https://www.databridgemarketresearch.com/reports/global-gmp-cytokines-market

DEPRESSION-
Depression, Serotonin, and the Gut.
New findings explore SSRI efficacy and dysbiosis in major depressive disorder.
Reviewed by Hara Estroff Marano

KEY POINTS-
A new report indicates a direct correlation between gut dysbiosis, major depressive disorder, and SSRI efficacy.
Although the gut makes more than 90% of the body's serotonin, gut-derived serotonin does not cross the blood-brain barrier.
Instead, a related metabolic pathway producing kynurenine is associated with decreased serotonin, increased inflammation, and depression.
The gut microbiota may serve as a prognostic indicator and a treatment target for major depressive disorder.
By: Nicole Cain, ND, MA

In a report scheduled for publication in the June 2023 issue of the Journal of Affective Disorders, researchers explore the association between the gut microbiome and the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder (MDD). Their findings indicate that an increase in specific microbial genera (Blautia spp., Coprococccus spp., and Bifidobacterium spp.) may be useful as markers predicting treatment efficacy. They also help lay to rest the notion that low serotonin is a causative factor in depression

A 2022 systematic umbrella review published in Molecular Psychiatry examined the breadth and quality of evidence behind that once-popular theory. After reviewing 17 studies involving more than 150,000 individuals, they concluded that “the main areas of serotonin research provide no consistent evidence of there being an association between serotonin (5-hydroxytryptamine, or 5-HT) and depression, and no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.” Their review also revealed evidence that long-term antidepressants may actually reduce serotonin concentration.

Serotonin Production
L-Tryptophan, an essential amino acid and building block of serotonin, is not produced by the body. Humans thereby rely primarily on dietary intake to provide tryptophan. The metabolism of tryptophan within the human body can follow one of two pathways, toward serotonin or toward production of kynurenine, a substance that plays a role in niacin production. Serotonin is the main focus here, but it's noteworthy that the kynurenine pathway definitely plays a role in mood.

Tryptophan Pathways
Tryptophan is metabolized into serotonin in the central nervous system by the brain’s neurons.1 It is also metabolized by specific gut microbes (e.g., Lactococcus, Lactobacillus, Streptococcus, Escherichia coli, and Klebsiella species)2 and specialized intestinal epithelial cells known as enterochromaffin cells.3 More than 90% of the body’s serotonin (5-HT) is produced in the gut. But gut-derived, peripheral serotonin typically does not cross the blood-brain barrier.4-6 Rather, it is associated with digestive activity including nutrient absorption and transport.7 Gut-derived serotonin is also involved with inflammatory response8 and glucose and lipid homeostasis,9 among other effects. A deficit of 5-HT in the gut is also associated with irritable bowel syndrome (IBS).10

Although peripheral serotonin produced by the gut cannot directly enter the brain,11 it can influence blood-brain barrier permeability.7 Furthermore, vagus nerve stimulation by the gut microbiota can alter concentration of serotonin, GABA, and glutamate within the brain—all known to influence mood.12

Additionally, peripheral serotonin itself plays a role in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis, via neuroendocrine interaction.13 Notably, stress-induced hyperactivation of the HPA axis is associated with a dysregulation in the serotonergic system, including a chronic increase in the stress hormone cortisol, which is associated with both depression and suicidal ideation.14,15

The gut clearly plays a significant role in serotonin production, and peripheral serotonin does influence the brain directly and indirectly through immune function, vagal nerve stimulation, neuroendocrine feedback, and the HPA axis. But the larger question surrounding the relationship between serotonin levels in the brain and mood, specifically depression, remains unclear.

The Difference a Pathway Can Make
As shown in the illustration above, enzymes are vital to the metabolism of serotonin from L-tryptophan and its metabolite, L-5-hydroxytryptophan (5-HTP). Evidence suggests that the transport of 5-HTP across the blood-brain barrier is deficient in depressed individuals.16 As such, the most commonly prescribed antidepressant medications, SSRIs, block the serotonin transporter (SERT) in the brain, allowing more serotonin to remain in the synaptic cleft between neurons; blocking the reuptake of serotonin ostensibly keeps it active, in theory, to promote antidepressant effects.17,18 But as the 2022 review reports, the relationship between serotonin levels and depression is not clearly established.

