Nav: Home

Our intestinal microbiome influences metabolism -- through the immune system

June 21, 2018

Research tells us that the commensal or "good" bacteria that inhabit our intestines help to regulate our metabolism. A new study in fruit flies, published June 21 in Cell Metabolism, shows one surprising way they do this.

The study, led by Paula Watnick, MD, PhD, of the Division of Infectious Diseases at Boston Children's Hospital, reveals that innate immune pathways, best known as our first line of defense against bacterial infection, have a side job that's equally important.

In the intestine, digestive cells use an innate immune pathway to respond to harmful bacteria. But other intestinal cells, enteroendocrine cells, use the same pathway, known as IMD, to respond to "good" bacteria -- by fine-tuning body metabolism to diet and intestinal conditions.

"Some innate immune pathways aren't just for innate immunity," says Watnick. "Innate immune pathways are also listening to the 'good' bacteria - and responding metabolically."

Metabolic syndrome, fatty liver in flies

Watnick and her colleagues knew from their previous research that bacteria living in flies' intestines make a short-chain fatty acid, acetate, that is essential for the flies' own lipid metabolism and insulin signaling. Flies with no bacteria in their intestines (and hence, no acetate) accumulated fat droplets in their digestive cells. The lab of Norbert Perrimon, PhD, at Harvard Medical School had previously found similar fat droplets in flies whose enteroendocrine cells lacked tachykinin, an insulin-like protein important in growth, lipid metabolism and insulin signaling.

"When there's a problem processing glucose or lipids, fats get stuck in these droplets in cells that are not designed for fat storage," she says.

The new study again used fruit flies, which are easy to breed and manipulate genetically, and have cell types in their intestines much like humans'. When Watnick and colleagues examined flies with mutations in the IMD innate immune pathway, they again saw fat droplets in their intestines.

Watnick believes these fat droplets, whether caused by loss of intestinal bacteria, loss of tachykinin or loss of the innate immune pathway, are the equivalent of fatty liver. Their accumulation is a sign that the body cannot properly metabolize carbohydrates and fats. In essence, Watnick thinks these flies have metabolic syndrome, commonly associated with obesity and type 1 diabetes.

Defining the immune system's role in metabolism

How are intestinal bacteria, the innate immune system and metabolism related? Through a series of experiments, the team began to tease out exactly how bacteria exert their metabolic influence. They showed that:
  • The innate immune pathway spurs enteroendocrine cells to produce tachykinin.
  • In the absence of either bacteria or their breakdown product, acetate, no tachykinin is made.
  • When germ-free flies are given acetate, the innate immune pathway is reactivated and their metabolism normalizes.
  • A specific innate immune receptor on enteroendocrine cells, PGRP-LC, is required to receive the acetate signal.
"We know bacteria control our metabolism, but no one realized that bacteria were interacting with innate immune signaling pathways in enteroendocrine cells," says Watnick. "Maybe these pathways are really a system that allows cells to recognize bacteria for different reasons."

A two-pronged interaction

The study also showed that activation of the innate immune pathway in enteroendocrine cells is essential for normal fly growth and development. When Watnick and colleagues inactivated the pathway, they got growth-stunted flies. Feeding the flies acetate or directly reactivating the innate immune pathway got them growing again.

Though Watnick would now like to confirm these findings in a mammalian model, the study further sketches out what appears to be a two-pronged interaction between our microbiome and our metabolism. Good bacteria ferment nutrients in our diet and release short-chain fatty acids like acetate, which help us optimize our use and storage of nutrients. Pathogenic "bad" bacteria do the opposite: They consume fatty acids, impeding healthful metabolism. An imbalance in our intestinal microbiome has been linked to obesity and sometimes contributes to malnutrition. (More in this comprehensive review article authored by Watnick with lab members Adam Wong and Audrey Vanhove).

And because acetate is produced through fermentation, Watnick and colleagues speculate that eating more fermentable carbohydrates may boost acetate levels and promote good metabolism. Such foods may help counteract imbalances in our gut bacteria, such as those caused by protracted antibiotic use, they suggest.
-end-
Layla Kamareddine, PhD, was first author on the paper. Watnick was senior author. Coauthors were William P. Robins, PhD and John Mekalanos, PhD, of Harvard Medical School, and Cristin D. Berkey, PhD, formerly in Watnick's lab. The study was supported by the National Institutes of Health (R21 AI109436, R01 AI112652 and R01AI018045).

About Boston Children's Hospital

Boston Children's Hospital, the primary pediatric teaching affiliate of Harvard Medical School, is home to the world's largest research enterprise based at a pediatric medical center. Its discoveries have benefited both children and adults since 1869. Today, more than 3,000 scientists, including 8 members of the National Academy of Sciences, 17 members of the National Academy of Medicine and 12 Howard Hughes Medical Investigators comprise Boston Children's research community. Founded as a 20-bed hospital for children, Boston Children's is now a 415-bed comprehensive center for pediatric and adolescent health care. For more, visit our Vector and Thriving blogs and follow us on social media @BostonChildrens, @BCH_Innovation, Facebook and YouTube.

Boston Children's Hospital

Related Immune System Articles:

The immune system may explain skepticism towards immigrants
There is a strong correlation between our fear of infection and our skepticism towards immigrants.
New insights on how pathogens escape the immune system
The bacterium Salmonella enterica causes gastroenteritis in humans and is one of the leading causes of food-borne infectious diseases.
Understanding how HIV evades the immune system
Monash University (Australia) and Cardiff University (UK) researchers have come a step further in understanding how the human immunodeficiency virus (HIV) evades the immune system.
Carbs during workouts help immune system recovery
Eating carbohydrates during intense exercise helps to minimise exercise-induced immune disturbances and can aid the body's recovery, QUT research has found.
A new model for activation of the immune system
By studying a large protein (the C1 protein) with X-rays and electron microscopy, researchers from Aarhus University in Denmark have established a new model for how an important part of the innate immune system is activated.
Guards of the human immune system unraveled
Dendritic cells represent an important component of the immune system: they recognize and engulf invaders, which subsequently triggers a pathogen-specific immune response.
How our immune system targets TB
Researchers have seen, for the very first time, how the human immune system recognizes tuberculosis (TB).
How a fungus inhibits the immune system of plants
A newly discovered protein from a fungus is able to suppress the innate immune system of plants.
A new view of the immune system
Pathogen epitopes are fragments of bacterial or viral proteins. Nearly a third of all existing human epitopes consist of two different fragments.
TB tricks the body's immune system to allow it to spread
Tuberculosis tricks the immune system into attacking the body's lung tissue so the bacteria are allowed to spread to other people, new research from the University of Southampton suggests.

Related Immune System Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Changing The World
What does it take to change the world for the better? This hour, TED speakers explore ideas on activism—what motivates it, why it matters, and how each of us can make a difference. Guests include civil rights activist Ruby Sales, labor leader and civil rights activist Dolores Huerta, author Jeremy Heimans, "craftivist" Sarah Corbett, and designer and futurist Angela Oguntala.
Now Playing: Science for the People

#521 The Curious Life of Krill
Krill may be one of the most abundant forms of life on our planet... but it turns out we don't know that much about them. For a create that underpins a massive ocean ecosystem and lives in our oceans in massive numbers, they're surprisingly difficult to study. We sit down and shine some light on these underappreciated crustaceans with Stephen Nicol, Adjunct Professor at the University of Tasmania, Scientific Advisor to the Association of Responsible Krill Harvesting Companies, and author of the book "The Curious Life of Krill: A Conservation Story from the Bottom of the World".