GLP-1 from the gut: what bacteria do and what “natural Ozempic” cannot do

Healthy state

GLP-1 GLP-1 A hormone from the gut wall that controls insulin release after eating, slows the stomach and makes you feel full. Weight-loss injections mimic it. is a hormone from the gut wall. It is made by L-cells, which sit mostly in the lower small intestine (ileum Ileum The last section of the small intestine. It recovers bile acids, absorbs vitamin B12 and joins the colon via the ileocaecal valve. More in the chapter “Where the small intestine meets the colon: ileum, valve and caecum”) and the colon, i.e. far back along the digestive tract. When nutrients arrive there, the L-cells release GLP-1. It makes the pancreas release insulin matched to the sugar, slows the opposing hormone glucagon, slows stomach emptying and signals fullness to the brain. Because the L-cells sit so far back, a lot depends on what arrives there undigested: a meal that is fully absorbed in the upper small intestine stimulates them less than one with fat, protein and fibre.

The start of the digestive tract plays a part as well. Thorough chewing and a well-working stomach portion the food so that it arrives in the small intestine in pulses. Bile acids Bile acids Substances made by the liver that make fat digestible. About 95 percent are reabsorbed in the last part of the small intestine; gut bacteria transform the rest. More in the chapter “Bile acids: when bile causes diarrhoea”, needed to digest fat, can also stimulate L-cells through a receptor called TGR5; this is shown mainly in cells and animals. And because the first hours after eating are partly steered by the vagus nerve Vagus nerve The tenth cranial nerve and the most important nerve of the rest-and-digest system. It connects the brainstem and the abdominal organs; most of its fibres tell the brain what is happening in the gut. More in the chapter “The vagus nerve: the data line between belly and head” and nerves in the gut wall, part of the GLP-1 effect runs through nerve pathways instead of the blood.

L-cells respond not only to sugar, fat and protein but also to substances from bacteria. Short-chain fatty acids Short-chain fatty acids Acids such as acetate, propionate and butyrate that gut bacteria make from fibre. They nourish the gut wall and act throughout the body. More in the chapter “Butyrate and other short-chain fatty acids” such as propionate and butyrate Butyrate A short-chain fatty acid and the main energy source for the cells of the colon wall. It strengthens the barrier and dampens inflammation. More in the chapter “Butyrate and other short-chain fatty acids”, produced when fibre is fermented, dock onto two receptors of the L-cells, FFAR2 and FFAR3. In cell experiments and in mice, this triggered GLP-1 release; mice without these receptors lacked the effect and had worse blood sugar control.

In humans the same pathway showed up in small studies. Ten healthy people took 16 g of prebiotics Prebiotics Food components, usually certain fibres, that specifically feed beneficial gut bacteria, such as inulin or GOS. More in the chapter “Prebiotics that build up gently” a day for two weeks: fermentation in the gut tripled, GLP-1 and the satiety hormone PYY rose, hunger fell, and blood sugar after a test meal was lower. The more fermentation, the more GLP-1.

In a British study, propionate was delivered specifically to the colon, bound to inulin. A single portion raised GLP-1 and PYY and reduced the amount eaten. Over 24 weeks, 60 people with overweight gained less weight with the propionate ester, stored less belly fat and kept their insulin sensitivity better than with inulin alone.

Individual bacteria also send signals. Akkermansia muciniphila Akkermansia A gut bacterium that lives on the mucus of the gut wall and stimulates its renewal. In studies, high levels often go along with good metabolic health. More in the chapter “The mucus layer and additives” releases a protein called P9 that, in mice, was enough on its own to release GLP-1 and improve metabolism. This has not been studied in humans.

Disrupted state: causes and effects

The body's own GLP-1 acts only briefly. An enzyme called DPP-4 breaks it down so fast that a large part becomes inactive already in the gut wall before it reaches the bloodstream. Part of the effect therefore probably runs through nerves in the gut wall and the vagus nerve instead of through the blood.

The drugs, by contrast, are built so that DPP-4 can hardly touch them. Semaglutide is injected once a week and produces round-the-clock drug levels far above what a meal triggers. In the large approval trial, people with overweight lost on average 14.9 percent of their weight in 68 weeks, versus 2.4 percent with placebo Placebo A dummy treatment without an active ingredient. Comparing with it shows how much a remedy achieves beyond expectation and chance. .

That is why "natural Ozempic" is a misleading promise. For berberine, often advertised this way, a meta-analysis Meta-analysis An analysis that combines the results of several studies. It is only as good as the studies it includes. of 23 studies found on average just under 0.9 kg less weight. With fibre and prebiotics, fullness and blood sugar can be measurably improved, but on a different scale.

A reduced GLP-1 release might contribute to the development of overweight, according to a review. A low-fibre diet gives bacteria little food and therefore fewer fatty acids for the L-cells. This is where diet comes in: it can support your own GLP-1 pathway, even though it does not replace a drug.

Another part of the system is the ileal brake. When undigested nutrients reach the end of the small intestine, the L-cells there release GLP-1 and PYY. Stomach emptying slows down and you feel full. After some stomach operations, nutrients arrive there faster, which explains part of their effect on weight and blood sugar.

The drugs have effects on the gut that are worth knowing. Because they strongly slow stomach emptying and gut movement, nausea, vomiting, constipation and diarrhoea are the most common side effects; in a review of 39 studies with more than 33,000 people without diabetes with overweight, all drugs studied raised the risk of nausea, and semaglutide and liraglutide also raised the risk of constipation. A slowly emptying stomach can matter for anaesthesia and sedation, because stomach contents could then reach the airways. If you are unsure whether stomach symptoms, fullness or vomiting on the drug are still normal, talk to your doctor. The effect on the gut microbiota Microbiome, gut microbiota The community of all microbes in the gut, mainly bacteria, plus viruses, fungi and archaea. Most live in the colon. More in the chapter “Building microbial diversity” itself is still hardly clarified in humans.

Important for perspective: the drug changes appetite and stomach emptying, not the cause of problems such as bloating or irritable bowel. If you eat less and therefore less fibre, you also take food away from the bacteria. Caution is also needed in people whose stomach already empties slowly (gastroparesis Gastroparesis Delayed gastric emptying without a mechanical obstruction, with nausea, vomiting, early satiety and fullness. More in the chapter “Gastroparesis: when the stomach empties too slowly”), because the drugs can worsen the problem.