With this in mind, it's worth taking a look at the alternative, much more common, pathway for tryptophan metabolism. In normal human physiology, more than 90% of 5-HTP is metabolized via the kynurenine pathway. But overactivation of this busy pathway in the brain results in increased production of neurotoxic compounds and lower neuroprotective compounds as well as reductions in mood-balancing neurotransmitters including dopamine, choline, and GABA.19,20

This excessive kynurenine pathway activity also happens to be correlated with exaggerated inflammation, which is itself associated with decreased levels of serotonin in the brain.21 Moreover, inflammation alone is implicated in mood disorders, with increased levels of proinflammatory proteins (cytokines) a well-established marker of major depressive disorder and treatment-resistant depression.22,23

Perhaps serotonin as a marker of depression is something of a canary in the coal mine. It may be possible that addressing serotonin reuptake between neurons is not the most efficient path toward healthy brain function, neurotransmitter optimization, and mood balance. Perhaps the root cause of depression may be better addressed with a focus on the so-called second brain: the gut microbiome.

This aligns with the findings reported in the Journal of Affective Disorders in June 2023 in which the authors conclude that the gut microbiome of patients with major depression is distinct and changes with SSRI treatment. They believe that gut dysbiosis offers a prognostic tool and therapeutic target for individuals with major depression.

TRAUMA-
The Pandemic Is Not Over.
What have we learned over the past three years.
Reviewed by Abigail Fagan

This is not the time to let down our defenses, with over 120,000 new cases and 1,700 deaths caused by COVID each week in the U.S. Regrettably, only 16.7% of Americans have updated booster doses. SARS-CoV-2 not only induces respiratory symptoms but can affect multiple organ systems, including the kidneys, gastrointestinal tract, heart, and brain. SARS-CoV-2 is known to cause strokes, venous sinus thrombosis, encephalitis, and acute sensorimotor neuropathies. There have been over 760 million confirmed cases of COVID-19 as of April (World Health Organization, 2023). Most persons infected with SARS-CoV-2 remain asymptomatic, but many experience mild (40%) or moderate (40%) disease. Approximately 15% develop severe COVID-19 that requires oxygen support. An 18-month follow-up of those with symptomatic infections found that 6% had not recovered and 42% had recovered only partially.

Clues are beginning to emerge as to why some have persisting symptoms following COVID-19. There is a higher risk of Long COVID in those with a more severe initial infection, but Long COVID can occur even after a mild infection. Risk factors for developing Long COVID include the presence of Epstein Barr virus, SARS-CoV-2 virus, certain auto-antibodies, diabetes type II, obesity, high blood pressure, chronic lung disease, and depression.

For example, the lingering symptoms of difficulty thinking may be caused by ongoing low-grade brain inflammation following the acute viral infection, and even individuals with initial mild COVID symptoms may be vulnerable. While there is no evidence of widespread SARS-CoV-2 infection in the brain, many neurological symptoms of Long COVID-19 are likely a result of a post-inflammatory response including the presence of antibodies that react with the nervous system. The inflammatory response occurs particularly around blood vessels, with macrophages producing free radicals and cytokines that persist and cause damage.

Finally, COVID-19 infection can also cause some arteries and veins in the brain to become thin; breaks in small blood vessels can cause bleeding in the brain. COVID-19 can also cause blood cells to form clots in arteries and veins which reduce or block the flow of blood, oxygen, and nutrients that cells need to function and can lead to a stroke. In sum, the inflammatory immune system response to the virus, injury to blood vessels, and lack of oxygen in the brain may account for diagnostic images that show changes in the brain’s white matter that contains the long nerve fibers, which transfer information from one brain region to another. This “diffuse white matter disease” might contribute to cognitive difficulties.

The neurocognitive problems that intensify over time in some patients with Long COVID are similar to those in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) Several studies have indicated that about 40% of patients with Long COVID fulfilled ME/CFS criteria. The clinical similarities between ME/CFS and ME/CFS-Long COVID allow us to suggest common pathobiology. With Long COVID, there is evidence that the initial SARS-CoV-2 infection reactivates latent viruses such as Epstein Barr virus, which has been linked to many other illnesses including multiple sclerosis. By studying those who test negative for SARS-CoV-2, but have ME/CFS, we could learn more about the relationship between Epstein Barr Virus and both Long COVID and ME/CFS.

A recent book by international scholars around the world, edited in part by one of us, Leonard Jason, Understanding the Behavioral and Medical Impact of Long COVID, describes what is known in different areas of functioning affected by Long COVID and how this knowledge can facilitate the application of appropriate assessment and treatment. There are clear benefits that can occur when multidisciplinary approaches can help better understand the complicated behavioral and medical systems of those affected by Long COVID. We all remain at risk for this deadly virus, and we need to continue to exercise caution and engage in safe behaviors to protect ourselves and our loved ones.

