Optogenetic control of the enteric nervous system and gastrointestinal transit

ABSTRACT

Introduction: There are limited effective therapies available for improving gastrointestinal (GI) transit in mammals with intractable or chronic constipation. Current therapeutics to improve GI-transit usually require oral ingestion of therapeutic drugs, such as the serotonin receptor agonist prucalopride. However, most receptors are distributed all over the body and unsurprisingly drugs like prucalopride stimulate multiple organs, often leading to unwanted side effects. There is a desperate need in the community to improve GI-transit selectively without effects on other organs.

Areas covered: We performed a systematic review of the literature on Pubmed and report significant technical advances in optogenetic control of the GI-tract. We discuss recent demonstrations that optogenetics can be used to potently control the activity of subsets of enteric neurons. Special focus is made of the first recent demonstration that wireless optogenetics can be used to stimulate the colon in conscious, freely-moving, untethered mice causing a significant increase in fecal pellet output. This is a significant technical breakthrough with a major therapeutic potential application to improve GI-transit.

Expert opinion: The ability to selectively stimulate the ENS to modulate GI-transit in live mammals using light, avoids the need for oral consumption of any drugs and side effects; by stimulating only the GI-tract.

KEYWORDS:

• Enteric nervous system
• colon
• peristalsis
• gastrointestinal transit
• optogenetics
• wireless optogenetics

Article highlights

• Optogenetics can be used to successfully target specific neurons of interest in the ENS leading to direct stimulation of enteric neurons.

• Wireless optogenetics can now be used to increase gastrointestinal transit in vivo in conscious freely moving animals. This offers many advantages over other conventional therapeutic agents to stimulate the ENS, like tegaserod, that involve oral consumption and can act in many different organs with unwanted side effects.

• There are major advantages of using optogenetics to stimulate the ENS; that includes being able to selectively stimulate only the region of gut that is focally illuminated and being able to instantaneously stimulate the ENS to induce GI motility.

• Disadvantages of using optogenetics to stimulate the ENS include the fact that specific cells of interest must be genetically modified and incorporate foreign DNA. Also, light illumination can inadvertently heat the tissue of interest.

• Recent studies have now shown that harmless adeno-associated viruses can be used to express functional light-sensitive ion channels in non-transgenic animals and respond to photo-illumination.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by grants from the NIH, R01GM101218, R01DK103901 (to HH), Washington University School of Medicine Digestive Disease Research Core Center (NIDDK P30 DK052574), The Center for the Study of Itch of Department of Anesthesiology at Washington University School of Medicine. N J Spencer is supported by NH&MRC of Australia, grants 1156427 & 1156416.