Red Meat Interacts with Bacteria in the Gut to Raise Heart Disease Risk
A 2018 study by a group of researchers at the Cleveland Clinic have clarified the way that a diet heavy in red meat may lead to heart disease. The research centers on trimethylamine N-oxide (TMAO), a gut bacteria byproduct that is formed during digestion. When gut bacteria digest choline, lecithin, and carnitine, nutrients that are common in certain animal products and red meat, TMAO is produced.
In an article by Robert A. Koeth and colleagues in the European Heart Journal, the researchers show that diets that rely on red meat as the main protein source lead to more circulating TMAO than diets in which white meat or something other than meat is the primary source of protein. They found that in people who eat a lot of red meat, the kidneys are less efficient at expelling TMAO, and levels creep even higher. High levels of TMAO have been linked to hardening and narrowing of the arteries (atherosclerosis) and heart disease complications. High levels of TMAO in the blood can be a predictor of heart attack, stroke, and death.
The study of 113 participants consisted of three different diets that each participant followed in random order (with a washout period in between each diet). A month of eating a diet in which red meat was responsible for at least 25% of participants’ daily calories led to higher levels of TMAO in the blood and urine. TMAO increased threefold during the red meat diet periods compared to periods in which white meat or non-meat protein were the source of those calories, and in certain participants, TMAO increased as much as tenfold. When participants stopped eating the red meat diet, their TMAO levels fell over the following month.
Rich Western Diet Reprograms Immune Cells in Mice
A 2018 article by Anette Christ and colleagues in the journal Cell describes the process by which a Western diet can trigger changes to the immune system in mice. The mice fed a calorically rich Western diet started to show systemic inflammation. Blood measures of inflammation returned to normal after the mice resumed their regular diet, but their immune responses remained heightened, as if the immune system had been trained to overreact.
The vast majority of deaths in Western cultures are caused by noncommunicable diseases such as type 2 diabetes and cardiovascular disease, which have been linked to lifestyle factors such as diet and exercise. The immune system has two wings: one that responds to specific pathogens, and one that mounts general protection against infection and is triggered by immune signaling receptors. However, according to Christ and colleagues, in addition to reacting when microbes are present, this second wing may also respond to “sterile” danger signs, such as consumption of a Western diet. The immune system may become trained to react this way chronically, something that the researchers believe may trigger inflammation in noncommunicable diseases.
The Western diet triggered epigenetic changes to the mice’s immune system. Epigenetic changes are ones that affect the structure of DNA, for example how tightly it is packaged. In the case of the Western diet, these changes resulted in a heightened immune system that launched strong inflammatory responses in reaction to even small stimuli. Myeloid cells from bone marrow were reprogrammed to proliferate and provide a stronger immune response.
The researchers also took human monocyte cells trained with LDL (“bad”) cholesterol and stimulated them with lipopolysaccharide (an inflammatory compound made of fat and sugar). The cells showed a heightened immune reaction similar to that seen in the mice.
Mice genetically engineered to lack the inflammasome NLRP3, which activates inflammatory responses, did not show the systemic inflammation or the enhanced myeloid activity when fed the Western diet, so Christ and colleagues believe NLRP3 may play an important role in mediating the immune response to the Western diet.
Eating Walnuts and Other Tree Nuts May Lower Cholesterol
In a 2018 meta-analysis and systematic review published in the American Journal of Clinical Nutrition, researcher Marta Guasch-Ferré and colleagues shared their analysis of 26 studies of the effects of diets rich in walnuts on blood lipids and cardiovascular health. The studies included a total of 1059 participants. The walnut-heavy diets were associated with lower total cholesterol, lower LDL (“bad”) cholesterol, and lower triglyceride concentrations. They were also associated with lower apolipoprotein B, a component of LDL.
When walnut-enriched diets were compared to American diets and Western diets, the benefits of the added walnuts on total cholesterol and LDL cholesterol were even more dramatic. The researchers described a Western diet as high in red and processed meats, high-fat dairy products, processed and artificially sweetened foods, and with little intake of fruits, vegetables, fish, legumes, or whole grains.
Compared to control diets, the diets rich in walnuts did not cause weight gain or an increase in body mass index (BMI), and they also did not affect blood pressure.
The studies included in the meta-analysis lasted from four weeks to one year, with a mean length of 8 weeks. The amount of walnuts ranged from 15 to 108 grams per day. In most cases, participants were given whole walnuts to incorporate into whatever daily meal plan they were following, which in some cases was their usual diet and in others was an intervention diet such as a Mediterranean diet or a low-fat diet.
Another meta-analysis published in the American Journal of Clinical Nutrition in 2015 by Liana C. Del Gobbo and colleagues analyzed 61 studies about the effects of tree nuts on cholesterol and related measures, and similarly found that eating tree nuts lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. Del Gobbo and colleagues wrote, “The major determinant of cholesterol lowering appears to be nut dose rather than nut type.” Tree nuts include walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts.