RESILIENCE-
6 Underestimated Drivers of Well-Being.
Research shows these psychospiritual forces may be critical for health.
Reviewed by Kaja Perina

KEY POINTS-
Meaning, purpose, value, connection, resilience, and transcendence are key drivers of well-being.
Research shows these psychospiritual forces may be critically important for decreasing risk of illness.
When I was in graduate school studying world religion, philosophy, and psychology, I became intrigued by what, if anything, undergirds the world’s wisdom traditions. I had no interest in diluting them or melting them into one. I was more curious about what was beneath belief. After much research, I arrived at what I termed the Six Fundamental Human Desires. Taken together, they are what all the major traditions, each in their own way, using their own language, care about and try to make real for people’s lives.

It turns out these desires can positively affect the body and mind as much as the spirit and soul.

1. Meaning
Meaning helps us to make sense of life and find significance in life. It satisfies our desire to have a life filled with understanding, awareness, peace, and satisfaction. Meaning helps us to see how we fit into the world, and that greatly shapes the stories we live by. Meaning gives us the sense that we, others, and certain things in life matter, which helps us to craft a rich and rewarding existence. Meaning gives us confidence that within each moment or each situation, there is something important and worthwhile that can orient us, carry us forward, and help us to be well.

Research (Bigony & Keitel, 2020) shows that meaning-making can lessen the negative effects of people adjusting to and living with chronic illness. Studies (Fredricksona et al., 2013) also reveal that people who believe their existence has meaning have lower levels stress hormones and more favorable gene expression related to inflammation. Further research (Park, 2012) shows that meaning-making can positively influence the transition of cancer patients into longer-term survivorship and help people harness the will to live, which has been shown to contribute to longevity.

2. Purpose
Purpose grounds and motivates us, unifies our life, and directs us toward some ultimate concern or “North Star” around which we shape our lives. Purpose satisfies our desire to have a reason to get up in the morning and go to bed at night feeling as though we’ve done something important or worthwhile. Purpose gives us confidence that we have “miles to go before we sleep.”

In a meta-analysis of 10 studies involving more than 136,000 people, researchers found that having purpose in life can lower your mortality risk by roughly 17% (Cohen et al., 2016) — about as much as following the much-celebrated Mediterranean diet. Another study (Boyle, 2012) found that if a 90-year-old with a clear purpose in life develops Alzheimer’s disease, that person will probably continue to function relatively well despite pathological changes in the brain.

Research (Alimujiang et al., 2019) also shows that people who have high levels of purpose spend fewer nights in hospitals and have lower odds of developing diabetes and over two times lower risk of dying from heart conditions than others. People with purpose are similarly more likely to keep active, get their cholesterol levels checked, even undergo colonoscopies; they can also buffer stress better (Kim, 2014).

3. Values
Values help us determine what we give priority and precedence to, and what we pursue in life. Values satisfy our desire to have something to work for, find deserving, invest in, and live by. Values give us confidence that there are certain things we can always turn to and rely upon to keep our integrity intact and keep us headed in the right direction.

Emotional or affective states, in particular the shame and guilt that often come from not living our values, can have a significant impact on health, illness, and health-related behaviors.

Shame has been linked to high levels of stress-related hormones that can meaningfully impact the immune system. Shame has also been linked to high elevation of cytokine activity. Cytokines are signs in the body of inflammation, indicating that a disease process may be in progress. Toxic shame — different from ordinary shame, which passes in a day or a few hours — has been shown to result in substance abuse, eating disorders, and self-harm. One large-scale meta-analysis (Kämmerer, 2019) showed shame’s link with depression is especially strong. Shame has also been linked to irritable bowel syndrome (IBS; Muscatello et al., 2016).

Similarly, guilt is related to anxiety and depression, but also to obsessive-compulsive disorder (OCD), insomnia, loss of appetite, stomach and digestion issues, and an overall dreary or “weighted down” feeling (Hotchkiss, 2013).

4. Connection
Connection helps us relate to and form relationships with others and the world around us. Connection satisfies our desire to bond and belong — to have a type of familial warmth and security. Connection gives us confidence in the very real power of trust, intimacy, community, empathy, and love.

