Friends for Life: How Good Bugs Keep You Healthy (Op-Ed)
People who follow the hunter-gatherer lifestyle and don't have contact with industrialized cultures tend to have more diverse bacteria in and on their bodies.
Credit: V. Alounian | Science Advances

Jeremy Taylor is author of "Body by Darwin: How Evolution Shapes Our Health and Transforms Medicine" (University of Chicago Press, 2015), a former career science television documentary maker with the BBC, and author of "Not A Chimp: The Hunt For The Genes That Make Us Human" (OUP, 2009). He contributed this article to Live Science's Expert Voices: Op-Ed & Insights.

What is the heaviest organ in the body? Is it the heart? Might it be the liver? Or is it the brain? 

Wrong! It is none of these. The heaviest organ in the human body is the total mass of friendly bacteria — collectively known as the microbiota — in the human gut. In fact, the heart weighs in at a modest 350 grams (12 ounces), the brain at approximately 1.4 kilograms (3.1 lbs.) and the liver up to 1.5 kg (3.3 lbs.). But gut microbes dwarf them all, weighing in at a colossal 2 kilos (4.4 lbs.)! And those 2 kg consist of several tens of trillions of microorganisms — 10 times the number of cells in the entire human body — and 3 million microbial genes, outnumbering the human genome by 150 times. ['Body by Darwin: How Evolution Shapes Our Health and Transforms Medicine' (US 2015): Book Excerpt ]

But in what sense do gut microbes constitute an organ?

It turns out that the bugs in the human gut are massively interconnected through a bewilderingly complex network of chemical signals. Through this system, the microbes "talk" to each other in an analogous way to the chatter among vast networks of neurons and their synapses in the brain. In fact, the gut microbiota has been called the second brain. 

During the last 10 years, human microbiota research has burgeoned, because it has become increasingly obvious that these friendly bugs are essential for human health. People cannot live without them. When they are absent or depleted, people fall prey to the misery of a variety of allergic and autoimmune diseases, along with other illnesses.[How Gut Microbes Affect Your Health ]

Gut-triggered illness, and cures

For example, only this October, a team of researchers at the University of North Carolina School of Medicine in Chapel Hill examined women of low weight attending an eating-disorders clinic for treatment of anorexia nervosa. These women had very abnormal gut microbes, with the mix of species differing from that in un-affected individuals, the researchers found. Gut microbes were less abundant, and the microbial species were less diverse. All this greatly improved as the patients gained weight under treatment and were released from clinical care. But had the microbes caused the anorexia, or had the anorexia depleted the microbes? [The Microbes in Your Gut May be Making You Fat ]

The researchers decided that the eating disorder changed the composition of the microbiota, which then communicated with the brain so as to contribute to the anxiety, depression, and further weight loss that attend the illness. As the patients' health improved and they put on weight, the gut microbial population crept back toward normal, and the depression and anxiety lifted.

Studies like this pile up almost daily in the science media. There's now evidence that a healthy gut microbiota can help prevent metabolic syndrome, which increases a person's risk of contracting heart disease, diabetes and stroke. It protects against obesity and lowers inflammation, as shown by reduced inflammatory indicators in the blood, like C-reactive protein. 

Establishing a healthy microbial gut population in very young children seems to protect them against asthma, and some studies find that healthy gut microbes also protect against eczema, hay fever and food allergies. There's evidence that friendly bacteria like Bifidobacterium and Bacteroides increase the efficacy of anti-cancer immunotherapy. Studies also show that gut microbes stimulate the production of a powerful anti-oxidant, glutathione, which fights type 2 diabetes, atherosclerosis and non-alcoholic fatty liver disease. 

It has even been discovered that a friendly variant of the bacterium E. coli, which is common in the gut, can mobilize complement proteins in the innate immune system to recognize and blast apart Plasmodium parasites injected into the bloodstream in mosquito-infested parts of the world. This gives individuals high natural immunity to malaria

Is there anything these little critters cannot do?

Microbes manipulating brains

The spookiest aspect of gut microbes' impact, however, is the idea that they actually manipulate the way animals and people think. For example, scientists took two strains of mice, one bold and the other timid. Some of the mice were reared normally, so that their guts contained populations of bacteria, and some of the mice were reared in a germ-free environment so that their guts were sterile. They then injected the gut contents of normally reared, bold mice into germ-free timid mice, and vice versa. Timid mice became bold, and bold mice became timid. The results showed that the microbiota injections altered mouse behavior as if the scientists were flipping a switch. In another experiment, mice fed a broth rich in a classic probiotic bacterium, Bifidobacterium, became bold and adventurous and much less likely to give up and float on a forced-swim test. 

In a similar experiment performed on people, Emeran Mayer, a professor in the departments of medicine, physiology and psychiatry and biobehavioral sciences at UCLA, who is both a gastroenterologist and neuroscientist, together with research associate Kirsten Tillisch, treated one group of women with fermented probiotic drinking yogurt, while another group did not take the yogurt. The women then took a psychological test, which involved looking at a range of emotional facial expressions. The yogurt drinkers had much calmer emotional reactions in those parts of their brains involved in processing emotional stimuli than did the untreated women. The bugs were talking to the women's brains long-distance, using the vagus nerve to make the connection. Specifically, the researchers used fMRI brain-imaging to identify a tract of nerve fibers in the brainstem called the tractus solitarius. This was shown to receive inputs from the vagus nerve and pass them on to the amygdala, the insula, and the anterior cingulate cortex.

