Intermittent fasting can help heal nerve damage by altering the gut microbiome.

Intermittent fasting alters gut bacterial activity in mice, increasing their ability to recover from nerve damage.

Scientists observed how fasting caused the gut bacteria to increase production of a metabolite known as 3-indolepropionic acid[{” attribute=””>acid (IPA). This potent neuroprotective antioxidant is required for regenerating nerve fibers called axons – thread-like structures at the ends of nerve cells that send out electrochemical signals to other cells in the body. The new research is published in Nature and was conducted by researchers from Imperial College London.

Although this novel mechanism was discovered in mice, it is hoped to also hold true for any future human trials. The research team states that the bacteria that produce IPA, Clostridium sporogenesis, is found naturally in the guts of humans as well as mice and IPA is present in human bloodstreams too. 

“There is currently no treatment for people with nerve damage beyond surgical reconstruction, which is only effective in a small percentage of cases, prompting us to investigate whether changes in lifestyle could aid recovery,” said study author Professor Simone Di Giovanni from Imperial’s Department of Brain Sciences.

“Intermittent fasting has previously been linked by other studies to wound repair and the growth of new neurons – but our study is the first to explain exactly how fasting might help heal nerves.”

Fasting as a potential treatment

The experiment assessed nerve regeneration of mice where the sciatic nerve, the longest nerve running from the spine down the leg, was crushed. Half of the mice underwent intermittent fasting (by eating as much as they liked followed by not eating at all on alternate days), while the other half were free to eat with no restrictions at all. These diets continued for a period of 10 days or 30 days before their operation, and the mice’s recovery was monitored 24 to 72 hours after the nerve was severed.

The length of the regrown axons was measured and was about 50% greater in mice that had been fasting.

Professor Di Giovanni said, “I think the power of this is that opens up a whole new field where we have to wonder: is this the tip of an iceberg? Are there going to be other bacteria or bacteria metabolites that can promote repair?”

Investigation reveals metabolism link

The scientists also studied how fasting led to this nerve regeneration. They discovered that there were significantly higher levels of specific metabolites, including IPA, in the blood of diet-restricted mice.

To confirm whether IPA led to nerve repair, the mice were treated with antibiotics to clean their guts of any bacteria. They were then given genetically-modified strains of Clostridium sporogenesis that could or could not produce IPA.

“When IPA cannot be produced by these bacteria and it was almost absent in the serum, regeneration was impaired. This suggests that the IPA generated by these bacteria has an ability to heal and regenerate damaged nerves,” Professor Di Giovanni said. 

Importantly, when IPA was administered to the mice orally after a sciatic nerve injury, regeneration and increased recovery were observed between two and three weeks after injury.

The next stage of this research will be to test this mechanism for spinal cord injuries in mice as well as testing whether administering IPA more frequently would maximize its efficacy.

“One of our goals now is to systematically investigate the role of bacteria metabolite therapy.” Professor Di Giovanni said.

More studies will need to investigate whether IPA increases after fasting in humans and the efficacy of IPA and intermittent fasting as a potential treatment in people.

He said: “One of the questions that we haven’t explored fully is that, since IPA lasts in blood for four to six hours in high concentration, would administering it repeatedly throughout the day or adding it to a normal diet help maximize its therapeutic effects?”

Reference: “The gut metabolite indole-3 propionate promotes nerve regeneration and repair” by Elisabeth Serger, Lucia Luengo-Gutierrez, Jessica S. Chadwick, Guiping Kong, Luming Zhou, Greg Crawford, Matt C. Danzi, Antonis Myridakis, Alexander Brandis, Adesola Temitope Bello, Franziska Müller, Alexandros Sanchez-Vassopoulos, Francesco De Virgiliis, Phoebe Liddell, Marc Emmanuel Dumas, Jessica Strid, Sridhar Mani, Dylan Dodd and Simone Di Giovanni, 22 June 2022, Nature.
DOI: 10.1038/s41586-022-04884-x

Intermittent fasting can help heal nerve damage by altering the gut microbiome.

Intermittent fasting alters gut bacterial activity in mice, increasing their ability to recover from nerve damage.

