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The ecosystem within: How the microbiome contributes to endocrine regulation

Issue: October 2014

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The cells that make up the gut ecosystem may be microscopic, but they outnumber human cells 10-fold and are powerful enough to promote the progression of diseases, including obesity and diabetes, according to researchers.

New evidence suggests the bacteria based in the gastrointestinal tract — at least 10,000 species strong and weighing more than 4 lb — may actually command behavior by sending signals to the endocrine, immune and nervous systems.

Gut microbes are also sensitive and susceptible to change in a time frame as short as 24 hours, according to research, suggesting humans have the weapon of choice in the battle for the microbiome.

Introducing microbes

Only recently has the microbiome made its way into the spotlight, mostly due to technology, according to Meghan Jardine, MS, MBA, RD, LD, CDE, associate director of diabetes nutrition education for the Physicians Committee for Responsible Medicine in Washington, D.C.

“We now have the methods for evaluating bacteria and genes and the different functions of groups of bacteria living in the gut and how they interact with each other as a community, as well as the human host,” Jardine told Endocrine Today.

Each person has approximately 30 trillion human cells but hosts 100 trillion bacterial and fungal cells, Jardine said in a presentation at the 2014 American Association of Diabetes Educators meeting.

Human genomes encode for 23,000 genes stacked up against the 3.3 million encoded by genomes for bacteria and viruses in the gut, Jardine said.

Although stabilized by age 3 years, gut microbiota are influenced by variables such as birth method, antibiotics, environment, immune function and travel, research has shown.

Joe Alcock, MD, MSCR, of the University of New Mexico, Albuquerque, said the influence of the microbiota likely goes beyond gastrointestinal mechanisms due to the many nerve endings present, even suggesting that gut microbes influence eating habits.

Photo courtesy of Joe Alcock, MD, MSCR.

“Babies are inoculated during vaginal delivery, but miss out on some of the healthier bacteria if they are delivered by cesarean section,” Jardine said. “Breast milk also improves the diversity of bacteria and health of the gut.”

As a registered dietitian and diabetes educator, Jardine has grown her expertise of the microbiome by studying gut bacteria in relation to various eating patterns — specifically how the microbiome factors into obesity and diabetes.

“It may be what makes it so hard for people to lose weight,” Jardine said in an interview. “People with less diversity in the genetic makeup of their microbiota tend to be more obese, and diet can really affect the diversity.”

People who consume a high–fat diet and fewer plants and fiber are losing microbial variety, and sometimes key bacteria, Jardine said.

Mounting research diverges in terms of which specific bacteria to target to remediate disturbances in microbiota, Jardine said. The main phyla, however, can be separated into six categories: primarily Firmicutes and Bacteroidetes, with smaller amounts of Actinobacteria, Proteobacteria, Fusobacteria and Verrucomicrobia.

Shaping communities

The richness of bacterial species in healthy adults is currently characterized by three enterotypes, according to Christina Kafity, RN, BSN, CHC, who owns Bay Area Gastroenterology in Norwalk, Ohio.

“They have a high proportion of Bacteroides, the biosynthesis pathways for biotins and riboflavin, a high proportion of Prevotella, which synthesize thiamin and folate, and a high proportion of Ruminococcus, very important in digestion of cellulose plant cell walls,” Kafity told Endocrine Today.

These conditions flourish in patients who follow a plant-based eating pattern, Kafity said while presenting with Jardine at AADE. Conversely, patients with obesity appear to have increases in Firmicutes and Staphylococcus aureus but a depletion of Bifidobacterium and Lactobacillus, Jardine said.

Children and elderly individuals who consume more plant carbohydrates vs. the standard American diet can have rapid, reproducible alterations of the gut microbiota for the better in a time frame of 24 hours to 1 week, Kafity said.

Appearing in Nature, data from a research letter by David A. Lawrence, MD, of the FAS Center for Systems Biology, Harvard University, and colleagues demonstrated how short-term consumption of an entirely plant or entirely animal diet alters microbial communities and overcomes differences in individuals’ microbial gene expression.

The scientists recruited a small group of volunteers, aged 21 to 33 years, to consume diets rich in grains, legumes, fruits and vegetables, or rich in meats, eggs and cheeses for 5 consecutive days.

