Bugs To Drugs: Can Probiotics Treat Depression?

Depression is a debilitating mental illness that affects up to 15 million Americans in the US alone, yet we are far from understanding the root cause. Multiple genes have been associated with depression, but whether these genes produce symptoms depends on the individual’s environment. New research is showing that one of the biggest environmental factors impinging on mental health comes from within.

Our body is home to trillions of microscopic creatures, mostly bacteria, which are collectively referred to as our microbiota. As unsettling as that may sound, these microbes are not necessarily the kind we want to evict from our body. The bacteria dwelling within our gut serve many important functions; for example, they help digestion, produce vitamins, and keep other types of microbes that cause disease at bay.

Our microbial inhabitants bring countless additional genes into our body called the “microbiome.” These microbial genes can be considered an extension of our own DNA – a so-called “second genome.” In other words, your body is not only influenced by the genes in your DNA, but it can also be affected by genes carried by your microbiota. These microbial genes not only affect physical health, but may also alter your mood and personality.

It is convenient to refer to species of our microbiota as "good" or "bad", but in reality they are neither. There are bacteria that can cause serious disease, like C-diff, but usually only after the microbiota has been disrupted (e.g. after prolonged antibiotic treatment). Likewise, "good" bacteria like E. coli can cause life-threatening disease under the right circumstances.  

Our microbiota help produce surprising amounts of neurotransmitters – chemicals that function in brain signaling. When laboratories produce “germ-free” mice by raising them in sterile environments, the mice exhibit strange neurological issues. Lacking their gut microbiota, germ-free mice do not respond to stress properly. These studies have given rise to the concept of the “gut-brain” axis, a conduit of biochemical communication between these organ systems. Such an axis exists in people too, as researchers have noted a strong correlation between intestinal problems and mental illness. For example, anxiety and depressive disorders are associated with both irritable bowel syndrome and ulcerative colitis.

A study by Ioana A. Marin and colleagues at the University of Virginia, published on March 7, 2017 in Scientific Reports, provides new evidence that intestinal bacteria influence mental disorders such as depression. In this experiment, mice were subjected to unpredictable chronic mild stress (UCMS), which involves strobe lights, irritating noise, cage tilting, and crowded conditions. Kind of like being shoved into noxious nightclubs against your will at random times throughout the day.

Unlike Disco Mickey, laboratory mice become stressed out when subjected to stimuli that resemble your average nightclub.

Over time, mice subjected to UCMS begin to show symptoms that resemble depression in humans. The researchers look for “despair behavior,” which can be detected in a number of ways. In this study, the mice were placed in a tub of water to evaluate despair behavior. Unstressed mice quickly swam to a platform and escaped, but the stressed mice did not make a strong effort to escape and had to be rescued from the tub.

The researchers then compared what the intestinal microbiome looked like in stressed versus unstressed mice. The different species of bacteria comprising the microbiota can be determined by sequencing the DNA in mouse droppings. Each species has a signature DNA sequence that serves as an identifier for that type of bacteria.

The results showed that stress altered the mouse microbiome by reducing a type of bacteria called Lactobacillus. It might have occurred to you that stress could have simply changed the eating habits of the mice, which in turn would affect the composition of the microbiome, but the researchers did not observe any change in eating habits or weight of the stressed mice. Furthermore, when they administered Lactobacillus as a probiotic, the symptoms of depression improved.

Why would stress cause changes in the microbiome? No one knows for sure, but this could be a result of altered brain chemistry making the gut less hospitable to some bacteria. Researchers also noted that intestinal physiology was altered in the stressed animals, which could have played a role in microbiota changes.

When someone consumes a probiotic they are ingesting live bacteria. That concept should no longer gross you out. Probiotics include the so-called "good" bacteria that have been shown to confer health benefits in some studies. These bacteria can be delivered into your body in numerous ways, including food (like yogurt) or pills.  

Does this mean you should rush out to purchase probiotics to battle depression? There are important caveats to studies like this that should be considered. The study was performed in a mouse model of depression, which may not fully represent the condition in humans. The microbiome of controlled laboratory animals is more uniform than humans, who tend to have vastly different bacteria in their guts depending on such things as diet, geography, illness, and age.

