Our intestinal microbiome influences metabolism — through the immune system

microbiome metabolism concept - in Drosophila. In absence of intestinal bacteria to modulate metabolism, flies develop fat droplets.

Research tells us that the “good” bacteria that inhabit our intestines help to regulate our metabolism. A new study in fruit flies shows one of the ways in which these commensal microbes keep us metabolically fit.

The findings, published today in Cell Metabolism, suggest that innate immune pathways, our first line of defense against bacterial infection, have a side job that’s equally important.

The intestine’s digestive cells use an innate immune pathway to respond to harmful bacteria by producing antimicrobial peptides. 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.

“What’s most interesting to me is that some innate immune pathways aren’t just for innate immunity,” says Paula Watnick, MD, PhD, of the Division of Infectious Diseases at Boston Children’s Hospital. “Innate immune pathways are also listening to the ‘good’ bacteria – and responding metabolically.”

Fly fatty liver

human vs. fly intestine schematicThe fly intestine shares much of the same physiology of the human intestine, just simpler and on a smaller scale. Click to enlarge. (Credit: Adam Wong, modified from Disease Models & Mechanisms. doi: 10.1242/dmm.023408)

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.

Wanting to dig deeper, Watnick’s team again turned to fruit flies, which are easy to breed and manipulate genetically, and have cell types in their intestines much like humans’. They first studied flies with mutations in the IMD innate immune pathway — and again saw fat droplets in their intestines.

Whether caused by loss of intestinal bacteria, loss of tachykinin or loss of the innate immune pathway, the fat droplets are the equivalent of fatty liver, Watnick believes — a sign that the body cannot properly metabolize carbohydrates and fats. Watnick thinks that these flies essentially 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.

Loss of intestinal bacteria, tachykinin or the innate immune pathway left flies unable to properly metabolize carbohydrates and fats. The researchers also showed that 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. “What we don’t know is how it is that the same pathway that defends against disease also regulates metabolism and health. Maybe this pathway is really a recognition system, allowing cells to recognize bacteria for different reasons.”

Two sides of the same coin

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, PhD, and Audrey Vanhove, PhD).

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.

The fine print

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).