Participants were observed for 4 days before obtaining baseline measurements and 6 days after to assess microbial recovery. Food intake was tracked, and gut microbes were tested through daily samples. DNA extracted from fecal samples was sequenced, analyzed and mapped into databases.

Significant macronutrient shifts were observed with both diets. Fecal analysis of short-chain fatty acids (SCFAs) and bacterial clusters suggested these shifts altered metabolic activity. Gene abundance in the plant- and animal-based diets was consistent with herbivorous and carnivorous mammals.

The researchers wrote that their findings “demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.”

Mysterious mechanisms

At Harvard Medical School, Suzanne Devkota, PhD, a Branco Weiss fellow at Joslin Diabetes Center, and colleagues are working to hammer out the metabolic mechanisms behind how bacteria obtain and transfer energy from calories and investigate the potential of energy-harvesting and inflammatory microbes.

Suzanne Devkota

Excitement grew around manipulating gut microbes as a “silver bullet” cure for obesity after seminal studies in rodents by Jeff Gordon, MD, of the Washington University School of Medicine, St. Louis, suggesting that lean mice became obese after receiving stool transfers from obese mice, Devkota told Endocrine Today. But researchers attempting similar studies have had mixed results.

“The current state of what we know in terms of the microbiome and metabolism is based on correlation,” Devkota said. Studies looking at fecal samples in human patients with obesity, type 1 and type 2 diabetes have demonstrated distinct microbial signatures, she said; investigations have been conducted in groups with chronic disease vs. without and also in discordant twins.

“Microbial signatures are starting to be identified that distinguish diabetic or obese from healthy,” Devkota said. “But we don’t really have a mechanism yet.”

Devkota’s research focuses on the gut as a source for the systemic inflammatory responses seen in diabetes and insulin resistance — particularly so-called “pathobionts,” which are present in low levels in healthy individuals but can bloom under certain dietary conditions.

“What is unique about these microbes is they are like a switch,” Devkota said. “They can be pathogenic or they can be neutral.”

The gram-negative lipopolysaccharide (LPS) endotoxins living in cell walls get absorbed into the host due to permeability of the gut lining, Jardine said, noting that high-fat diets are associated with higher serum LPS levels.

“LPS triggers pro-inflammatory cytokines, and that leads to a low-grade inflammation and causes insulin resistance,” she said.

Inflammation affects the secretion of fasting-induced adipose factor (FIAF), which has a ripple effect on lipoprotein lipase and energy metabolism, Jardine said.

“If FIAF is not present to inhibit lipoprotein lipase, the body is going to be storing more fats into adipose tissue,” she said. “It basically slows down the activity of enzymes in mitochondria inside the fat cells and muscle cells.”

With the growth of these microbes causing a very specific immune response that leads to severe inflammation in the gut, Devkota is looking at how intestinal inflammation induced by diet is leaking out into systemic circulation and inducing disease.

“We believe this affects adipose-related inflammation and insulin resistance, as well as autoimmunity,” Devkota said. “The research will be applicable to type 1 and type 2 diabetes.”

Bacteria breakthroughs

The knowledge coming out about the gut microbiome is “eye-opening for many endocrinologists and revolutionary for most,” according to Mark L. Heiman, PhD, chief scientific officer and vice president of research at MicroBiome Therapeutics.

Mark L. Heiman

Heiman said specialists with training and background in the field did not anticipate these developments. “In the past, we never even considered the gastrointestinal microbiome would have anything to do with the endocrine system,” Heiman said. “But now it’s going to be part of the axes.”

Heiman highlighted neuroendocrine axis communication — hormones in the brain stimulate the pituitary, hormones there stimulate the adrenal, creating cortisol that inhibits the hypothalamus — as an example, but said messages travel similarly in the areas of reproduction, thyroid and growth.

“They all work the same way,” Heiman said. “Now, they are going to be extended to include the microbiome.” The stomach and duodenum do not have many bacteria because they are relatively hostile environments, he said. The beginning of the colon is where hundreds of trillions of microbes call home.

“Most of the studies are really focused on the large intestine” Heiman said. “In many cases, we sample that ecosystem by sampling feces; 50% of our stool is bacteria itself.”

Study results published in The American Journal of Clinical Nutrition showed that, in humans, aberrant compositional development of bacteria in the gut precedes overweight and highlighted potential for preventive and therapeutic applications in weight management.

