Story
Digestive System
Last updated
In one pass Stomach acid (hydrochloric acid) is the strongest acid in the body: on an empty stomach, gastric juice sits at about pH 1.5–2.0, more acidic than lemon juice.
Educational content, not medical advice — consult a clinician.
Story path
Chapter 1
Three jobs of stomach acid
Stomach acid (hydrochloric acid) is the strongest acid in the body: on an empty stomach, gastric juice sits at about pH 1.5–2.0, more acidic than lemon juice. It is secreted by the parietal cells of the stomach wall, where a proton pump in the cell membrane moves hydrogen ions into the stomach one by one against their concentration gradient, spending energy on every stroke.
Stomach acid has three jobs:
Stopping bacteria: most bacteria are killed quickly below pH 2, the first line of defense against foodborne infection.Starting protein digestion: it activates pepsin, which works only below pH 4 and cuts proteins into peptides.Releasing minerals and B12: it keeps iron dissolved so it can be absorbed, and frees vitamin B12 from food proteins.
So in people who take strong acid-suppressing drugs (proton pump inhibitors, ) for a long time, the problems observed are the mirror image of those three jobs: certain gut infections, low B12, low iron and a slightly higher fracture risk — mostly from observational studies. With a clear indication a PPI is still a good drug; how to use it and how to come off it are covered in the story.
Stomach acid has three jobs:
Stopping bacteria: most bacteria are killed quickly below pH 2, the first line of defense against foodborne infection.Starting protein digestion: it activates pepsin, which works only below pH 4 and cuts proteins into peptides.Releasing minerals and B12: it keeps iron dissolved so it can be absorbed, and frees vitamin B12 from food proteins.
So in people who take strong acid-suppressing drugs (proton pump inhibitors, ) for a long time, the problems observed are the mirror image of those three jobs: certain gut infections, low B12, low iron and a slightly higher fracture risk — mostly from observational studies. With a clear indication a PPI is still a good drug; how to use it and how to come off it are covered in the story.
Mechanism · What the stomach does besides grinding
An adult stomach can stretch to about 1–1.5 L and shrinks to about 50 mL when empty; it secretes 2–3 L of gastric juice a day. A meal stays in the stomach for 2–4 hours: protein and fat stay longer, liquids leave quickly.How fast the stomach empties affects blood glucose after a meal. A sugary liquid reaches the small intestine within 30 minutes and blood glucose rises fast; eaten with protein and fiber, the sugar is released slowly and the glucose curve is flatter. Eating vegetables and protein first and the starch last has been seen to lower the post-meal glucose peak in small trials, and by mechanism part of the reason is slower stomach emptying. drugs (such as semaglutide) keep people from feeling hungry for a long time, and slowing stomach emptying is one of the ways they do it.
What changes stomach acid:
Helicobacter pylori: one of the few bacteria that can live in the stomach for years. It burrows into the mucus layer and breaks down urea to make a small, less acidic pocket around itself. Infection is common, and it is the most important known risk factor for stomach cancer; after long-standing chronic gastritis from the infection, acid output may actually fall.Antacids (calcium carbonate, magnesium salts and the like): neutralize acid already secreted; the effect lasts only a few hours.Proton pump inhibitors: block the proton pump irreversibly. The drug has a very short half-life in the blood, but a blocked pump recovers only when the stomach builds new ones, so one tablet works for 24–48 hours. Stop suddenly after long-term use, and acid briefly rebounds.
Chapter 2
How pancreatic juice and bile work
Food leaves the stomach and enters the duodenum, where it meets two kinds of support at once: the pancreas sends a full set of digestive enzymes, and the gallbladder squeezes out bile it has stored overnight.
The pancreas works in two beats: neutralize first, then dismantle. It first releases bicarbonate to neutralize the strong acid arriving from the stomach — a hard precondition, because the enzymes downstream do not work in strong acid. Only then does it release four classes of enzymes, for protein, fat, carbohydrate and nucleic acids.