Scientists observed how fasting caused the gut bacteria to increase production of a metabolite known as 3-indolepropionic acid[{” attribute=””>acid (IPA). This potent neuroprotective antioxidant is required for regenerating nerve fibers called axons – thread-like structures at the ends of nerve cells that send out electrochemical signals to other cells in the body. The new research is published in Nature and was conducted by researchers from Imperial College London.

Although this novel mechanism was discovered in mice, it is hoped to also hold true for any future human trials. The research team states that the bacteria that produce IPA, Clostridium sporogenesis, is found naturally in the guts of humans as well as mice and IPA is present in human bloodstreams too. 

“There is currently no treatment for people with nerve damage beyond surgical reconstruction, which is only effective in a small percentage of cases, prompting us to investigate whether changes in lifestyle could aid recovery,” said study author Professor Simone Di Giovanni from Imperial’s Department of Brain Sciences.

“Intermittent fasting has previously been linked by other studies to wound repair and the growth of new neurons – but our study is the first to explain exactly how fasting might help heal nerves.”

Fasting as a potential treatment

The experiment assessed nerve regeneration of mice where the sciatic nerve, the longest nerve running from the spine down the leg, was crushed. Half of the mice underwent intermittent fasting (by eating as much as they liked followed by not eating at all on alternate days), while the other half were free to eat with no restrictions at all. These diets continued for a period of 10 days or 30 days before their operation, and the mice’s recovery was monitored 24 to 72 hours after the nerve was severed.

The length of the regrown axons was measured and was about 50% greater in mice that had been fasting.

Professor Di Giovanni said, “I think the power of this is that opens up a whole new field where we have to wonder: is this the tip of an iceberg? Are there going to be other bacteria or bacteria metabolites that can promote repair?”

Investigation reveals metabolism link

The scientists also studied how fasting led to this nerve regeneration. They discovered that there were significantly higher levels of specific metabolites, including IPA, in the blood of diet-restricted mice.

To confirm whether IPA led to nerve repair, the mice were treated with antibiotics to clean their guts of any bacteria. They were then given genetically-modified strains of Clostridium sporogenesis that could or could not produce IPA.

“When IPA cannot be produced by these bacteria and it was almost absent in the serum, regeneration was impaired. This suggests that the IPA generated by these bacteria has an ability to heal and regenerate damaged nerves,” Professor Di Giovanni said. 

Importantly, when IPA was administered to the mice orally after a sciatic nerve injury, regeneration and increased recovery were observed between two and three weeks after injury.

The next stage of this research will be to test this mechanism for spinal cord injuries in mice as well as testing whether administering IPA more frequently would maximize its efficacy.

“One of our goals now is to systematically investigate the role of bacteria metabolite therapy.” Professor Di Giovanni said.

More studies will need to investigate whether IPA increases after fasting in humans and the efficacy of IPA and intermittent fasting as a potential treatment in people.

He said: “One of the questions that we haven’t explored fully is that, since IPA lasts in blood for four to six hours in high concentration, would administering it repeatedly throughout the day or adding it to a normal diet help maximize its therapeutic effects?”

Reference: “The gut metabolite indole-3 propionate promotes nerve regeneration and repair” by Elisabeth Serger, Lucia Luengo-Gutierrez, Jessica S. Chadwick, Guiping Kong, Luming Zhou, Greg Crawford, Matt C. Danzi, Antonis Myridakis, Alexander Brandis, Adesola Temitope Bello, Franziska Müller, Alexandros Sanchez-Vassopoulos, Francesco De Virgiliis, Phoebe Liddell, Marc Emmanuel Dumas, Jessica Strid, Sridhar Mani, Dylan Dodd and Simone Di Giovanni, 22 June 2022, Nature.
DOI: 10.1038/s41586-022-04884-x

Summary: Intermittent fasting alters gut bacteria in mice, facilitating damaged nerves’ ability to recover.

Source: Imperial College London

Intermittent fasting alters gut bacterial activity in mice, increasing their ability to recover from nerve damage.

The new study is published in Nature and was conducted by researchers from Imperial College London.

They observed how fasting caused gut bacteria to increase production of a metabolite called 3-indolepropionic acid (IPA), which is needed for the regeneration of nerve fibers called axons — thread-like structures at the ends of nerve cells that send electrochemical signals to them other body cells.