However, a 2016 meta-analysis (a study of studies) concluded that “probiotics were associated with a significant reduction in depression [in humans], underscoring the need for additional research on this potential preventive strategy for depression.” While that sounds encouraging, we are far from understanding how certain bacteria may ameliorate depression and whether this affect holds up in diverse patient populations. Probiotics certainly should not replace the more rigorously established treatments for depression recommended by health professionals.

Bill Sullivan is a professor at the Indiana University School of Medicine. Follow him on Twitter @wjsullivan.

Tryptophan vs. The NFL Fan

A turkey dinner with all the fixins can lead to a

satisfying nap. But the meal usually takes a little

longer than this to have an effect. This fellow might

be more affected by last night’s activities than today’s

meal.

Turkey dinner at Thanksgiving brings the family together, celebrates the bountiful harvest, and puts you to sleep just as the NFL games are ready to start. Many people think that if you eat less turkey and fill up on the other goodies you can escape the post-Thanksgiving meal sleepiness. Other people look forward to eating seconds and thirds and then stretching out on the couch for a long nap, forcing Aunt Ethel to sit in the chair with the spring that surprises you every once in a while.

The culprit, or the hero, in this eat and sleep saga is said to be the tryptophan in the turkey. Other people think that it is simply how much you eat, not the turkey's tryptophan, but it isn’t quite that simple. What is tryptophan, and is it indeed responsible for the snoring that follows Thanksgiving dinner?  Some background will help.

Tryptophan is an amino acid, one of the twenty standard building blocks of proteins. However, tryptophan is the least abundant amino acid in plant and animal proteins; it accounts for only 1-1.5% of the total number of amino acids in proteins. Tryptophan’s large structure and intricate rings make it costly to produce in terms of ATP invested. In fact, it takes so much energy to make that we have stopped making tryptophan all together. Tryptophan is abundant in a number of food sources commonly available to humans, so over evolutionary time we have turned it into an essential amino acid. True, it is essential for life, but here the word “essential” means that we MUST get it from our diet, we cannot produce it ourselves.

The genetic code is how mRNA codons (3 bases sequences)

get translated into a signal to build proteins from specific amino

acids. The first base of the codon is represented by the biggest

letters (ACGU), the middle base is the middle size letters, while

the third position (wobble position) is usually where you see an

amino acid coded for by more than one codon. For instance,

serine is coded for by UCU, UCC, UCA, or UCG. But tryptophan is

only coded for by UGG. Three codons signal the protein to stop

growing, called stop codons (UAG, UAA, and UGA).

Even though it is used sparingly in proteins, tryptophan is crucial - don’t eat enough of it and you die. This is because tryptophan’s most essential functions have nothing to do with protein synthesis or structure – tryptophan is important to your brain function. The crucial neurotransmitter, serotonin, is synthesized only from tryptophan.

It takes two enzymes to turn tryptophan into serotonin (also called 5-HT).  First is tryptophan hydroxylase; hydroxylase means it splits water, here it adds an OH to tryptophan. Next, the amino acid decarboxylase removes a carboxylic acid (COOH), producing serotonin.

The feeling of general well being induced by serotonin also participates in the sleep/wake cycle. So is tryptophan – through serotonin – responsible for the post-Thanksgiving nap? Well… yes and no, it's an accomplice in a larger conspiracy.

Serotonin is used to produce the hormone melatonin, and melatonin promotes sleep, so you could say turkey dinner promotes sleep. But turkey doesn’t have that much tryptophan! Tofu has much more tryptophan than turkey, but you don’t get a post-Chinese takeout urge to sleep, so what gives?

Melatonin is made from serotonin in the pineal

gland. Sunlight stimulates the suprachiasmatic

nucleus (SCN) which inhibits the pineal from

making melatonin. As the sun goes down,

inhibition is reduced, more melatonin is made

and released from the pineal, and sleep is

promoted.

The melatonin effect has to do more with how much of everything else you eat at Thanksgiving dinner, especially carbohydrates. Here is how it works – eating lots of carbohydrates causes a release of insulin into the blood (to reduced blood glucose levels). Another function of insulin is to promote the uptake of some amino acids (but not tryptophan) into muscle cells. This leaves the blood higher in tryptophan as compared to other amino acids than it would normally be.

The brain takes in amino acids through a neutral amino acid transporter, which now finds more tryptophan than other neutral amino acids, so the brain level of tryptophan goes up. More tryptophan in the brain, more serotonin – more serotonin, more melatonin. More melatonin = nap time! So if you want to avoid the post-Thanksgiving nap, eat the turkey and skip the mashed potatoes.

