Microbes and Us: Health, Disease, Inheritance, and Fecal Transplants

If one is not yet familiar with the term microbiome, the time has come to learn about some interesting scientific developments. Wickipedia tells what the term means.
"A microbiome is the totality of microbes, their genetic elements (genomes), and environmental interactions in a particular environment. The term "microbiome" was coined by Joshua Lederberg, who argued that microorganisms inhabiting the human body should be included as part of the human genome, because of their influence on human physiology."

There is also an associated theory of evolution:

"The hologenome theory proposes that the object of natural selection is not the individual organism, but the organism together with its associated microbial communities."

The human microbiome is the subject of significant scientific studies.

"The Human Microbiome Project (HMP) is a United States National Institutes of Health initiative with the goal of identifying and characterizing the microorganisms which are found in association with both healthy and diseased humans (their microbial flora). Launched in 2008, it is a five-year project, best characterized as a feasibility study, and has a total budget of $115 million. The ultimate goal of this and similar NIH-sponsored microbiome projects is to test if changes in the human microbiome are associated with human health or disease."

A fascinating article in The Economist summarizes for the lay reader some of the developments that are emerging from this field of study.

"WHAT’S a man? Or, indeed, a woman? Biologically, the answer might seem obvious. A human being is an individual who has grown from a fertilised egg which contained genes from both father and mother. A growing band of biologists, however, think this definition incomplete. They see people not just as individuals, but also as ecosystems. In their view, the descendant of the fertilised egg is merely one component of the system. The others are trillions of bacteria, each equally an individual, which are found in a person’s gut, his mouth, his scalp, his skin and all of the crevices and orifices that subtend from his body’s surface."

"A healthy adult human harbours some 100 trillion bacteria in his gut alone. That is ten times as many bacterial cells as he has cells descended from the sperm and egg of his parents. These bugs, moreover, are diverse. Egg and sperm provide about 23,000 different genes. The microbiome, as the body’s commensal bacteria are collectively known, is reckoned to have around 3m."

A human plus the resident bacteria has come to be viewed as an inseparable system.

"In exchange for raw materials and shelter the microbes that live in and on people feed and protect their hosts, and are thus integral to that host’s well-being. Neither wishes the other harm. In bad times, though, this alignment of interest can break down. Then, the microbiome may misbehave in ways which cause disease."

An example is provided to support the notion that humans and their resident microbes have coevolved. Mothers’ milk provides numerous forms of carbohydrates called glycans, but it is only the bacteria we carry that are capable of breaking down these compounds into nourishment.

"They are also better at extracting nutrition from mother’s milk because they turn out lots of an enzyme known as glycoside hydrolase. This converts carbohydrates called glycans, of which milk has many, into usable sugars.’

"That detail is significant. Glycans are indigestible by any enzyme encoded in the 23,000 human genes. Only bacterial enzymes can do the job. Yet natural selection has stuffed milk full of them—a nice example of co-evolution at work."

A number of interesting studies are emerging that indicate the role of these bacteria in regulating bodily functions. One study suggests the bacteria play a role in obesity.

"In 2006 Dr Gordon, who works at the Washington University School of Medicine, in St Louis, Missouri, published a study that looked at the mixture of bacteria in the guts of fat and thin Americans. Fat people, he discovered, had more Firmicutes and fewer Bacteroidetes than thin ones. And if dieting made a fat person thin, his bacterial flora changed to match."

"Experiments on mice suggest this is not just a question of the bacteria responding to altered circumstances. They actually assist the process of slimming by suppressing production of a hormone that facilitates the storage of fat, and of an enzyme that stops fat being burned."

If the web of bacteria can control important hormones and enzymes, then there may be many functions and diseases that are dependent on the behavior of the microbiome.

"Even more surprising than the microbiome’s contribution to diseases of nutrition, though, is its apparent contribution to heart disease, diabetes, multiple sclerosis and many other disorders."

There is, for example, recent data that suggest a role for intestinal bacteria in multiple sclerosis.

"In the case of multiple sclerosis, a confirmatory study was published last year by Kerstin Berer and her colleagues at the Max Planck Institute for Immunobiology and Epigenetics in Freiburg, Germany. They showed, again in mice, that gut bacteria are indeed involved in triggering the reaction that causes the body’s immune system to turn against certain nerve cells and strip away their insulation in precisely the way that leads to multiple sclerosis."

These few studies mentioned are sufficient to motivate researchers to look far afield for other areas in which these bacteria can affect human function. One of the most intriguing involves the hypothesis that bacteria could affect brain function by altering chemical compositions. A particular means by which autism might be triggered has been hypothesized.

"It has been known for a long time that people with autism generally have intestinal problems as well, and that these are often coupled with abnormal microbiomes. In particular, their guts are rich in species of Clostridia. This may be crucial to their condition."

"A well functioning microbiome is not one without internal conflicts—there is competition in every ecosystem, even stable, productive ones. Clostridia kill bacteria competing for their niches with chemicals called phenols (carbolic acid, the first antiseptic, is one such). But phenols are poisonous to human cells, too, and thus have to be neutralised. This is done by adding sulphate to them. So having too many Clostridia, producing too many phenols, will deplete the body’s reserves of sulphur. And sulphur is needed for other things—including brain development. If an unusual microbiome leads to the gut needing extra sulphur, the brain may pay the price by developing abnormally."

"But it is telling that many autistic people have a genetic defect which interferes with their sulphur metabolism. The Clostridia in their guts could thus be pushing them over the edge."

This is clearly an unproven hypothesis—one of many addressing the incidence of autism—but it is not an outrageous idea, and it is an avenue worth pursuing that would not have arisen if researchers had not begun to evaluate people as human microbiomes.

Researchers are also beginning to ask if these bacteria can play a role in inheritance. There seem to be conditions that appear to be inherited, but for which no direct genetic link can be established. Often infants will inherit not only traditional genetic material, but also the genetic material contained in the mother’s microbiome and her immediate environment.

"Though less reliably so than the genes in egg and sperm, microbiomes, too, can be inherited. Many bugs are picked up directly from the mother at birth. Others arrive shortly afterwards from the immediate environment. It is possible, therefore, that apparently genetic diseases whose causative genes cannot be located really are heritable, but that the genes which cause them are bacterial."

One of the reasons these types of findings are so exciting to scientists is that they have the potential to provide an entirely new means to address diseases and conditions that previously were difficult to understand and to treat.

There is one treatment described in the article that appears very effective, although far from ready for FDA approval.

There is a bacterium, Clostridium difficile, that contains strains that are highly resistant to antibiotics. Some people harbor this bacterium in their intestines, but it is generally kept under control by the other resident bacteria. Sick patients in hospitals are susceptible to exposure to this bacterium, and if they are on antibiotics that are strong, but not strong enough to eliminate the Clostridium, the controlling bacteria can be killed leaving the Clostridium to thrive. The result is a dangerously severe case of diarrhea that can cause death.

An approach that seems to work in attacking this bacterium is to reestablish the intestinal bacteria via what has the curious label of "fecal transplant."

"Dr Mellow has found that treating patients with an enema containing faeces from a healthy individual often does the trick. The new bugs multiply rapidly and take over the lower intestine, driving C. difficile away. Last year he and his colleagues announced they had performed this procedure on 77 patients in five hospitals, with an initial success rate of 91%. Moreover, when the seven who did not respond were given a second course of treatment, six were cured. Though faecal transplantation for C. difficile has still to undergo a formal clinical trial, with a proper control group, it looks a promising (and cheap) answer to a serious threat."

Life just keeps getting more complex—and more interesting.