Bacteria may help prepare you for cancer fight.

Sep11_Bact1-400x225

What’s that smell? It’s just your personal community of microbes, living in you intestines and helping you digest your food. Other than producing socially unacceptable gaseous emissions, researchers have been finding that the population of bacteria residing in your innards (aka the human microbiota) also influences other bodily processes such as immunity and your brain’s response to stress. A recent paper by Goldszmid’s research group at the National Cancer Institute is now finding that gut microbes may also influence a cancer tumor’s response to therapy via its effect on the immune system. Previous cancer studies have found that the immune cells can be both beneficial and harmful in the treatment of cancer, its role depending on the type of cancer and cancer therapy used. In a related field, researchers have discovered gut bacteria are essential to the full maturation/function of gut immune cell activity. This study by Iida et al. now links the two concepts and shows that the gut microbiota is essential for the effectiveness of cancer therapy in specific cancer treatment scenarios. These finding highlight the importance of strategic planning of a patient’s cancer treatment which may include modulating the immune system in the near future.

For the past decade, scientists are finding that the state of the immune system can interact with other aspects of biology, which can have disadvantageous outcomes: exacerbating type II diabetes and even contributing to the cause of certain cancers. On the flip side, the immune system is critical in keeping our bodies infection free and even helping cancer therapies eliminate malignant cells. In fact, a class of cancer therapeutics, called immunotherapies, aim to harness the destructive power of the immune system to target cancer cells. In addition, some cytotoxic chemotherapies (drugs that are toxic to all dividing cells) utilize immune cells to injure and kill cancer cells. For example, breast cancer patients who carry mutations in a gene important for the full activation of the immune system (Toll-like Receptor 4) relapsed more quickly after chemo- and radiation therapy than those who do not. Given this emerging knowledge, considering a patient’s immune system biology may become a part of the development of personalized medicine.

Unsurprisingly, the large amount of bacteria colonizing your digestive tract influences the state of your immune system. Who can blame them for moving in? It’s cozy, warm and nutrients are delivered on a daily basis (hopefully). Hundreds of different bacterial species find their own niche by consuming specific materials, which can range from your indigestible food (cellulose from plants) to by-products of other bacteria’s activities. Don’t worry, this relationship is not one-sided. In addition to helping humans maximize digestion, commensal bacteria help the host keep pathogenic bacteria out in three ways: 1) by competing for limited nutrients, 2) by stimulating the mucosal barrier between the intestinal tissue and bacteria, and 3) by priming the host’s immune system. These friendly bacteria are actually necessary for the optimum immune activity in your intestines – a place that constantly encounters foreign material. Animal experiments have shown that in the absence of gut bacteria, achieved through use of antibiotics or raising mice in a completely sterile environment, result in a thinner protective mucosal barrier, decreased presence of gut immune cells and increased susceptibility to pathogenic infection. The state of gut bacteria can promote immunity and in the case of certain cancer therapy scenarios, Goldszmid’s group has found it beneficial.

Iida et al. investigated the contribution of gut bacteria to chemotherapy response using a mouse tumor model system. Mice bearing lymphoma, colon and melanoma tumors were pre-treated with a three week course of antibiotics and then given one of two types of cancer treatment: 1) an immunotherapy cocktail that stimulates innate immune cell activation, or 2) a traditional cytotoxic chemotherapy (oxaliplatin) that causes DNA damage in dividing cells. Both treatments were less effective when the mice microbiota were abolished with either anti-biotic pretreatment or raising the mice in a germ free environment. The scientist then investigated the state of immune function in the antibiotic treated mice and found that expression of a cytokine that triggers cell death (Tumor Necrosis Factor or TNF) was overall reduced in tumors and that the presence innate immune cells capable of secreting TNF were reduced inside tumors as well. Interestingly, the tumor response to both cancer therapies were restored in antibiotic treated mice with two different methods: 1) dosing with an especially immune reactive bacteria (Alistipes Shahii), 2) dosing with a bacterial protein that illicits a strong immune response (Lipopolysaccharide). The study neatly links the presence of microbiota, the immunological state and the effectiveness of some cancer treatments.

  1. Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science (New York, N.Y.) 342, 967–70 (2013).
  2. Kamada, N., Seo, S.-U., Chen, G. & Núñez, G. Role of the gut microbiota in immunity and inflammatory disease. Nature reviews. Immunology 13, 321–35 (2013).
  3. Grivennikov, S., Greten, F. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–99 (2010).
  4. Apetoh, L. et al. Toll-like receptor 4 – dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nature Medicine 13, 1050-1059 (2007).
Advertisements

Your Brain: Your Pharmacist. Brain prescribes opioids for rejection – and rewards social acceptance with opioids!

For the last decade researchers have found that emotional pain experienced from social rejection activates the same region of the brain that physical pain activates – the pain center. Scientist believe that since mammals live in social groups that are crucial to survival, social rejection is akin to a physical threat to our brain (which kind of explains middle school and high school). A recent paper by Hsu et al. from the University of Michigan, has now shown that the same opioid receptors located in the brain’s pain center activated in response to physical pain are also activated by emotional pain and that the more opioid response an individual releases, the more that person scores high on the trait “resiliency”.  The study also found that the brain rewards social acceptance with activation of opioid receptors located elsewhere in the brain.

