Why the future of medicine is all in your gut

It is the culmination of our burgeoning awareness of life in the human gut. Our swirling inner cosmos of microscopic creatures — the gut microbiome — is now known to be more than just a motley crew of strange passengers and potential foes. Instead, it is a fully integrated metabolic co-pilot whose every act may either help to keep us spry or pitch us into chronic sickness.

As a clinician, Hov specialises in primary sclerosing cholangitis (PSC). This chronic inflammatory disease destroys the liver by causing blockages in the bile ducts. Hov believes that dysfunctional gut bacteria can drive patients’ immune systems to attack their livers. By treating specific bacteria in new ways, this may open the way to a new world of therapies.

“In PSC gut inflammation and liver disease are strongly linked. Some 80 per cent of patients have inflammatory bowel disease,” he says. “PSC seems a perfect model for using the microbiome to prove the link between what’s going on in the gut and in the liver.”

Hov is leading a European Research Council-funded project called StopAutoimmunity, which is scanning PSC patients’ blood for genes and chemicals emitted by gut bacteria that may provoke their immune defences into damaging their livers. Once culprits are identified, the project aims to use drugs to block the bacteria from inflicting this damage.

In this way the project aims to significantly improve PSC patients’ treatment and recovery, and also to build new foundations for understanding how gut bugs can provoke autoimmune disease more broadly. Hov is also working with patients with HIV and those with type 2 diabetes to discover if these are triggered by unhealthy gut microbiomes that are causing their bodies to become chronically inflamed.

Scientists believe that bacteria, fungi and viruses in the gut can wreak havoc on numerous organs by leaking toxic substances from the stomach into the bloodstream. These in turn cause persistent inflammation throughout the body.

Inflammation is a keystone of our defence against infection but sustained at high levels, it can seriously damage organs and tissues, and may cause cancer and cardiovascular disease.

In February laboratory studies by researchers at the Oregon Health & Science University in the US reported in the journal Scientific Reports that a potential link had been found between gut biome dysfunction and Alzheimer’s disease — another condition that has an inflammatory element.

What turns our microbiome poisonous? Hov points a finger at changes in our lifestyles and environment. “The incidence of related illnesses such as inflammatory bowel disease has increased significantly in only a few decades. The genetics involved can’t change that quickly,” he says.

“We have only started scratching the surface of diet. But we have found that our patients have been drinking a lot less coffee than the general population. We can speculate that coffee is protective. This has also been found in other groups of liver disease patients.”

Breastfeeding may be another factor, with toxicants in the mother’s milk possibly sending their children’s microbiome awry. “We are at the top of the food chain so are most vulnerable to toxins accumulating through the food chain,” Hov says.

Poor childhood diets may be another cause. In February evolutionary physiologists at the University of California Riverside warned in the Journal of Experimental Biology how their laboratory studies indicate that children who eat high levels of fat and sugar can damage their microbiomes for life, even if they later learn to eat more healthily.

Meanwhile, Hov and colleagues the world over are pioneering microbiome-based treatments for autoimmune and inflammation-based diseases. The bluntest, most impactful therapy is the stool transplant — taking gut microbiome extracts from healthy people and giving them to patients whose illnesses seem driven by gut imbalances.

“Two Dutch microbiome stool transplant trials have improved overweight people’s blood-sugar control, although they did not change their weight. But to change the way the body regulates blood sugar is impressive in itself,” Hov says. “If patients’ symptoms improve, then that is strong evidence. But it is not likely that this will be the final treatment.”

Stool implants don’t only sound unpleasant, they might transmit toxic bacteria that may cause obesity, cardiovascular disease, infections and autoimmune disease. Hov has established a safe donor biobank for stools. “You need to have donors who are screened for disease so that transplants are as safe as possible. The criteria we use are even stricter than for blood donors,” he says.

Probiotic supplements of health-promoting microbes are also being trialled. Hov is giving them to patients with HIV. “The virus attacks immune cells, which are prevalent in the gut,” he says. “People with HIV can have chronic inflammation that causes high levels of cardiovascular disease. Our probiotic trial hints that the treatment has improved inflammation. But the results are not conclusive.”

He also conducted a trial with heart failure patients. “People with heart failure tend to have a different microbiome than healthy people,” Hov says. “With heart failure you may have oedema because your heart isn’t pumping fluids well. Oedema in the bowel wall makes the stomach leaky, which lets toxins into the bloodstream and causes chronic inflammation that further harms the heart.

“In the trial we gave patients a probiotic fungus called Saccharomyces boulardii to see if this could improve heart function. A pilot trial has shown some promise.”

We all know (not least thanks to probiotic yoghurts) how our guts host billions of bacteria. Microbiome science is exploring the rest of the neighbourhood, which involves viruses and fungi. All play their part, individually and collectively.

“Bacteria exist in by far the biggest numbers in our guts,” Hov says. “There are fewer fungi but they are a lot bigger. We know a lot less about them. But it seems like fungi and bacteria interact in the gut. We need to know more.”

Indeed, last month microbiologists at the University of Tennessee warned that eating a high-carb junk-food diet alters the balance of gut fungi in ways that propel obesity.

The study on laboratory mice in the journal Communications Biology found that eating highly processed carbohydrates boosts the abundance of a fungal genus called Thermomyces, while decreasing another genus, called Saccharomyces. This caused metabolic changes that made the mice’s livers unhealthily fatty, raised their blood sugar and increased levels of the “hunger hormone” ghrelin.

Such vast complexities can be multiplied by other factors. For example, bacteria leaking into the bloodstream and sparking chronic inflammation may not be the only way microbiomes hurt us. Hov explains that microbes’ everyday behaviour also produces a miasma of by-products that enter our bloodstream. Some may be beneficial, for example actually reducing inflammation (although this seems to be knocked out by high-salt diets). Other bacterial by-products seem toxic.

“The food we ingest meets our bacteria first, as part of the digestive process. This generates a huge number of metabolic by-products,” Hov says. “Studies measuring the metabolites in the blood of lab mice have shown that these may be driving disease.

“For example,” he says, “TMAO [Trimethylamine N-oxide] may drive arteriosclerosis via systemic inflammation, as has been suggested by studies of mice.” TMAO is formed after we eat choline, a nutrient in red meat, eggs, fish and poultry. As bacteria feed on the choline they produce trimethylamine (TMA). The liver takes that TMA and converts it into TMAO.

“TMAO means we have a link between food, gut bacteria and the by-product that is driving the disease. It may also be happening in type 2 diabetes, with metabolites that influence glucose regulation.

“This provides us with opportunities for treatment. In TMAO mouse studies investigators used drugs to stop the reaction in the bacteria that produces the metabolite and thus improved the creatures’ health. It did not kill the bacteria. It stopped them producing the metabolite. This is the new approach that we call ‘drug the bug’.”

In most conditions, Hov says, the contribution of the microbiome should be investigated. “We have strong indications that we may be able to improve the treatment of autoimmune diseases, along with more common metabolic diseases such as obesity and type 2 diabetes.”

Medical treatments aside, Hov says that we may also enter a world where we each receive personalised eating prescriptions to keep our gut bugs happy. He cites a set of large personalised diet trials conducted on 800 people in Israel that found that some people’s blood sugar levels spike perilously after eating biscuits but respond healthily after eating bananas. Some people, however, respond the opposite way.

“Tests on the volunteers’ microbiomes showed that the results could be used to predict how they would respond to different foods. Scientists could thus design personalised diets for better glucose regulation.”

Certainly the promise of “everyone eat the same probiotic yoghurt and your life will be transformed” now looks obsolete. The era of individually personalised diets awaits.