Marko Kalliomäki, MD, of the University of Turku in Finland, and colleagues, analyzed 7-year-old children involved in a follow-up study on probiotics in allergies; 25 were obese or overweight and 24 normal weight. Participants were matched for gestational age and birth BMI, method of delivery, probiotic supplementation, duration of breast-feeding, antibiotic use during infancy, and frequencies of atopic diseases and sensitization.

The researchers analyzed early fecal microbiota composition using fluorescent in situ hybridization (FISH) with microscopic and flow cytometry detection and quantitative real-time polymerase chain reaction (qRT-PCR).

Based on FISH with flow cytometry, bifidobacterial numbers in fecal samples taken during infancy were higher in children who remained normal weight compared with those who became overweight; FISH with microscopic detection and qRT-PCR showed similar tendencies. In children who became overweight compared with those remaining normal weight, microbiota aberrancy during infancy was also associated with a greater number of S. aureus.

Seeking causation

Gut microbiota studies in mice outnumber those in humans 10-fold, Steven E. Shoelson, MD, PhD, a professor of medicine at Harvard Medical School and head of pathophysiology and molecular pharmacology at Joslin Diabetes Center, estimates. This is simply because the research is easier. A mainstay is making mice “germ-free” — something that cannot be done with humans — and testing individual bacteria within a cluster by giving it back to the mice, Shoelson said. However, human feces is an area readily available for testing.

“Fecal material is an imperfect reflection of what’s happening in the gut,” Shoelson said. “Intestinal scrapings may be better, but access to feces may be all we have. Getting biopsies is much more difficult and is not typically done in endocrine patients.”

Two classes of disease entity that have come to the foreground in microbiome research are metabolism and inflammatory bowel diseases, Shoelson said. Similar studies are being done in both, and there is a lot to be learned by comparing them, he added.

“With changes in the bacterial flora, one certainly sees parallel changes in the lining of the gut but also in the cells that participate in preventing invasion of bacteria, which means the immune system is intimately involved,” Shoelson said. “The immune system doesn’t only respond to bacteria in the gut as invaders, but the immune system itself requires exposure to gut bacteria to properly develop critical aspects of the immune system are shaped by exposure to gut bacteria early in development and throughout life.”

Increases in circulating LPS have been documented in obesity, and bacterial changes in the gut have been observed in obesity, but causation has not been determined, he said.

“People have suggested changes in bowel permeability are associated with certain bacteria, and we can see a thickening of certain coatings inside the bowel,” Shoelson said.

Because the microbiome is such a vast and important topic, he said, Harvard researchers are participating in an aggregate of studies, in humans and animals, ranging from fasting and re-feeding effects to the impact of diabetes drugs. “Each of us is only going to put a couple of bricks into this big wall,” Shoelson said. “Hopefully in the end, the wall will support the roof.”

Harvesting energy

Although much of the manipulation of gut microbiota might still remain a mystery, Kafity said she knows firsthand that choosing a plant-based eating pattern creates a positive shift. She and her family lost more than 500 lb and reversed obesity and type 2 diabetes by making the change.

“It’s really simple. You eat more vegetables and fruits, and you have more of the good bacteria because they need those plants to survive,” Kafity said. “You eat high fats, and you’re feeding bad bacteria, and you have a toxic soup in the gut.”

In patients with obesity and diabetes, Kafity highlighted how a lack in diversity and, therefore, microbial imbalance in the gut, known as dysbiosis, set off a string of mechanisms that encourage disease state.

Christina Kafity

At the most severe, “pro-inflammatory diets” can disrupt the gut epithelial barrier sending bacteria or their toxins leaking into the blood system, leading to endotoxemia, according to Devkota. Still, many people unknowingly experience low-grade inflammation, she said.

Devkota likened human beings to doughnuts — hollow in the middle, with the inside exposed to the entire outside world at all times.

“Our gut sees every possible environmental antigen,” Devkota said. “For this reason, it’s a rich source of immune cells.”

With each bacteria having its own relatively “normal” concentration, discovering one or two having detrimental effects on metabolism and one or two having beneficial effects — and figuring out how to increase the good and decrease the bad — could affect metabolic conditions, Shoelson said.

“You can give the bacteria, even orally in pill, so that it opens up when it gets to the colon, and then you can repopulate or increase the population of a particular bacteria. Even up-regulating one might decrease another,” he said.