Meanwhile, Joe Alcock, an evolutionary medicine researcher at the University of New Mexico, together with Carlo Maley and Athena Aktipis of The Center for Evolution and Health at Arizona State University, have pulled together a sheaf of evidence that suggests that gut microbes can make their human hosts crave foods that will give the microbes a competitive edge in the large intestine. It appears that they can induce profound states of unease or dissatisfaction in people until they are sensually rewarded by particular food, like chocolate, that the bugs also hanker for. 

Could scientists handcraft a particular mix of bacterial species for people's guts specifically designed to change eating habits and ward off obesity?

Friends for life

Gut microbes are literally friends for life for their hosts. At birth, a baby's microbiota becomes rapidly established, because Lactobacilli(probiotic microbes common in yogurt, for instance), which are profuse in the mother's vagina, are involuntarily swept into the baby's mouth and ingested as the infant forces its way down the vagina and into the world. The breast milk the baby receives soon afterward pumps more than 100 million immune cells into the baby every day, together with a wide variety of friendly bacterial species that have been translocated from the mother's large intestine, via her lymphatic system, to the mammary glands. Once resident in the baby's large intestine, these friendly bacteria go about protecting the baby from harmful pathogens, and building and maturing the immune system. 

However, this elegant evolutionary mechanism is at the mercy of contemporary culture. Some studies suggest that obese women have a poorer, more species-depleted microbiota than lean women, which, if they breast-feed, is passed on to the baby. That can result in the child inheriting the obese metabolic settings of the mother. Mothers who have been given strong doses of broad-spectrum antibiotics will be similarly compromised — the good bugs are flushed away with the bad — which then compromises the baby. 

Bottle-fed babies are initially colonized by high levels of potentially harmful bugs like Clostridium and Enterococcus, and strong associations between babies born via cesarean section or C-section, and later susceptibility to allergies, celiac disease, obesity, type I diabetes and even autism, have been shown.

Maria Dominguez-Bello, who studies host-microbial interactions at the NYU School of Medicine, and colleagues from the United States and Puerto Rico, became so worried by the downside of C-section that they did a pilot study in which they incubated gauze swabs for one hour in the vaginas of women electing for C-section. As soon as the baby was surgically removed from the womb, it was painted, first in the mouth, then over its entire body, with the swabs. This resulted in the effective establishment of a rich and diverse gut microbiota.

Beyond the bacteria

Friendly bacteria are not the only long-term residents in peoples’ guts. Until the last century, most people in Westernized parts of the world were infected by parasitic gut worms, collectively known as helminths. These infections are still rife in the undeveloped world, and humans have hosted helminths, as they have hosted friendly bacteria, throughout pre-history. Since the middle of the last century, scientists have noticed that levels of a number of autoimmune diseases — including diabetes, multiple sclerosis and various irritable bowel syndromes — have all risen sharply. All these diseases are associated with affluence, which means they are associated with high levels of hygiene with the consequent removal of helminths from people's environment. This is mirrored by the discovery, from, admittedly, a few very preliminary trials, that experimental introduction of helminths, by inserting them under the skin, or ingestion of their eggs, can often ameliorate these conditions, as well as some allergies.

What, precisely, is the link between helminths and friendly bacteria and all these "modern" diseases? Throughout evolutionary time, these organisms have chronically infected humans, because the bugs were ubiquitous in the environment. And because, until the advent of modern medicine, they could not be removed, people had to tolerate the organisms rather than seek to eradicate them through permanently raging, inflammatory immune systems. Similarly, long-term gut parasites, be they bacteria or worms, needed to hide from our immune systems to prevent themselves from being attacked. They found the answer in taking over the regulation of our immune systems by controlling the production of the regulatory T-cells that hold immune action in check and damp down inflammation. Humans have co-evolved with these organisms such that people's immune settings have evolved to be appropriate to the presence of these organisms.

So, when people remove all these bacteria and helminths through obsessive hygiene, sterile food processing and detergents that kill 99.9 percent of household germs, immune systems overshoot and start attacking people, giving rise to the worrying spectrum of allergic and autoimmune disorders seen today. 

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The discovery of this long-time evolutionary dimension to humans' relationship with microbiota has resulted in the hygiene hypothesis. This seeks to explain allergy and autoimmunity as a function of the depletion of these microorganisms, being recently re-named the "old friends" hypothesis.

A group of researchers in Dublin and the London School of Hygiene and Tropical Medicine found an extraordinary clue to this evolutionary history. Huge numbers of people worldwide suffer from allergies, the researchers acknowledged. But why do they suffer from specific allergens, like birch pollen or peanut? The researchers examined thousands of protein sequences from common allergens and compared these to protein sequences from parasitic worms. The investigators found more than 200 protein sequences common to both allergens and worms

It seems peoples' bodies mistake the antigen signature of a range of common allergens for the presence of parasites, and immediately mount an immune attack. But because the helminths are no longer present, there is nothing to regulate that off-target attack. This sentences millions of people to swollen, runny nasal passages; unsightly skin irritation; and even anaphylactic shock.

Much "old friends" scientific research is just that — research — at the moment, and it cannot be stressed too strongly that such human trials as have been done are either small, have demonstrated only mixed success, or are one-off attempts by private individuals to self-medicate. 

Nevertheless, researchers worldwide are urgently investigating new probiotic products and trying to isolate the active ingredients from helminths. The target is an evolutionary medicine to combat a raft of modern diseases that society has brought upon itself through a mismatch between an ancient evolved relationship with worms and bacteria and the way people live today. It represents one of the most active current areas of evolutionary health research, and if ultimately successful, will come as good news for any sufferers of allergy and autoimmunity.

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