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What Is Motilin? Function & Role in Gut Health

Written by Carlos Tello, PhD (Molecular Biology) | Reviewed by Nattha Wannissorn, PhD | Last updated:
Puya Yazdi
Medically reviewed by
Puya Yazdi, MD | Written by Carlos Tello, PhD (Molecular Biology) | Reviewed by Nattha Wannissorn, PhD | Last updated:

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Motilin is a very important protein in the digestive system. It helps move food through the digestive tract by causing muscle contractions. Read on to learn more about this hormone, its effects on the body, and complications associated with its abnormal levels.

What Is Motilin?

Motilin is a hormone produced by cells in the small intestine. Its name comes from its ability to stimulate the movement (motility) of the digestive organs. Its main function is to cause movement and emptying of the digestive tract by initiating intestinal muscle contractions [1, 2].

Blood motilin rises during fasting periods and after digesting a meal, but its levels drop during food consumption. Its release is influenced by water, fat, and pressure in the digestive system (mechanically-induced release) [1, 2, 3].

Motilin secretion in the small intestine is crucial because this organ is responsible for digestion and nutrient absorption. Motilin release is strongly blocked during pregnancy [1, 2, 3].

Motilin Function

Motilin regulates the migrating motor complex (MMC). This complex is involved in the muscle activity of the digestive system. In humans, MMC activity starts in the upper gut [2, 4].

The MMC has a few phases, where the most important one, phase III, is controlled by motilin. This stage involves a burst of muscle contractions originating at the beginning of the small bowel (duodenum) and moving along all the way to the end. Phase III is also involved in hunger [5, 4, 2, 1].

Motilin increases the action of acetylcholine, which is a neurotransmitter that causes intestinal muscles to contract in the gut [4, 2, 1].

This process clears the small bowel of undigested food, preventing bacterial overgrowth and stimulating hunger. Additionally, it ensures that leftover debris does not block nutrient absorption, which increases the risk of nutrient deficiency [4, 2, 1].

Migrating Motor Complex (MCC) and the Vagus Nerve

The vagus nerve is a major component in the rest-and-digest (parasympathetic) nervous system). This nerve controls the migrating motor complex (MMC) in the stomach. Cutting this nerve stops MMC activity in the stomach, but not in the small intestine (MMC phase III intact) [6, 4, 1].

While the vagus nerve regulates levels of digestive hormones like gastrin and other pancreatic enzymes, it does not control motilin levels. However, in an experiment where the vagus nerve of dogs got blocked, motilin levels had a higher peak during phase III of MMC [6, 4, 1].

Motilin Receptors

Motilin receptors are found along the digestive tract (stomach, small bowel, and colon). The highest concentration of human receptors for motilin is found in the narrow part of the stomach (pyloric antrum). These receptors are functionally (and possibly structurally) different from those found in other species like rabbits [7, 8].

Motilin receptors are also found in the brains of mice, although whether this is also the case for humans remains unknown [9].

Health Aspects

Motilin levels rise and fall throughout the day cyclically. The measurement of blood motilin levels requires fasting for about 10 hours before the test. One study on 38 healthy individuals saw a big variation in fasting blood motilin ranges (50-545 pg/mL, with an average of 217 pg/mL) [10].

Abnormally high motilin levels may cause some negative health effects, while supplementing with motilin has some potential benefits (aside from the normal functions of this hormone in the body) [2].

High Motilin Associations With Disease

The following conditions have been linked to high motilin levels in association studies, meaning a cause-and-effect relationship has not been established. Nevertheless, work with your doctor to identify and treat any underlying conditions that may be causing your high motilin levels.

Ulcerative Colitis

In a study on 26 people with ulcerative colitis (inflammation and ulcers in the digestive tract), their motilin levels were unusually high (350-1000 pg/mL) [11].

Increased food movements and small intestinal contractions due to high motilin levels may cause diarrhea and acidification of the digestive tract (because bicarbonate release to balance acid levels is obstructed) [11].

Diabetes

In a study on 70 people, those with diabetes tended to have higher fasting motilin levels. Although there was a certain overlap between healthy and diabetic individuals at about 200-400 pg/mL, only diabetics had blood motilin levels greater than 550 pg/mL [10].

