Australasian Science Magazine

Credit: vchalup/Adobe

By Nick Spencer & Hongzhen Hu

A new treatment for chronic constipation involves sticking lights “where the sun don’t shine”.

The human gastrointestinal tract is more than 6 metres long. Muscle contraction along the gastrointestinal tract, not gravity, is responsible for moving contents along the large lengths of bowel. However, for the muscle cells to contract, the nerves within the gastrointestinal tract must also be activated.

Recently we showed for the first time that pulses of light can be used to stimulate the gastrointestinal tract in conscious mice. These pulses of light caused the gastrointestinal tract to expel content more frequently, leading to improved transit of content along the gut. This new approach, called wireless optogenetics, could be a major step forward in the treatment of a variety of diseases of the gastrointestinal tract associated with reduced transit of the bowel’s contents.

The study, published in June in Gastroenterology (https://goo.gl/c5DBrQ), demonstrated that specific types of nerves in the gastrointestinal tract can be activated with blue light to increase the amount of content expelled from the colon. This means that conventional drugs used to stimulate the gut and improve colonic transit could be a thing of the past. Instead, wireless optogenetics has the potential to improve transit along the gastro­intestinal tract in people.

Improper transit along the gastrointestinal tract is one of the most common concerns in health care. It usually presents in patients as chronic constipation, which is becoming more common as the number of elderly people in nursing homes increases.

Improper transit along the gastrointestinal tract can be caused by many factors. Currently there are limited therapies to improve the condition. While laxatives can reduce constipation, they have a number of unpleasant consequences with repeated use. Despite this, laxative abuse is high in the elderly. Hence there is tremendous interest in developing new techniques to improve transit along the gastrointestinal tract without the use of non-specific drugs that act throughout the body and have a range of side-effects.

How Does Optogenetics Work?

Optogenetics is a relatively new technique that typically involves the activation or inhibition of neurons using different wavelengths of light, usually blue or green light, respectively. The technique offers the unique ability to determine the function of specific types of neurons in complex neural circuits. Optogenetics has been tested as a treatment for a variety of different neurological diseases, including Parkinson’s disease.

The question that is often asked is whether all neurons respond to light and, if not, which ones do? Of course, none of the neurons in the gastro­intestinal tract would normally be exposed to any type of light, let alone respond to it. Therefore, to make gastrointestinal neurons respond to light they must be genetically modified with DNA coding for light-sensitive ion channels.

We decided to genetically target only the excitatory neurons in the gastrointestinal tract. This meant that if the gut was illuminated with blue light, the excitatory neurons would become activated and the muscle cells would contract and expel the waste material. Conversely, illumination of these neurons with green light allows these neurons to be “switched off”.

It has been known for many years that plants and algae express light-sensitive proteins that respond to light and can grow toward the light. The light-sensitive opsin genes that we have inserted into gastrointestinal neurons are the same as those that originally come from algae.

There are two major types of opsins. Channelrhodopsin is a naturally occurring ion channel that causes neurons to become excited when illuminated with blue light. Halorhodopsin is activated by green light and leads to neuronal inhibition.

In our mouse model of the gastro­intestinal tract, we inserted algal channelrhodopsin DNA into neurons in the gut wall. We also implanted wireless-controlled miniature light-emitting diodes onto a single point of the gut wall to selectively activate the excitatory nerves in the colon. When we illuminated blue light onto the gut wall, the light-sensitive neurons responded, causing the muscle cells to contract and expel the gut contents.

Once stimulated, the enteric nervous system is able to propagate the neural activity required to generate contractions along the colon. This is a self-regenerative neural process. So, in other words, once the nervous system is stimulated at a single point with micro-LEDs, it is not necessary to illuminate further down the colon with additional LEDs. The same principles apply in the human gastrointestinal tract.

We believe that light stimulation is a smart way to promote gastrointestinal motility in mice, and could potentially be used in humans once we figure out how to implant and control light-sensitive enteric neurons in humans. The ability to selectively stimulate transit along the gut in live mammals using optical stimulation of specific regions of the intestine could remove the need for non-specific prescription drugs that can induce a long list of unpleasant side-effects.

We are firm believers that light therapy offers major benefits in chronic cases of impaired colonic transit. Our research paves the way to use this technique in humans.