Doomed by Your Genes?

One of the most inspiring collaborations in the history of medicine was the Human Genome Project. Taking place from 1998 to 2003, it was an enormous international effort to create a map of all the genes in human DNA. With this map in hand, we would surely be able to navigate our way through all the protein and enzymatic pathways that make a human tick. The fervent hope was that by matching up ailments with genetic variations, we would soon discover the root of all diseases.

It was not to be. Although a few genes were found to be associated with disease, the connection was rarely clean. Finding a one-to-one link between genes and disease was the exception, not the rule. Since then, we’ve discovered that the wealth of microbial species in our gut contain a hundred times more genes than our own surprisingly paltry DNA. Genetically, we are mostly microbe! The Human Genome Project, by missing our microbiota, captured only a tiny sliver of our total genetic toolkit.

Tiny microbes turn out to play an outsized role in our health. Friendly microbes provide us with protection against the other far nastier microbes blanketing the planet. They even help us digest our food and provide us with nutrients that feed and heal the cells lining our guts. If you take care of them, they will reward you with a long healthy life. If you don’t, all hell can break loose.

A poorly balanced microbiota is called dysbiotic. Instead of a bustling cosmopolitan bacterial society, a dysbiotic gut is more like an autocracy where a handful of species take over with few counterbalancing microbes. Without pushback from a diverse microbiota, even mild-seeming commensals can become marauding pathogens. When that happens, the mucus layer in the gut starts to get eaten away, and the gut lining can become porous, letting bacteria enter the bloodstream where they get pumped to every organ in the body. That bodily infection leads to an immune response that, over time, can develop into chronic systemic inflammation.

The collateral damage from inflammation is astonishing. It is a scorched earth campaign that can save you – or kill you trying. Inflammation is at the root of almost all chronic diseases, from Alzheimer’s and Parkinson’s to diabetes, heart disease, obesity, autoimmunity, allergies and pretty much all the scourges of mankind. Most of our problems – as well as the probable solutions – come from our microbiota, not our genes. Our lives are at the mercy of our bacterial overlords. We can only fight them for about 100 years before they take us back.

An interesting question is: do our genes affect our microbiota? Is there a human trait that could make you the perfect bacterial host, or is it all the luck of the draw, the microbes you happen to bump in to as you move through life? Recent research from Eran Segal of the Weizmann Institute in Israel has given us the answer to this nature vs. nurture question. It turns out that our human genes account for a puny 2% of our microbial composition.

It’s a little humbling to know our contribution is so meager, but it’s actually a boon. We can’t control our genome – it’s the parental gift we can’t return – but we can control our diet.

Here’s the takeaway: A poor diet leads to an unbalanced, dysbiotic microbiota that can lead to systemic inflammation – the root of most chronic diseases. That’s the bad news. The good news is that we hold the reins. A proper diet rebalances the microbiota, which can protect you from chronic illness. Our genes may not hold much sway over disease, but our will-power definitely does. No more excuses, no more blaming your parents. This one is up to you.


The Upside of Rabies

Rabies is an awful way to die. The bullet-shaped virus, which is transmitted by a bite from an infected animal, doesn’t move through your circulatory system like most pathogens. Instead, it travels exclusively through nerve cells. Unlike a blood vessel, nerve cells don’t pump fluid around. But they do have some flow, courtesy of protein transporters that travel back and forth along the nerve axons. Rabies viruses grab a ride from these transporters, doggedly hopping across synapses and traveling toward the brain. The outcome is dire for the victim, whose muscles will spasm as hallucinations set in and paralysis finally kills them. However, the propensity to travel along nerves makes rabies a wonderful scientific tool to track nerve networks.

This is how Diego V. Bohórquez discovered that intestines can directly sense what is happening in the gut and then can transfer that info to the brain. Using fluorescently tagged rabies vaccines, he was able to follow the neural path from cells lining the gut called enteroendocrine cells as they connected to the “second brain” surrounding the gut. That pathway offers as yet another way that bacteria in your gut can communicate with your brain. Along with the vagus nerve, hormones and immune reactions, this line of communication makes it easier to understand the gut-brain connection.

We know that bacteria can produce a number of neurotransmitters, including dopamine, serotonin and GABA, but this research now shows us how those chemicals can access the brain without needing to breach the blood-brain barrier. As more of these mechanisms come to light, the story of how psychobiotics work their magic becomes clearer every day.

Bring back the 50s!

The 1850s, that is.

Believe it or not, our health has been sliding ever since the Victorian ages. Between 1850 and 1880, people in England lived better and longer than at any other time in history. They got plenty of exercise, at least partly because Karl Benz had yet to perfect his automobile. Farmers finally figured out how to efficiently deliver their crops to the city folk, who ate tons of veggies and fruit and consumed some ten times more phytochemicals and fiber than we do today. They ate onions (cheap), leeks, watercress, Jerusalem artichokes (homegrown), cabbage, broccoli, peas, and beans.

