A diverse gut microbiome is now accepted as a key component of healthy living, but UK researchers add another surprising contribution. They report that a metabolite produced by a Clostridium bacterial species in the gut encouraged the repair of nerve injuries in lab mice (Nature, 2022, doi: 10.1038/s41586-022-04884-x).
Nerve damage cannot be self-repaired in the human body, so injuries can lead to life-long impairment. Evidence has piled up that exercise and environmental circumstances can improve the regenerative potential of nerve cells. Intermittent fasting has also been found to promote metabolic pathways involved in wound repair, akin to exercise.
Researchers led by a group at Imperial College London decided to investigate whether intermittent fasting – one day of feeding, one day of fasting – would promote nerve regeneration and recovery in mice with damaged sciatic nerves.
‘That was the case,’ says Simone Di Giovanni at Imperial, ‘and what was striking was that the top metabolites were from gut bacteria, not endogenously produced [by the body].’ When the antibiotic vancomycin was given to the mice, they stopped responding positively to nerve damage. When their serum was examined, a rise in the metabolite indole-3-proprionic acid (IPA) was observed. This is produced by Clostridium sporogenes bacteria.
IPA is a product of bacterial metabolism of the amino acid tryptophan in the lower gut, and its receptor PXR has been implicated in immune responses in several tissues, the study scientists note. PXR activation in vascular cells was previously reported to trigger an inflammatory response and muster neutrophils, the most abundant type of white blood cells in the body.
‘When we gave IPA to animals it promoted regeneration after nerve injury,’ says Di Giovanni. Analysis of RNA sequences around the nerve injury in mice given the IPA suggested neutrophils were involved in repair. When the researchers depleted neutrophils or blocked their movement with monoclonal antibodies, the positive effects of IPA disappeared.
‘Neutrophils seemed to mediate IPA-dependent regeneration [of neurons],’ concludes Di Giovanni. Often, neutrophils encourage inflammation, but in this case the neutrophils seemed to provoke regenerative signals around the damaged nerves.
The results in principle should translate to people, says Di Giovanni, because the sciatic nerve injury in the mice reflects well what happens in humans. It seems that intermittent fasting and IPA could benefit people who are recovering from injury.
‘If you practice intermittent fasting, that primes your system for better capacity to repair following nerve injury,’ says Di Giovanni. ‘This opens the possibility up of consuming IPA following a nerve injury, since the bacteria metabolites are potentially very safe, though this all needs to be tested.’
‘I’m not suggesting that people should go out and drink IPA, unless it’s a beer,’ he quips.
‘There have been studies showing that intermittent fasting can improve the quality of bacterial flora in the gut,’ notes neuroscientist Mark Mattson at Johns Hopkins University in Baltimore, US. He was involved in some of the earliest studies showing intermittent fasting can protect neurons in animals (Annals of Neurology, 1999, 45, 8) and recently published a book, The Intermittent Fasting Revolution: The Science of Optimizing Health and Enhancing Performance.
‘IPA is produced in gut bacteria from the amino acid tryptophan – so foods high in tryptophan (fish, nuts, milk) should increase IPA levels,’ Mattson explains. ‘However, I am not aware of studies that actually measured blood IPA levels after ingesting tryptophan-containing foods. IPA is sold as a dietary supplement, but the quality of such IPA supplements is unclear.’
Mattson adds that the new study did not prove that the IPA coming from the gut bacteria was mediating the beneficial effects caused by intermittent fasting or even that IPA from gut bacteria encouraged nerve repair. ‘They didn’t nail down the amount of IPA that reached the damaged nerve and it could be that there was neuroprotection due to the intermittent fasting’ - and that neurotrophic factors or other mechanisms mediated some of the protection, he adds.