You didn’t know how much tryptophan controlled your daily life, did you? Well, there’s more. Tryptophan is also important in synthesizing niacin, a.k.a. vitamin B3 or nicotinic acid. Niacin is important in production of NAD/NADH for energy metabolism, for production of steroid hormones and balance of lipid forms in the blood, and as an anti-convulsant.

The tryptophan-niacin connection is made stronger by recent evidence that high dietary tryptophan can prevent epileptic seizures in mice. In this study, a whey protein called alpha-lactoalbumin (ALAC) was found to have much tryptophan, much higher levels than in most proteins. Feeding epileptic mice ALAC resulted in reduced numbers of seizures.

So even if you don’t want to sleep or think happy thoughts, you still need to eat food that contain tryptophan or niacin. And many of those foods are plants, because plants use tryptophan to control their own activities. Tryptophan is easily converted to auxins, a type of plant hormone. Auxins are responsible for several different plant behaviors, namely the falling leaves in autumn and ripe fruits all year long.

Here is an interesting attempt to get kids to read

history. During the spring, captive warriors were

killed by cutting out their hearts, then their skin was

flayed off their body, and the priests would wear them

around for 20 days. This was meant to celebrate the

god who sacrificed himself to allow a new growing

season to begin. This time period corresponds

 to when they would have had the lowest amount of

 tryptophan in their daily diet.

Having dietary choices for tryptophan is good, and plants provide our major source. However, cooking grains and corn reduces usable tryptophan and niacin levels dramatically, so poorer environments where corn is the staple food need also to have additional dietary sources of tryptophan. A deficiency of this amino acid leads to some disturbing conditions. Low tryptophan leads to low serotonin levels and agitation, insomnia, and depression. A study in the Archives of General Psychiatry stated that chronically low levels of tryptophan led to relapses of purging behaviors in bulimics.

More amazingly, studies in the 1970’s to 1990’s suggest that low tryptophan levels can lead to increases in religious fanaticism. Several studies from a single author correlate the Aztec human sacrificial ceremonies to the times of year when their diets depended more on foods that had less tryptophan. Think of all the lives that could have been saved by tofu!


Contributed by Mark E. Lasbury, MS, MSEd, PhD
As Many Exceptions As Rules

Russo, E., Scicchitano, F., Citraro, R., Aiello, R., Camastra, C., Mainardi, P., Chimirri, S., Perucca, E., Donato, G., & De Sarro, G. (2012). Protective activity of α-lactoalbumin (ALAC), a whey protein rich in tryptophan, in rodent models of epileptogenesis Neuroscience, 226, 282-288 DOI: 10.1016/j.neuroscience.2012.09.021
 
Bruce KR, Steiger H, Young SN, Kin NM, Israël M, & Lévesque M (2009). Impact of acute tryptophan depletion on mood and eating-related urges in bulimic and nonbulimic women. Journal of psychiatry & neuroscience : JPN, 34 (5), 376-82 PMID: 19721848

Dying To Make Us Laugh

It is the height of irony that Robin Williams (left) played Dr.

Patch Adams (right) in the 1998 film of the same name.

Adams used humor to heal and promote health, while new

research is showing that humorists are susceptible to more

harm when they improve our health with laughter.

One of the five funniest people to ever live died recently. Robin Williams was at least as funny as Jonathan Winters, Bill Cosby, Steve Martin, and Groucho Marx. He was 63 years old at the time of his death, and the others on my list have lived good long lives as well. Jonathan Winters was 88 when he died in 2013, Groucho Marx was 87, and Steve Martin and Bill Cosby are 68 and 77, respectively.

But a long-lived comedian is more of an exception than a rule. John Belushi, Gilda Radner, John Candy, Lenny Bruce, Patrice O’Neal, Madeline Kahn, Chris Farley, Bernie Mac, and Andy Kaufman all died in their 30’s or 40’s. This is sad to be sure, but it's even sadder when you consider that comedians hasten their own deaths while improving our health.

“Laughter is the best medicine.” The saying has been around for years – and it has merit. Laughter reduces cortisol production, which is a stress hormone that taxes our health and makes us gain weight. Laughter may improve our immune system function as well, and this fights off or prevents infection. A 2009 review showed that several studies indicated that laughter improved immune cell function (natural killer cells) and increased antibody levels (sIGA).