Victorian Health: no corset required.

Their life expectancy at age 5 was better than it is currently. Almost no one had any of the chronic degenerative diseases that plague us these days. Rates of arthritis, diabetes, dementia, cancer and depression were practically nonexistent. Shockingly, all of this ridiculous health came before modern medicine, antibiotics and nutrition. Their diet likely explains most of their improved health.

From what we now know about the gut-brain axis, the extra fiber in their diet probably kept them in a good mental state. Fiber is indigestible by the gut, but is manna to the microbes living there. These microbes convert fiber into chemicals like butyrate that keep the gut in the pink of health. Microbes also make neuro-chemicals like serotonin and dopamine that may help to forestall mental problems like depression and anxiety.

If you want to be as healthy as a Victorian Brit, do what they did and eat a ton of veggies, especially low-carb, high fiber veggies. And get some exercise. No, running a bath doesn’t count.

It turns out that probiotics and prebiotics can do more than just ease your mind; they can improve your lifespan. So what are you waiting for?


Human Studies are a Pain

Yesterday, salt was bad for you, but today it’s just fine. Multiply these  findings by a hundred and you have the confounding noise that passes for research in most nutritional studies. What the heck is going on?

The problem is, human dietary studies are hard. Most of them depend on people recalling what they ate over the last few weeks, and the combination of forgetfulness and the desire to look good makes the data suspicious. A truly randomized, controlled trial needs to take place in some kind of uber-regimented locked-down facility that even college volunteers wouldn’t appreciate. This is why many of these studies are done with mice and rats.

There’s another way, and it’s called a meta-analysis: a mathematical technique that combines multiple studies to wring the most out of all of them. Meta-analyses have their own issues, mainly because studies need to be well-matched to combine them. But they provide a way to create data sets with larger populations and potentially greater power.

So it has been reassuring to see studies like this recent Chinese meta-analysis of over 700 people demonstrating that probiotic consumption is indeed associated with reduced measures of anxiety. The researchers point out that there were conflicting data, but overall, the results were significant. With over 350 million people in the world afflicted with anxiety and depression, studies like this provide some hope.

Pitting Viruses against Bacteria

Big fleas have little fleas,
Upon their backs to bite ’em,
And little fleas have lesser fleas,
and soad infinitum

Bacteria are everywhere, but it’s not always an easy life. Just as all creatures have tormentors, out gut bacteria have viruses that can kill them in a most gruesome way: they sneak into the bacteria and force the poor microbe to produce hundreds of copies of themselves. Finally the viruses are too numerous to fit. They explode out of the bacteria’s body and spread out to infect more bacteria. These special viruses are called phages, which means “eaters”.

Each phage is very particular about which kinds of bacteria they will attack. Unlike broad-brush antibiotics, they home in on a single species and leave other bacteria alone. They are pretty easy to target: you just smear the bacteria you want to kill on a petri dish and let them grow to form a film. Then you place spots of various phages on top. When a clear spot shows up in the dish, that means a phage has obliterated the target bacteria. Just cut out that spot and you have a few million phages, ready to go. Unlike antibiotics that may require multiple rounds to do the job, phages keep multiplying as long as their target exists.

Surprisingly, phages have been known and used for decades — in Eastern Europe. Only recently has the FDA shown an interest. But there are some great anecdotes that are making the FDA sit up and take notice. With antibiotic resistance and all the other problems that come with antibiotics, it’s about time. Phages could represent the medicine of the future.

The Stress of Loneliness

The connection between the brain and the gut goes both ways. Psychobiotics in the gut can soothe your brain, but the brain can also affect your microbes. In a new study from the University of Nottingham, rats raised in isolation showed differences in their gut bacteria as well as changes in anxiety and brain development. The study suggests that life in solitary is no picnic. Early stress can produce lasting changes in gut microbes, leading to abnormal brain and immune function. This in turn can produce abnormal behavior and may play a key role in the development of psychiatric illness.

Early Brain-Gut Experiment

Highly romanticized: Dr. Beaumont experiments on St. Martin’s stomach juices.

We’ve known for a hundred years that the brain can control important aspects of the stomach. In 1822, a fellow named Alexis St. Martin was shot in the stomach and was treated by Dr. William Beaumont, who didn’t expect his patient to live. Against the odds, St. Martin survived, but his body formed a fistula, or a hole, from his stomach to his side. It was pretty much gross and had to be bandaged up to keep stomach acids from squirting out, but Dr. Beaumont was delighted. It gave him an unprecedented living laboratory for studying human digestion.