Potential Benefits of Motilin Supplementation

The following purported benefits are only supported by limited, low-quality clinical studies (diabetic gastroparesis) or only animal studies (anxiety). There is insufficient evidence to support the use of motilin for any of the below-listed uses. Remember to speak with a doctor before taking motilin supplements and never use it as a replacement for approved medical therapies.

Diabetic Gastroparesis

Nerve damage is common in diabetics due to the high blood sugar levels. If it affects the digestive system, it can cause problems such as constipation (diabetic gastroparesis) [12].

In a small trial on 9 diabetic patients with this complication, intravenous motilin therapy restored stomach emptying [12].

Anxiety

In a study in mice, direct motilin injection into the brain significantly decreased anxiety. The effect was reversed with a motilin receptor blocker (GM-109) [9].

Motilin Drug Interactions

Molecules that mimic the structure and action of motilin are of high interest to researchers attempting to develop new therapeutic drugs. Those that increase the activity of motilin receptors, also called motilides, help reduce nausea and increase gastric emptying (in diabetics). The most important phase (III) of the migrating motor complex (MMC) can be triggered by the administration of motilin and other functionally similar drugs [13].

Drugs that block motilin receptors are also a growing field of research. In theory, these drugs help with digestive conditions caused by too much food movement in the bowels (hypermotility). They have potential use in treating conditions like diarrhea and irritable bowel syndrome (IBS) [1].

Motilides (Motilin Receptor Activators)

Erythromycin

Erythromycin, an antibiotic normally used to treat infections, is also a potent activator of motilin receptors. In a clinical trial on 14 healthy volunteers, erythromycin stimulated hunger and food intake [5].

ABT-229, an erythromycin derivative, strongly increased gastric emptying with a single dose (4-16 mg) in a clinical trial on 9 healthy volunteers [14].

Azithromycin

Another antibiotic, azithromycin, can also activate motilin receptors in a similar way to erythromycin. In a clinical trial on 120 people with delayed stomach emptying (gastroparesis), both azithromycin and erythromycin were similarly effective but azithromycin had fewer adverse effects [15].

Camicinal

In 3 clinical trials on 29 healthy volunteers, camicinal helped improve stomach emptying and heartburn (gastroesophageal reflux disease) at single doses of 125 and 150 mg [16, 17, 18].

Altimotin

In 2 clinical trials on 58 healthy volunteers, intravenous altimotin increased gut motility [19, 20].

Mitemcinal (GM-611)

In 2 clinical trials on almost 500 diabetic people with gastroparesis, mitemcinal (5-10 mg) improved stomach emptying [21, 22].

Motilin Receptor Blockers (Antagonists)

Experimental motilin blockers (MA-2029 and GM-109) reduced bowel contractions in rabbits and dogs, and helped treat diarrhea caused by motilin administration [23, 24, 25].

Motilin administration into the brain significantly reduced anxiety in mice. Giving mice a motilin receptor blocker (GM-109) reversed the anxiety effects of motilin in the brain [9].

Motilin Genetics

Health Risks

In an observational study on almost 1,500 people (439 with biliary cancer, 429 with gallstones, and 447 controls), the incidence of gallstones and biliary (gallbladder/liver) was significantly higher in people with two variants of the motilin receptor (MLNR) gene (MLN rs2281820 and MLNR rs9568169, respectively) [26].

Remember that these SNPs have only been found to be associated with gallstones and biliary cancer but haven’t been established as their cause. This means having them will not necessarily make you more likely to develop these diseases. More work is needed before we determine whether and how much they may increase the risk of developing them.

Limitations/Caveats

Most research involving motilin is focused on developing motilin receptor activators or blockers. Clinical trials evaluating abnormally high or low motilin levels are very limited. Additionally, the effects of motilin in other parts of the body outside of the digestive system are still being speculated.

About the Author

Carlos Tello

Carlos Tello

PhD (Molecular Biology)
Carlos received his PhD and MS from the Universidad de Sevilla.
Carlos spent 9 years in the laboratory investigating mineral transport in plants. He then started working as a freelancer, mainly in science writing, editing, and consulting. Carlos is passionate about learning the mechanisms behind biological processes and communicating science to both academic and non-academic audiences. He strongly believes that scientific literacy is crucial to maintain a healthy lifestyle and avoid falling for scams.

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