Vitamin D Deficiency in Newborns Linked to Higher Risk of Schizophrenia in Adulthood
A 2018 study by Darryl W. Eyles in the journal Scientific Reports found that newborns with vitamin D deficiency were more likely to develop schizophrenia later in life. The study made use of several Danish data depositories and had a large sample size of 2,602 participants. In this case control study, registries of patients treated for schizophrenia were matched up to preserved dried blood samples collected at their births, and these were compared to other dried blood samples from people without schizophrenia who shared the same sex and birthdate.
The researchers divided participants into quintiles based on vitamin D levels at birth. Compared to those who fell into the fourth quintile, those in the lowest quintile were 44% more likely to be diagnosed with schizophrenia in adulthood. The researchers also determined polygenic risk scores for each participant, that is, they calculated schizophrenia risk based on the presence of various genes. The two processes together explained 1.2% of the variance in schizophrenia diagnoses.
Risk factors for vitamin D deficiency include being born in the winter or spring, living in high-latitude locations, spending early life in an urban setting, and being darker-skinned (especially in high-latitude locations). These risk factors are all correlated with decreased skin absorption of UV rays from the sun, which is how the human body produces vitamin D. The vitamin D receptor is expressed in the brain in areas that are relevant to schizophrenia, such as areas with a lot of dopamine activity, and each of the above risk factors also applies to schizophrenia.
As expected, participants born in the winter and spring had lower vitamin D levels. Participants whose parents had immigrated to Denmark had lower vitamin D than those with parents native to Denmark.
Newborns’ vitamin D levels depend completely on their mothers’ vitamin D levels, so Eyles and colleagues suggest that ensuring pregnant women have adequate vitamin D levels could prevent some cases of schizophrenia.
Adolescents with Bipolar Disorder May Have Higher Levels of Vitamin D–Binding Protein
Vitamin D binding protein. Illustration: Emw [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]
A 2018 article by Brawnie Petrov and colleagues in the journal Translational Psychiatry suggests that adolescents with bipolar disorder have higher levels of vitamin D–binding protein than adolescents without a mood disorder. The researchers wrote that vitamin D–binding protein “responds early to cellular damage by binding…structural proteins and activating inflammatory cells.”
This pilot study suggests that measuring levels of vitamin D–binding protein could be a useful marker of bipolar disorder. The study was small, with only 12 participants who had bipolar disorder, 11 who had unipolar depression, and 13 with no mood disorder. The researchers hope to follow up with larger studies in adolescents and adults using blood that has already been collected from people with bipolar disorder.
Vitamin D–binding protein is not measured by a standard blood test. The study authors used a technique where they “fished” for inflammatory factors that might be linked to mood disorders. The researchers began by looking for a link between other inflammatory markers in the blood and bipolar disorder, which have repeatedly been found in other studies, but they did not find any such association. There also did not seem to be a link between bipolar illness and vitamin D levels in the blood, only vitamin D–binding protein levels.
It can be especially difficult to distinguish early bipolar disorder from unipolar depression, and if the results of this small study are replicated, a blood test might eventually help to identify people with bipolar disorder earlier.
Eating Beef Jerky and Other Nitrate-Cured Meats Linked to Increased Mania Risk
In a 2018 article in the journal Molecular Psychiatry, researcher Seva G. Khambadkone and colleagues reported that a history of eating nitrated dry cured meat, such as beef jerky, was associated with a more than threefold increase in the risk of current mania. Eating other types of meat and fish products was not linked to mania.
The study included 217 people with mania, 91 with bipolar depression, 79 with unipolar depression, and 371 with schizophrenia, plus 343 control participants without a psychiatric disorder. Each participant responded to a questionnaire assessing whether they had ever eaten certain foods. The researchers had the idea that eating foods such as undercooked meat or fish, which might carry infectious agents, could be connected with mania, since inflammation seems to be linked to psychiatric illness. To the researchers’ surprise, their analysis found an independent link between eating nitrated dry cured meat (such as beef jerky, turkey jerky, or meat sticks) and being admitted to a hospital with acute mania.
Having eaten other cured meats such as salami or prosciutto was not linked to mania, nor was having eaten any other food.
Following these findings, Khambadkone and colleagues designed a study in which rats were given meat with added nitrate. The rats showed hyperactivity that resembled human mania, alterations in brain pathways that have been linked to bipolar disorder, and changes to gut microbes.