Gut therapy

Until further research elucidates the microbe roles, consistently feeding the gut army to encourage diversity could arm patients to combat the inflammation.

“You want to improve nutrition at the cellular level,” Kafity said. “The only way you can do that is to eat the proper food and avoid the ones that are going to cause problems.”

Kafity recommends patients opt for fiber as a top strategy, particularly cruciferous vegetables that contain the metabolite glucosinolate, which has been found to protect DNA from damage and inactivate carcinogens, triggering the death of sick cells.

Heiman and fellow researchers launched a business to develop “medical food” and are currently studying the effect of novel gastrointestinal microbiome modulators on diabetes.

The scientists asked a few questions to create the first modulator, NM504: What are people with diabetes eating? What are they eating in abundance? What are they missing?

The novel therapy — composed of bioactive ingredients isolated and purified from foods, including inulin (from the agave plant), beta glucan (from oat) and polyphenolic antioxidant compounds (from blueberries) — addresses a lack of fiber and antioxidants and considers bioavailability and gut lining. Heiman and colleagues conducted a double blind, randomized, placebo-controlled trial in patients with prediabetes and untreated type 2 diabetes. The results were presented in a poster at the 16th International Congress of Endocrinology and the Endocrine Society’s 96th Annual Meeting.

Improved glucose tolerance correlated with decreased circulating levels of alkaline phosphatase, high sensitivity C-reactive protein and total cholesterol. Treatment with NM504 decreased patients’ desire to eat, increased stool immunoglobulin A levels and decreased stool pH. Patients reported mild increase in flatulence.

“We have a combination where we are hitting the microbiome from three parts,” Heiman said.

Heiman said there is a new product that recently completed a proof-of-concept trial showing improved tolerability of metformin in conjunction with the product.

Behavior modification

The influence of the microbiota likely does not stop at gastrointestinal mechanisms, however, with as many nerve endings present in the gut as there are in the brain, according to Joe Alcock, MD, MSCR, of the University of New Mexico, Albuquerque.

“Crosstalk happens all along the neural highway that goes from the gut to the brain,” Alcock told Endocrine Today. “It’s been shown that one way microbes might be able to influence their hosts is through the vagus nerve.”

A recent review of evidence by Alcock and colleagues published in BioEssays suggests microbiota are actually under pressure to manipulate eating behavior to increase their own health, even if that means hurting their host.

“Our review looked at the different ways microbes can affect human behavior, but at this point it is still speculative, and we’re proposing different ways to test these ideas in people,” Alcock said.

The meta-analysis suggests that microbes might strategically generate cravings for foods that either help them or ones that hurt their competition, or they induce dysphoria until the host eats foods that enhance their fitness.

“There are potential avenues for treatment for unhealthy eating and obesity that involve microbiota,” Alcock said.

Interventions might involve specially designed combinations of probiotics or certain specific antibiotics, Alcock said. Others could include doctors targeting the vagus nerve, which Alcock said researchers are already investigating, or fecal transplant.

“Introducing microbes from one person to another might affect the way that we eat, obesity and some other things,” Alcock said. “There is intriguing pilot data where this has been tried in people and it does seem to have an effect on metabolic syndrome. We don’t know yet whether or not it affects eating behavior, but it’s possible and it needs to be tested.”

Everything about the microbiome is experimental, Shoelson said, and everyone is excited.

“Part of the attraction is the ease with which we envision being able to modify and manipulate the gut microbiome, ultimately, when we understand it better,” Shoelson said. — by Allegra Tiver

Do we know enough about the microbiome that it should have role in the management of patients with obesity and diabetes?

We can be confident in sharing this knowledge with patients.

We know approximately 100 trillion, predominantly anaerobic, bacteria reside within the human gut, comprising approximately 800 different bacterial species with over 7,000 strains.  It’s clear that the host and gut microbiota have a mutual relationship; the host provides a safe niche and food supply for the gut microbiota, and the gut microbiota provides protective, metabolic and nutritional signals in health to the host.

Gail Cresci

It has been shown that factors influencing the gut include host age, geographical residence, physiological and psychological stress, medications and diet.

Diet is the primary lifestyle modifier of the gut microbiota. Although more long-term than short-term dietary changes influence shifts in the microbial enterotypes, we can be confident in sharing this knowledge with patients who may be dealing with diseases like diabetes or obesity.