Connection is a critically important contributor to good health and longevity. According to the Harvard Women’s Health Watch, numerous studies (2010) have shown that people who have satisfying relationships are happier, have fewer health problems, and live longer. One study (Harvard Woman’s Health Watch, 2010) of more than 309,000 people, found that not having strong relationships increased the risk of premature death by 50% — that’s comparable to smoking as many as 15 cigarettes a day, and greater than obesity and physical inactivity. Another study (Berkman et al., 1979) showed that people who were disconnected from others were roughly three times more likely to die than people with strong social ties.

Researchers (Ruberman, 1984) at the Health Insurance Plan of Greater New York found that of 2,320 men who had survived a heart attack, those with strong bonds had only a quarter the risk of death within three years as those who lacked social connectedness. Researchers (Brummet, 2021) at Duke University Medical Center also found that connection can reduce deaths in people with serious medical conditions. Among adults with coronary artery disease, the mortality rate was nearly two and a half times higher among those who were socially isolated. Other studies show that connecting with others also helps relieve harmful levels of stress and inflammation, which can have an adverse effect on gut function, insulin regulation, and the immune system.

In contrast, loneliness can lead to disrupted sleep patterns, elevated blood pressure, delayed recovery from injury, surgery, illness, cognitive and functional decline, including dementia, and a wide range of diseases, including cardiovascular disease and cancer (American Psychological Association, 2017).

Overall, there is consistent and compelling evidence (Umberton & Montez, 2010) that connection contributes to lower rates of anxiety and depression, higher self-esteem, greater empathy, and more trusting and cooperative relationships.

5. Resilience
Resilience shows us how to flourish, not despite but because of adversity, in a way that improves, rather than hurts our lives, and fortifies, rather than weakens our spirit. Resilience satisfies our desire to live fully, love deeply, and thrive—every day, come what may. Resilience gives us confidence that life is always worth living.

More and more research shows that resilience can buffer various mental health conditions, such as depression and anxiety. Resilience can also help offset factors that increase the risk of mental health conditions, such as being bullied or previous trauma.

Resilience has been found to lower blood pressure; offset insomnia, heartburn, indigestion, and heart disease; and boost a weakened immune system (Harvard Health Publishing, 2017).

The link to resilience and the immune system is particularly important. In one study (MentalHeath Net, 2023), depressed women suffering from breast cancer were found to have fewer immune system cells and weaker overall immune functioning when compared to non-depressed breast cancer sufferers. Because the job of the immune system is, in part, to hunt down and kill cancer cells, depressed breast cancer sufferers’ weaker immune function means that their bodies are less likely to be able to resist their cancers. Similarly, another study found that depressed bone marrow transplant patients were significantly more likely to die during the first post-treatment year than non-depressed transplant recipients. In a third study (McGowen, 2018) in adults with HIV, high resilience was related to a lower prevalence of depression, anxiety, and problems with ADLs.

6. Transcendence
Transcendence wakes us up to the fullness of life — to experience something greater than our daily to-do lists, something truly sublime or, for some, even the divine. Transcendence satisfies our desire for wonder and awe. Transcendence gives us confidence that there are things in life that will always inspire, encourage, humble, and excite us.

Many people associate transcendence with religion and spirituality. Researchers (Mueller, 2001) at the Mayo Clinic concluded that religious or spiritual involvement is associated with better health outcomes, including greater longevity, coping skills, and health-related quality of life (even during terminal illness), and less anxiety, depression, and suicide. Other studies have found that addressing a patient’s spiritual needs enhances recovery from illness.

Frequent attendance at church, temple, mosque, or other spiritual gatherings may also improve health. For instance, in one study, religious or spiritual attendees were more likely to stop smoking, increase exercise, increase social contacts, and stay married. Multiple studies (Koenig et al., 2012; Strawbridge et al., 1997) also show that religiously inclined people live longer. Research at Duke University has similarly found that those who are religious have a strong internal sense of control, which can help people cope with depression and anxiety and deal better with adversity.

Of course, you don’t have to be religiously inclined to benefit from the experience of transcendence. Research (Allen, 2018) at the University of California, Berkeley on the relationship of positive emotions and levels of proinflammatory cytokines found that awe, more than any other emotion, significantly reduced inflammation. As mentioned previously, proinflammatory cytokines are cell-signaling proteins that help to fight infection or injury. High levels of these cytokines have been linked to several chronic diseases, such as cancer, cardiovascular disease, diabetes, and depression. In this study, awe was the strongest predictor of lower IL-6 levels, a proinflammatory cytokine.

