not, the provincial pickle packs a punch of prime probiotics.[8] In the U.S., the term “pickle” usually refers to pickled cucumbers specifically, but most vegetables can be pickled. All of them boast the same briny goodness and probiotic potential.
8. Tempeh
A great substitute for meat or tofu, tempeh is a fermented, probiotic-rich grain made from soybeans.[9] A great source of vitamin B12,[10] this vegetarian food can be sauteed, baked or eaten crumbled on salads. If prepared correctly, tempeh is also very low in salt, which makes it an ideal choice for those on a low-sodium diet.
9. Kimchi
An Asian form of pickled sauerkraut, kimchi is an extremely spicy and sour fermented cabbage, typically served alongside meals in Korea. Besides beneficial bacteria, Kimchi is also a great source of vitamin C, B vitamins, beta-carotene, calcium, iron, potassium, and dietary fiber.[11] Kimchi is one of the best probiotic foods you can add to your diet, assuming you can handle the spice, of course.
10. Kombucha Tea
Kombucha is a form of fermented tea that contains a high amount of healthy gut bacteria.[12] This probiotic drink has been used for centuries and is believed to help increase your energy, enhance your well-being and maybe even help you lose weight.[13] However, kombucha tea may not be the best fit for everyone, especially those that have had problems with candida.
Probiotic Supplements
For excellent digestive health, fill your diet with as many prebiotic and probiotic foods as possible. I additionally recommend taking a good probiotic supplement. I recommend Floratrex™, a unique formula of 23 probiotic strains that helps support your digestive tract and boosts your immune system.
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