Low Levels of Acetyl-L-Carnitine Associated with Insulin Resistance in Traumatized Children
Researcher Carla Nasca and colleagues from the Rockefeller University reported at a late-2018 scientific meeting that depressed patients with a history of childhood adversity had low levels of the amino acid acetyl-L-carnitine and also exhibited insulin resistance. This is noteworthy because in a series of small studies, acetyl-L-carnitine supplements have had antidepressant effects. In laboratory animals, acetyl-L-carnitine also sensitizes insulin receptors. This suggests the possibility that the supplements could provide a two-for-one benefit in depressed patients with a history of adversity in childhood.
Inflammation Linked to Poor Sleep Quality and Worse Executive Functioning
At a recent scientific meeting, researcher Ellen E. Lee and colleagues reported that compared to healthy volunteers, people with bipolar disorder or schizophrenia had elevated levels of inflammatory markers, which were associated with poor sleep.
According to self-reports, people in the schizophrenia and bipolar disorder group had worse sleep quality than the control group. Those with schizophrenia or bipolar disorder also had significantly higher levels of the inflammatory markers CRP, IL-6, and TNF alpha compared to the healthy volunteers. Among people with bipolar disorder, executive functioning and sleep quality had a strong inverse association to levels of IL-6, such that lower sleep quality and worse executive functioning were associated with higher levels of IL-6. These findings suggest that sleep disturbance and inflammation may have negative consequences for cognitive functioning.
American Academy of Pediatrics Recommends Parents Avoid Spanking and Verbal Abuse
The American Academy of Pediatrics (AAP) has issued a policy statement calling for an end to corporal punishment, including spanking. These forms of punishment are tied to negative outcomes in every developmental area.
Children spanked regularly at age 3 had increased aggression risk by age 5. They also had more negative behaviors and lower vocabulary scores at age 9. Abusive behavior raises stress hormones and is associated with mental health struggles.
Verbal abuse should also be avoided. Verbal abuse includes punishment that shames, humiliates, threatens, frightens, or ridicules a child. Use of time outs, removal of privileges, and other forms of quiet discipline are recommended alternatives.
Editor’s Note: In our research network, the Bipolar Collaborative Network, we found that verbal abuse by itself (without the physical or sexual abuse that often accompany it) is associated with an earlier age of onset of bipolar disorder and a more difficult course of illness.
Family focused therapy (FFT) and other forms of family therapy are highly recommended for children of a parent with bipolar illness. These children are at high risk for a variety of psychiatric diagnoses, and those already experiencing depression, cyclothymia (mood swings between high and low) or a diagnosis of bipolar disorder not otherwise specified (BP-NOS) are much improved with FFT compared to treatment as usual. FFT teaches family members to recognize symptoms of illness for what they are rather than interpreting them as deliberate hostility, increases family communication and problem solving, and leads to good long-term outcomes.
Civil War Data Shows Father’s Trauma Can Affect Son’s Lifespan
An economist at the University of California Los Angeles (UCLA) has used Civil War data to determine that trauma experienced by a father can affect the lifespan of his son, but that a mother’s healthy diet during pregnancy can neutralize this risk.
Researcher Dora Costa used records from the National Archive to identify Union soldiers who were held as prisoners of war (POWs) by the Confederacy. She compared records of their children’s lifespans to the children of Union soldiers who were never held as POWs, finding that the sons of POWs were more likely to have died at any given age. (The study included only children who lived to be at least 45 years old.) Detailed records were kept because families of soldiers and POWs were eligible for generous pensions.
When looking at the data, Costa expected to find that socioeconomic status was the factor that explained discrepancies in lifespans among children of Civil War veterans. However, she noticed that the difference in lifespan only appeared in sons, and only to sons born after the war.
This pointed to an epigenetic explanation. Epigenetics is the idea that some aspects of a parent’s experiences (such as deprivation, drug use, etc.) can be passed on to their children during the gene transcription process. While a parent’s inherited genetic sequence doesn’t change, the structure of their DNA can be wound tightly or loosely depending on life experiences, and this affects how easily their genes are transcribed when passed on to their children.
The sons of POWs in the worst camp environments (typically during the later years of the war when prisoner exchanges were less frequent and overcrowding and malnutrition were common in camps) had even shorter lifespans than the sons of POWs who were imprisoned in less dire circumstances.
The research also looked at birth months to determine whether mothers would have had access to good nutrition while pregnant. Sons born to POW fathers in the later months of the year (whose mothers were likely to have had access to good nutrition) had lifespans comparable to the sons of non-POWs, while sons of POWs born earlier in the year fared worse.
The research was published in the journal Proceedings of National Academy of Sciences in 2018.
Editor’s Note: This is another example in humans of findings that have been clear-cut in animal studies. A father’s experiences, such as stressors or substance abuse, can influence the next generation even if the parent has no contact with the offspring. Epigenetic marks on DNA, histones (the structures around which DNA is wound), or microRNA of the sperm appear to carry these unexpected transgenerational effects.