Experiencing transcendence while in nature or viewing awe-inspiring images decreases sympathetic activity and increases parasympathetic activity, effectively switching our nervous system from a heightened state of arousal to a place of calm (Shiota, 2011). A study (Chirico, et al., 2018) with Virtual Reality stimuli found that looking at high, snowy mountains increased people’s mood and sense of awe, while viewing the Earth from space or a forest did not; the mountain scene also induced the highest level of awe, although the other stimuli also increased awe significantly.

A study (Anderson et al, 2018) with military veterans and youth from underserved communities found that the transcendence and awe they experienced while whitewater rafting, significantly reduced stress and increased overall well-being. The effects continued to improve one week later. Researchers also found that on days participants spent time in nature, generally, they reported feeling more awe — as well as greater life satisfaction and well-being, suggesting that awe may be a crucial ingredient in nature’s restorative abilities.

The connection of the body, mind, and spirit and its relation to well-being has been a topic of discussion throughout millennia. Today, a holistic biopsychosocial-spiritual model of health is increasingly finding its way into the mainstream, as individuals, families, and health and mental health providers recognize that just as we have basic physical needs, we also have fundamental human desires like meaning, purpose, value, connection, resilience, and transcendence that may be as important for decreasing the risk of illness and death and increasing overall health.

How Diet Affects the Sex Lives of Women.
The consequences of the diet are underdiagnosed and rarely treated adequately.
Reviewed by Davia Sills

KEY POINTS-
A low-quality diet that leads to obesity and metabolic syndrome can negatively affect female sexuality.
Obesity produces excessive levels of inflammation, decreased blood levels of nitric oxide, and reduced clitoral blood flow and sexual enjoyment.
The Mediterranean diet may help alleviate the sexual dysfunction of obese women and reduce blood levels of inflammatory cytokines.
The incidence of female sexual dysfunction, at some point in their life, is high—at least 40 percent. Women are often uncomfortable bringing up sexual concerns with their doctors; physicians are often reluctant to ask about the topic. Sexual dysfunction is likely underdiagnosed and rarely treated adequately. Obviously, sexual health is closely related to overall health. Chronic conditions, including neurological impairments, renal disease, inflammatory disorders, and cancer, can negatively impact sexual health.

All of these conditions, as well as general health, are strongly influenced by a person's diet. For most Americans, a low-quality diet is due to a greater intake of "highly processed foods." These foods are designed to be particularly rewarding by adding fat, salt, or refined carbohydrates, including cookies, ice cream, cheeseburgers, pizza, soda, and sweet coffee drinks. These food items offer a pleasurable taste, affordability, and easy availability. People often report that they specifically choose to eat highly processed foods to enhance their positive emotions and reduce their negative emotions. Previous studies have shown how a low-quality diet can negatively affect male sexual activity. Unfortunately, the role of diet in female sexuality has not been well studied.

The preliminary data on the topic are limited but suggestive that diet does influence female sexuality. A recent review outlined how female sexuality is affected by diets that lead to metabolic syndrome, obesity, and eating disorders. Metabolic syndrome is characterized by increased insulin resistance, plaque formation in the major arteries, and obesity. These conditions increase the risk of heart attacks and death. Obesity is often a consequence of metabolic syndrome and may directly affect sexual health. Essentially, obesity produces excessive levels of inflammation throughout the body leading to decreased levels of the blood gas nitric oxide. Consequently, blood flow to the genitourinary system is reduced, leading to decreased clitoral blood flow and sexual enjoyment.

Studies of obese women undergoing bariatric surgery reported a moderate level of improvement in sexual functioning that dissipated when the women returned to their baseline weight levels. Studies that incorporated a low-calorie diet and some physical exercise found significant improvements in sexual functioning that correlated with reduced body weight and improved insulin resistance. Some recent studies suggested that the Mediterranean diet may alleviate the sexual dysfunction of obese women and reduce blood levels of inflammatory cytokines.

Females with other eating disorders also tend to have a high rate of sexual dysfunction. For example, patients with bulimia tend to be impulsive and engage in higher-risk sexual behaviors, while anorexics report decreased arousal, lubrication, and orgasmic function.

Diet-induced metabolic syndrome and obesity, in concert with a significant elevation in systemic inflammation, place a strain on the body that can lead to sexual dysfunction. The good news is that a healthy diet, such as the Mediterranean diet, can potentially serve a protective function.