Laughter improves respiratory function and cardiac function because it increases respiratory rate and requires increased blood flow. These were reviewed in a very funny Christmas article in the British Medical Journal in 2013.

Laughter works on our brain too. Besides relieving stress, laughter triggers the release of endorphins that help our mood – and a good mood is a definite benefit to our health. Laughter also works on the neural pathways of resilience, so that we bounce back from disappointment better.

Gelototherapy is a pseudoscientific term for laughter therapy.

I say pseudo- because I can’t really find anyone who uses the

 term. But other health ideas have sprung up around laughter

as well. Laughter yoga (hasyayoga) is done in groups with eye

contact. It may start out as forced laughter, which is said to

have much less effect on health, but forced laughter turns

readily to spontaneous or mirthful, laughter, which lengthens

our life so we can go out to more yoga classes.

As far back as the 1970’s, journalist Norman Cousins advocated laughter therapy (gelototherapy) after he was said to have healed himself of heart disease and ankylosing spondylitis using Marx Brothers movies. He was an adjunct professor of Medical Humanities at UCLA where he did more research on the healing aspects of spontaneous laughter. But most of his results were on a case description basis – anecdotal at best.

There have been few if any studies that link laughter to extended longevity; however, a 2013 study of centenarians showed that they do tend to laugh more, as part of the PATL (positive attitude toward life). Linking laughter directly to longevity would be very difficult in the scientific sense, but the above stated health benefits can’t be hurting us, can they?

Apparently all this benefit comes at a cost to those giving us their gift. Comedians don’t just seem to die young, they are dying younger. Several studies have looked longitudinally at the health problems and obituaries of people in different professions, and that funny kids have more health problems later in life.

As part of a study of high intelligence individuals called the Terman Life Cycle Study (1922-1991), those kids rated by their parents as having a good sense of humor tended to have more health problems as adults, including alcoholism and lung disease from smoking.

People say that fat guys are funny. I’m fat and my kids say I’m

not that funny. But the question remains, do fat boys become

funny to survive, or does being funny make guys fat? Curly

Howard of the Three Stooges got fat after a bout of depression

at the end of his first marriage. He had a series of strokes late in

his movie career and died at the age of 49.

In a three-year study of police officers in Finland, those that were rated funnier or more humorous tended to be overweight, smoked more, and have more cardiovascular disease. For funny people who choose to become comedians then numbers just get worse. A 1992 study showed that comedians and humor writers died at younger ages. They tended to have more physical and mental health problems. This might relate to the environments in which they work – smoke and alcohol filled clubs, or it might reflect their tendency to see the humor and positive in things and not pay attention to risks of the unhealthy habits in which they engage.

A recent review of deaths by profession shows that performers of all sorts, including comedians, tend to die younger – health problems most certainly playing a role in their earlier demise. Robin Williams had suffered for years with substance abuse problems, bouts of severe depression, and heart disease. Comedians tend to have more depression than the general population and the suicide rate of performers, including comedians, is twice that of the general population.

But which comes first, do depressives become comedians because their altered thinking lends itself to looking at the world differently, or perhaps it is a way of self-medicating (as is drug abuse they tend to fall into) and fitting in with the world. Or, does comedy and the rejection that often comes with it, lead to more bouts of depression? Whichever it is, the physical and mental health problems of humorists seem all the more tragic when it is considered how much good these people do for us.

Contributed by Mark E. Lasbury, MS, MSEd, PhD

As Many Exceptions As Rules

C.R. Epstein, R.J. Epstein (2013). Death in The New York Times: the price of fame is a faster flame QJM: monthly journal of the Association of Physicians, 106 (6), 517-521

Greengross G (2013). Humor and aging - a mini-review. Gerontology, 59 (5), 448-53 PMID: 23689078

Ferner RE, & Aronson JK (2013). Laughter and MIRTH (Methodical Investigation of Risibility, Therapeutic and Harmful): narrative synthesis. BMJ (Clinical research ed.), 347 PMID: 24336308

Bennett MP, & Lengacher C (2009). Humor and Laughter May Influence Health IV. Humor and Immune Function. Evidence-based complementary and alternative medicine : eCAM, 6 (2), 159-64 PMID: 18955287