Some very bright spots at year end for metabolism disease research
Amidst the depressing industry news that has been crossing my email lately–allegations of rampant fraud and public deception at BMS and Lilly, respectively, among the more disturbing–I’ve decided to focus one of my final posts of the year on some refreshingly positive basic research news of high therapeutic relevance. I’d classify these two independent research findings, both in the metabolic-disease arena, as genuine breakthroughs.
The first breakthrough, based on research led by Michael Dosch and his colleagues at the Hospital for Sick Children in Toronto, opens up a very promising, novel approach for prevention and early treatment of autoimmune diabetes mellitus (Type 1) and some other autoimmune diseases and, even maybe for Type 2 diabetes mellitus. The research is published in the December 15th issue of Cell.
In short, Dosch’s group, in collaboration with a group from the University of Calgary, has discovered that transient receptor potential vanilloid-1(TRPV1)-secreting afferent sensory neurons play a crucial role in islet inflammation and beta cell function. Islet inflammation is characteristic of Type 1 diabetes, and impaired beta cell function with variable islet inflammation characterizes type 2 diabetes.
Specifically, the group determined that removal of TRPV1+ neurons abrogates immune cell infiltration into the islets of mice genetically prone to developing autoimmune diabetes (called NOD mice), without affecting the autoimmune properties of the immune cells themselves. In other words, the sensory neurons were found to be responsible for accumulation of the destructive autoimmune cells into the pancreatic islets.
Sequencing of the TRPV1 sequence of NOD mice revealed DNA mutations resulting in two amino acid exchanges compared with wild-type that resulted in hypofunctional afferent sensory neurons in NOD mice. These neurons secrete the neuropeptide substance P (sP), which was found to have accumulated in the dorsal root ganglia of NOD mice, consistent with reduced secretion in these animals. Treatment of the NOD mice with sP or selective removal of TRPV1+ neurons prevented immune cell infiltration and the other manifestations of autoimmune diabetes, suggesting that a partially functioning TRPV1-islet cell circuit is causing the disease, and that either replacing the missing neuropeptide(sP) or eliminating the neural circuit can essentially prevent the diease.
This opens up an entirely new prevention/treatment strategy for type 1 diabetes (and prehaps some types of type 2 diabetes, especially the so-called LADA subtype) that has potential to be more effective and far less risky that generalized immunosuppression, which is currently being studied clinically.
The other breakthrough is a bit earlier in its therapeutic potential, but I believe it is no less important or interesting. It concerns the commensal bacteria that live within our guts, a topic I called your attention to this past July. The research, consisting of two related papers by Jeffrey Gordon and his colleagues at the Washington University in St. Louis, is published in the December 21st issue of Nature (Subscription required).
I have long believed that the population-wide increases in obesity we’ve been witnessing in recent human history represent more than meets the eye (see this blog post for a brief essay of my views). One possible hidden explanation is that humans have acquired the ability to become more efficient fuel extractors.
Recall that energy accumulation (in any form) represents that net effects of energy intake and energy expenditure. The two sides of the equation are generally balanced by a complex homeostatic network. Upsetting the balance presumably occurs by incompletely compensated network perturbations. For instance, in most people eating beyond satiety can be compensated only partially by increased energy metabolism before energy accumulation occurs.
Theoretically, one way to upset the balance is to increase the efficiency of energy extraction from the diet. Although it’s widely believed that a calorie-equivalent consumed by one person equates with a calorie-equivalent consumed by another, this is a misconception. Not only do the form of energy (e.g. carbohydrate vs. protein) and the functioning of the gut itself potentially impact the rate and extent of energy absorbed from food and available to the body, it now also appears that the microbes living in our guts play an important role in energy extraction from food.
Gordon and his colleagues have focused their research on two major groups of bacteria, the Bacteroidetes and the Firmicutes, that together make up more than 90 percent of microbes found in the intestines of mice and humans.
Ley et al followed 12 obese patients at a weight loss clinic over a one-year period. Half the patients were given a low-calorie, low-fat diet and half were given a low-calorie, low carbohydrate diet. At the outset of the study, the obese patients had depletion of Bacteroidetes and relative enhancement of Firmicutes. As the patients lost weight, the abundance of the Bacteroidetes increased and the abundance of Firmicutes decreased, irrespective of the diet they were on.
In a companion paper, Turnbaugh, et al compared genes present in the gut microbiome of genetically obese and lean mice using massively parallel DNA sequencing. The results of these so-called comparative metagenomic studies revealed that the obese animals’ microbiome had a greater capacity to digest complex carbohydrates. They then transferred the gut microbes of obese and lean mice to mice that had been raised in a sterile environment (i.e. bacteria-free) and found that the obesity-associated microbiome promoted energy accumulation, as fat, in the recipients.
Dr. Gordon himself raises the key outstanding questions arising from the work:
Are some adults predisposed to obesity because they ’start out’ with fewer Bacteroidetes and more Firmicutes in their guts? Can features of a reduced Bacteroidetes-Firmicutes enriched microbial community become part of our definition of an obese state or a diagnostic marker for an increased risk for obesity? And can we intentionally manipulate our gut microbial communities in safe and beneficial ways to regulate energy balance?
To these questions, I will add another. Will the pharmaceutical industry begin to appreciate the importance of our microbiome to human health and disease beyond drug absorption?
Nature has provided a free educational video describing our gut microflora and its importance on its website.