Dietary soluble-fermentable fiber (eg, oligosaccharides or complex polysaccharides) is the primary fuel source for the gut microbiota and include prebiotics. Patients stand to be greatly empowered by learning what good bacteria feed on and produce that beneficially affects them so they can make appropriate choices. Knowing what foods propagate bad bacteria and their resultant negative fermentation byproducts is becoming more apparent.

Disturbances in gut microbiota balance can disrupt intestinal homeostasis. Many factors have been demonstrated to alter the gut microbial balance (eg, antibiotic therapy, alcohol consumption, low-fiber/high-fat diet); and many disease states are linked with alterations in the gut microbial balance (eg, inflammatory bowel disease, obesity, metabolic syndrome, alcoholic and non-alcoholic liver disease).

Animal and human data already reveal that increased body fat and liver fat are linked with altered distributions in gut microbiota, and that weight loss with a carbohydrate and/or fat restricted diet shifts this distribution to that of lean controls.

The Bifidobacterium spp. represent an important and complex group of bacteria, whose presence is often associated with beneficial health effects, with normal weight children and pregnant females. People without diabetes exhibit higher levels of the Bifidobacterium genus compared to people who are overweight and those who have diabetes. This knowledge alone is a launching point to get patients on the path to better health. We may not have the whole picture about the gut microbiota, but we know enough to safely get started.

Gail Cresci, PhD, RD, is Associate Staff in the Department of Gastroenterology and Hepatology and Department of Pathobiology at Cleveland Clinic. Disclosure: Cresci reports no relevant disclosures.

No, we don’t know quite enough.

Right now, the answer is no, we don’t know quite enough. There’s a lot of tantalizing results, but there is no definitive therapy. Do I think there will be enough in the future? Absolutely. We’ll be able to change our microbiome either through diet or through probiotics, and that will help manage these conditions. That’s speculative, of course, but I think it’s likely to happen.

We need to know exactly how diet changes the microbiome in constructive ways that can be used to actually manage people’s glucose levels and obesity — even heart attacks can potentially be managed by our microbiome.

It’s very clear that the microbiome is associated with all these things, but we’re not at a point that we can definitively control this. It’s very clear that people with obesity have a different microbiome than those who don’t have obesity, and likewise for people with diabetes and those who don’t have diabetes. But how to actually control that in a true clinical or therapeutic fashion hasn’t been formally established.

It will come, we just need more research in this area. Among the goals in our microbiome project is to really understand how these things are associated; if we do more studies as to how diet controls the microbiome and metabolism, we will be able to do this, but we’re not quite there.

One of our studies follows people with prediabetes; we want to see how they change during very stressed times such as during respiratory viral infections and also in response to diet perturbation. We hope these kinds of studies will help tell us what’s going on. As people go through different diet regimes, how does that lead to changes in their microbiome? How does that lead to changes in their metabolic state, including their diabetic state?

There will be therapy to come out of this. It may be easier to change the diet than the microbiome itself. Although, in some cases it may be easier to just change the microbiome than the diet.

It’s hard to predict when we’ll have the data we need, but conservatively, within 10 years we’ll be in a much more constructive state than we are now. I hope it’s much faster than that, and frankly I think it will be faster than that. I don’t like to overpromise. If we knew the exact answer, we would be doing it right now, but we don’t, it’s the nature of science, we’re still trying to figure it out.

It’s very important to do these studies in humans because mice have a very different metabolism than humans. As much as they’re a wonderful model for many, many things, including all kinds of human diseases, when it comes to metabolism, there’s a lot of differences. Their hearts beat 600 beats a minute, whereas ours is more like 70 beats, so we’re 10 times slower. Their whole metabolic state is different from a human.

We are looking for how the environment affects diabetes, meaning diet and respiratory viral infections; we had a study published not so long ago suggesting there was a link between respiratory viruses and type 2 diabetes. The study is mine; I got type 2 diabetes after a very nasty respiratory syncytial virus infection. We think these links may exist, and that’s one of the things we’re trying to test in our study.

We also are trying to explore the genetic contribution to diabetes. We’re really trying to get a much more integrative package of the whole thing.

Michael Snyder, PhD, is Professor and Chair of Genetics, at Stanford University in Stanford, California, and Director, Stanford Center for Genomics and Personalized Medicine. Disclosure: Snyder reports no relevant disclosures.