The brain protects itself from feeling too much physical pain by dosing itself with endogenous opioids. It lets you feel pain so you know that whatever it is you are doing should stop, but then alleviates its own pain by activating opioid receptors located in the pain center of the brain. Presumably, this neat self-soothing mechanism exists so when we get hurt we don’t just lie down and cry (see Fig. 1). Given the similarities in the experience of physical and emotional pain, scientists have hypothesized that emotional pain also results in opioid receptor activation. In this study, Hsu and Zubieta used a radiotracer specific for opioid receptors to visualize the release of endogenous opioids with PET imaging in response to stimuli. Social rejection and acceptance was simulated via a pseudo-dating website experience: 1) Subjects created a profile that included their stats, positive self-description and photo, 2) Subjects selected 40 online profiles of preferred-gendered people they really liked and predicted whether those people would like them back, 3) Subjects’ egos were at turns stroked or bruised with the responses from 12 of the profiles they selected (i.e. the profile “liked” or “did not like” them back), and 4) Subjects self-reported mood.

Image

Expectedly, rejected subjects felt more “sad and rejected” and less “happy and accepted,” while accepted subjects felt the opposite. Interestingly, subjects with high opioid activity rated themselves as lower in the “sad and rejected” scale. These findings suggest that individuals with a robust opioid response bounce back more quickly in the face social rejection. This data corroborates a study by Way et al. from 2009 which examined the differences in activation of the brain’s pain center in response to social rejection between people who have a normal opioid receptor gene and those who have a mutation in the receptor. The mutated receptor is thought to have greatly reduced function and carriers of this mutation have been shown to need a greater amounts of opioids to treat physical pain (ex: post-surgical pain). Way and Eisenberg saw that carriers of the mutation had greater activation of the pain center than non-carriers when excluded from a game of “cyberball.” To sum up: more brain opioids after social rejection leads to less emotional pain and faster recovery. Wow, genetics once again sticking its nose in my business. But, knowledge is power! Social rejection can be cured with a quick bout of exercise or slap to the face for those who are less inclined to exertion. On a serious note, these findings will hopefully lead to new therapies and interventions with individuals suffering from depression, social anxiety, and other psychological disorders.

References:

1. Hsu, D. et al. Response of the μ-opioid system to social rejection and acceptance. Molecular psychiatry 18, 1211–7 (2013).

2. Way, B., Taylor, S. & Eisenberger, N. Variation in the mu-opioid receptor gene (OPRM1) is associated with dispositional and neural sensitivity to social rejection.Proceedings of the National Academy of Sciences of the United States of America 106, 15079–84 (2009).

3. Lötsch, J., Stuck, B. & Hummel, T. The human mu-opioid receptor gene polymorphism 118A > G decreases cortical activation in response to specific nociceptive stimulation. Behavioral neuroscience 120, 1218–24 (2006).

Incognito: The Secret Lives of the Brain

“Mind cannot arise alone without body, or apart from sinews and blood.” – Titus Lucretius Carus

In Incognito: The secret lives of the brain, David Eagleman tackles the controversial argument of materialism versus dualism and presents studies and anecdotes that support the idea that who we are is irrevocably tied to what we are – our brain. Eagleman recounts the glimpses scientist have recorded of the mind’s unknown vastness and introduces readers to the concept that our brains are more than our awareness.

Studies of perception demonstrate how little neuroscientists know about brain function and Eagleman includes engaging exercises that reveal to the reader, first hand, the secrets your brain keeps from your conscious self. For example, a seemingly random arrangement blobs only resembles a bearded figure when the author informs you what to expect. Thus, the conscious self (the part of you that thinks) is just a small fraction of your brain while the rest of your brain does the heavy lifting by sorting through huge amounts of sensory input and only presenting critical information to your conscious self. Stories of brain injuries affecting personalities and decision-making imply that brain architecture, not just the conscious self, dictates who we are and what we do. In 1966, Charles Whitman murdered 13 people (including his wife and mother) then took his own life. His suicide note indicated that Whitman began having uncharacteristically violent thoughts and suspected a change in his brain. His autopsy revealed a tumor near the amygdala, the brain structure involved in emotional regulation, suggesting that his violent behavior may have been a result of the damage to his brain. How then does the concept of free will survive in this view? Eagleman presents his theory that incorporates self-determination, the heavy influence of biology and reminds the reader that brain function is still a black box to science.

Incognito condenses much of the neuroscientific data that attempts to pick apart the conscious mind and presents it in a readable and engaging way. Eagleman eases into the intimidating concept of materialism with fascinating evidence in hand and possible solutions to the conundrum of free will in the other. Separate from the case for materialism presented, the notion that your brain directs your mind, thoughts and decisions without your awareness will have you examining the reasons behind your actions a little more closely.