Bile is made by the liver and concentrated and stored in the gallbladder. Its job is to emulsify fat: breaking big oil droplets into tiny ones so pancreatic lipase has a large enough surface to work on. The body secretes 500–800 mL a day, and most of it is reclaimed at the end of the small intestine and returned to the liver for reuse. This loop is the enterohepatic circulation, and bile makes the round trip 5–10 times a day.
So this stretch is not as crude as the stomach grinds and the gut absorbs. It is a chemical band that comes in on cue, section by section; who plays first and how much is decided by hormones the duodenum itself releases.
The pancreas works in two beats: neutralize first, then dismantle. It first releases bicarbonate to neutralize the strong acid arriving from the stomach — a hard precondition, because the enzymes downstream do not work in strong acid. Only then does it release four classes of enzymes, for protein, fat, carbohydrate and nucleic acids.
Bile is made by the liver and concentrated and stored in the gallbladder. Its job is to emulsify fat: breaking big oil droplets into tiny ones so pancreatic lipase has a large enough surface to work on. The body secretes 500–800 mL a day, and most of it is reclaimed at the end of the small intestine and returned to the liver for reuse. This loop is the enterohepatic circulation, and bile makes the round trip 5–10 times a day.
So this stretch is not as crude as the stomach grinds and the gut absorbs. It is a chemical band that comes in on cue, section by section; who plays first and how much is decided by hormones the duodenum itself releases.
Mechanism · The five things the pancreas sends
The five things the pancreas secretes:Bicarbonate (HCO₃⁻): raises pH from 2 to 6–8Trypsin, chymotrypsin and elastase: break down proteinPancreatic lipase and its helper, colipase: break down fatPancreatic amylase: breaks down carbohydrateNucleases: break down DNA and RNA
What is in bile: mainly bile acids (cholic acid, chenodeoxycholic acid), plus phospholipids, cholesterol and bilirubin. A bile-acid molecule is water-loving at one end and oil-loving at the other, so it can cling to the surface of an oil droplet and pry a big droplet apart. That is emulsification, and it is what lets pancreatic lipase get to work: the enzyme can act only at the boundary between oil and water, and the larger that boundary, the faster the breakdown.
The hormone signals that cue them in: as soon as partly digested food enters the duodenum, I cells in the gut wall release cholecystokinin (CCK), which makes the gallbladder contract and the pancreas release enzymes; when acid enters the duodenum, S cells release secretin, which makes the pancreas release bicarbonate. So the pancreas and gallbladder are not spraying all the time. They wait for the duodenum to report what just arrived, then decide what to release and how much — a sip of clear broth and a greasy feast get amounts of bile that differ by an order of magnitude.
Clinical · Gallstones and poor fat absorption
Gallstones mostly form when excess cholesterol crystallizes out of bile; the root is an imbalance between cholesterol and the bile acids and phospholipids. They are quite common in adults, and most people with them never have symptoms.What happens after the gallbladder is removed? The liver still makes bile; it just no longer stores it and squeezes it out after meals, but lets it flow into the gut continuously, a little at a time. After a very fatty meal, some people feel bloated or have greasy stools. The more common problem is bile-acid diarrhea: more bile acid flows straight into the colon, where it makes the colon secrete water, causing loose stools after meals. The treatment is a prescribed drug that binds bile acids — do not start taking bile or bile salts yourself. Obvious fat-soluble vitamin deficiency after a gallbladder removal alone is uncommon, and most people adapt gradually over a few months to a year.
Pancreatic insufficiency (chronic pancreatitis, cystic fibrosis and others) means the pancreas does not secrete enough enzymes. Fat is not broken down, and the result is steatorrhea: greasy, floating, foul-smelling stools, with weight loss. It needs prescribed pancreatic enzyme replacement, with monitoring and supplementation of the fat-soluble vitamins (A, D, E, K).