Seizing the opportunity, Dr. Beaumont took St. Martin on as a servant and semi-willing guinea pig. The doctor extracted  stomach juices through the fistula and had them analyzed. He tied string around different foods, dipping them into the stomach of the amazingly  tolerant St. Martin and then retracting them over time to monitor the digestion process. This catch-and-release strategy illuminated many new details of digestion.

St. Martin, on the other hand, was not always thrilled with these fishing expeditions and sometimes complained. During a particularly acrimonious examination,  Dr. Beaumont found significant changes in the acidity of St. Martin’s stomach juices. Beaumont had discovered something completely unexpected: emotions could directly affect the chemistry of the stomach.

This is not an atypical science story. Science advances when we get new tools, like microscopes and telescopes, that allow us to see things that are normally hidden. Alexis St. Martin’s fistula was just such a scope, providing one of the first windows into a living stomach, and making Alexis the true hero of this story.


How is the immune system involved in schizophrenia?

Schizophrenia, like many mental problems, is poorly understood. We know that nerves in the brain use chemicals called neurotransmitters to talk to each other, and psychiatrists have made a great deal of progress by tweaking these neurotransmitters. Selective serotonin-reuptake inhibitors (SSRIs) have vastly improved the lives of many people suffering from depression by increasing brain levels of the neurotransmitter serotonin. Nevertheless, everyone understands that the brain is complex, with many different neurotransmitters involved in many different parts of the brain. Just “topping off” some of these chemicals may be too simplistic. Schizophrenia, in particular, doesn’t always respond to such straightforward treatments.

A recent case study has shown that, remarkably, a bone-marrow transplant can throw schizophrenia into remission. How in the world is your bone marrow involved with your brain? The answer leads to a new understanding of mental health that is just starting to gain traction: inflammation seems to be behind many cases of mental illness. Inflammation is dealt with by the immune system, and much of that system starts in the bone marrow. How your particular immune system reacts to inflammation was determined when you were just a toddler. Disease, breast feeding and antibiotic treatments all affect how your immune system works. If you were lucky, you got a hardy immune system. If not, you may be stuck with a hinky immune system for the rest of your life — unless you get a bone-marrow transplant.

Inflammation research is leading to a new treatments for everything from depression and anxiety to many kinds of psychosis. The treatments of the future will likely be addressing inflammation — from the gut microbiota to the body’s defense system — rather than merely topping off your neurotransmitters. With depression now being labeled the number one cause of disability in the world, that future can’t come too soon.

Can Psychobiotics help MS?

Multiple sclerosis (MS) is an autoimmune disease with an uncertain cause. However, recent research has linked it to gut microbes. We know that the Western diet, full of processed “foods” and remarkably high in sugar, is associated with many diseases, and we may soon be able to add MS to that list.

Looking like tiny pickles, P. histicola may help treat MS.

What is it about the Western diet that is so unhealthy? It appears to be the impact of those manufactured foods on the microbes that live in the gut, the microbiota. In particular, it seems that a species of helpful bacteria, Prevotella histicola, is being steadily exterminated by the Western diet. That is largely due to the diet’s lack of prebiotics, the fiber that feeds microbes in the colon.

Using a mouse model of MS, researchers found that by feeding the mice P. histicola, they could reduce the symptoms. Apparently P. histicola is able to chill out the immune system and prevent it from attacking the mouse’s own cells. If this work translates into humans, it will be a welcome development, as current treatments can have unpleasant side effects.

Because it affects the brain and because depression is common among MS sufferers, P. histicola acts here as a psychobiotic.


What are Psychobiotics?

As defined by John Cryan and Ted Dinan:

“In 2013, we defined a psychobiotic as a live organism that, when ingested in adequate amounts, produces a health benefit in patients suffering from psychiatric illness. As a class of probiotic, these bacteria are capable of producing and delivering neuroactive substances such as gamma-aminobutyric acid and serotonin, which act on the brain-gut axis. Preclinical evaluation in rodents suggests that certain psychobiotics possess antidepressant or anxiety-reducing activity. Effects may be mediated via the vagus nerve, spinal cord, or neuroendocrine systems.[1] Recently we have suggested broadening the psychobiotic concept to include prebiotics—the fiber that acts as food for the psychobiotics.[2]

[1] Dinan, Timothy G., Catherine Stanton, and John F. Cryan. “Psychobiotics: A Novel Class of Psychotropic.” Biological Psychiatry 74, no. 10 (November 15, 2013): 720–26. doi:10.1016/j.biopsych.2013.05.001.

[2] Sarkar, Amar, Soili M. Lehto, Siobhán Harty, Timothy G. Dinan, John F. Cryan, and Philip W. J. Burnet. “Psychobiotics and the Manipulation of Bacteria–Gut–Brain Signals.” Trends in Neurosciences 39, no. 11 (November 1, 2016): 763–81. doi:10.1016/j.tins.2016.09.002.