This novel mechanism was discovered in mice and will hopefully apply to all future human studies as well. The team states that the bacterium that produces IPA, Clostridium sporogenesis, occurs naturally in the intestines of humans and mice, and that IPA is also present in the human bloodstream.

“There is currently no treatment for people with nerve damage beyond surgical reconstruction that is effective in only a small percentage of cases, prompting us to explore whether lifestyle changes could aid recovery,” study author Professor said Simone Di Giovanni from Imperial’s Department of Brain Sciences.

“Intermittent fasting has previously been linked to wound healing and the growth of new neurons by other studies – but our study is the first to explain exactly how fasting might help nerve healing.”

Fasting as a possible treatment

The study evaluated nerve regeneration in mice that had their sciatic nerve, the longest nerve that runs down the leg from the spine, crushed. Half of the mice underwent intermittent fasting (eating as much as they wanted followed by nothing on alternate days), while the other half were free to eat without restriction.

These diets were continued for a period of 10 days or 30 days before their surgery, and the mice’s recovery was monitored 24 to 72 hours after the nerve was transected.

The length of regrown axons was measured and found to be approximately 50% greater in fasted mice.

Professor Di Giovanni said: “I think the power of this is that it opens up a whole new field where we have to ask ourselves: is this the tip of an iceberg? Will there be other bacteria or bacterial metabolites that can promote repair?”

Examination shows a metabolic connection

The researchers also looked at how fasting led to this nerve regeneration. They found that there were significantly higher levels of specific metabolites, including IPA, in the blood of mice on a restricted diet.

To confirm whether IPA led to nerve repair, the mice were treated with antibiotics to rid their gut of bacteria. They were then given genetically engineered strains of Clostridium sporogenesis that may or may not produce IPA.

“When IPA cannot be produced by these bacteria and it was almost absent in the serum, regeneration was impaired. This suggests that the IPA produced by these bacteria has the ability to heal and regenerate damaged nerves,” said Professor Di Giovanni.

When mice were given IPA orally after sciatic nerve injury, regeneration and increased recovery were observed between two and three weeks after injury.

The next step in this research will be to test this mechanism in spinal cord injury in mice and see if more frequent administration of IPA would maximize its effectiveness.

“One of our goals now is to systematically investigate the role of bacterial metabolite therapy,” said Professor Di Giovanni.

Further studies need to investigate whether IPA increases after fasting in humans and the effectiveness of IPA and intermittent fasting as potential treatments in humans.

He said: “One of the questions we haven’t fully investigated is that since IPA stays in the blood for four to six hours at high concentrations, repeated dosing throughout the day or adding it to a normal diet would help to maximize the therapeutic effect?

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About this news from neuroscientific research

Author: press office
Source: Imperial College London
Contact: press office – Imperial College London
Picture: The image is in the public domain

Original research: Closed access.
“The gut metabolite indole-3-propionate promotes nerve regeneration and repair” by Elisabeth Serger et al. Nature

abstract

The gut metabolite indole-3-propionate promotes nerve regeneration and repair

The regenerative potential of mammalian peripheral nervous system neurons after injury is critically limited by their slow axonal regeneration rate.

The ability to recover is influenced by both injury-dependent and injury-independent mechanisms. Among the latter, environmental factors such as exercise and environmental enrichment have been shown to affect signaling pathways that promote axonal regeneration.

Several of these signaling pathways, including modifications in gene transcription and protein synthesis, mitochondrial metabolism, and neurotrophin release, can be activated by intermittent fasting (IF). However, whether IF affects axonal regenerative capacity remains to be investigated.

Here we show that IF promotes axonal regeneration after sciatic nerve crush in mice through an unexpected mechanism that relies on the gram-positive gut microbiome and an increase in the serum gut bacteria-derived metabolite indole-3-propionic acid (IPA).

IPA production of Clostridium sporogenes is required for efficient axonal regeneration, and administration of IPA after sciatic injury significantly improves axonal regeneration and accelerates recovery of sensory function. Mechanistically, RNA sequencing analysis from sciatic dorsal root ganglia suggested a role for neutrophil chemotaxis in the IPA-dependent regenerative phenotype, which was confirmed by inhibition of neutrophil chemotaxis.

Our results demonstrate the ability of a microbiome-derived metabolite such as IPA to facilitate regeneration and functional recovery of sensory axons through an immune-mediated mechanism.