Why the enterohepatic circulation matters clinically:
About 95% of bile acids are actively reclaimed at the end of the small intestine (the terminal ileum) and return to the liver through the portal vein to be secreted again.When the ileum is removed, or Crohn's disease involves it, bile acids cannot be reclaimed and steatorrhea follows; vitamin B12 is lost at the same time, because the terminal ileum is the only place B12 is absorbed.Bile-acid binders such as cholestyramine use this loop to lower cholesterol: bile acids are carried away, so the liver has to use up cholesterol to make new ones.
This is also one of the body's main exits for cholesterol, and it explains why soluble fiber lowers cholesterol: fiber wraps up bile acids and reduces how much is reclaimed, so the liver has to draw on blood cholesterol to make new bile acids.
boyer-2013-bile-formationiom-2005-macros
Chapter 3
How the small gut absorbs nutrients
The place where nutrients actually enter the body is the small intestine. Its lining is not a smooth tube but fold upon fold of ridges, villi and even finer microvilli, which stretch the absorbing surface to about 30–40 m² — roughly half a badminton court, folded up inside your belly.
The point is not the size of the area. It is that this surface is packed with doors, and each nutrient uses its own: glucose has a glucose door, short pieces of protein have their own door, and divalent metal ions such as iron and manganese crowd through the same one (called DMT1).
Sharing a door means competing for it. A high-dose single-mineral supplement arriving all at once crowds the others out at the door, and high doses of iron and zinc taken together also interfere with each other's absorption. Eaten together in food, the amounts are small and spread out, and they compete far less.
The point is not the size of the area. It is that this surface is packed with doors, and each nutrient uses its own: glucose has a glucose door, short pieces of protein have their own door, and divalent metal ions such as iron and manganese crowd through the same one (called DMT1).
Sharing a door means competing for it. A high-dose single-mineral supplement arriving all at once crowds the others out at the door, and high doses of iron and zinc taken together also interfere with each other's absorption. Eaten together in food, the amounts are small and spread out, and they compete far less.
Mechanism · The doors on the brush border
This absorbing lining is called the brush border, and under a microscope it really does look like a brush standing on end. Laid out, the small intestine is several meters long (about 6–7 meters when measured at autopsy, shorter in a living body), and its circular folds, villi and microvilli multiply the surface many times over — that is how the absorbing area gets folded in.The brush is studded with specialized transport proteins, each of which recognizes only its own cargo:
SGLT1: carries sodium and glucose in together; oral rehydration solution depends on it.PEPT1: carries dipeptides and tripeptides, so short pieces of protein are absorbed faster than single amino acids.DMT1: the divalent metal transporter; Fe²⁺, Mn²⁺ and others all use it and compete.NaPi-2b: absorbs phosphate.CFTR: a channel for chloride and bicarbonate; the mutation behind cystic fibrosis is here.
All these doors sit on very short-lived cells. Gut lining cells (enterocytes) live only 3–5 days, making this one of the fastest-renewing tissues in the body, because the cells are in direct contact with food, toxins and microbes and wear out fast.
That speed of renewal has consequences. Enterocytes need large amounts of amino acids and energy, and the main fuel of small-intestine enterocytes is glutamine, not glucose. During chemotherapy the whole lining of the digestive tract, from mouth to anus, takes the first hit, which is why mouth sores and diarrhea are common in people on chemotherapy. Under severe stress (sepsis, extensive burns), the gut barrier is one of the first things to fail.
Mechanism · Why oral rehydration solution saves lives
Oral rehydration solution (ORS) is widely regarded as one of the most important low-cost medical advances of the 20th century, and most of the lives it saves are children who would otherwise die of dehydration from diarrhea.Its mechanism is SGLT1. Cholera toxin makes gut cells pour water and electrolytes into the gut, and a person becomes severely dehydrated fast — but SGLT1 keeps working. It moves cargo only when it gets sodium and glucose together: two sodium ions and one glucose enter the cell together, and osmosis carries water along with them, back into the blood.
The formula (the low-osmolarity WHO formula revised in 2002, per liter):
Glucose 13.5 g/LSodium 75 mmol/LPotassium 20 mmol/LChloride 65 mmol/LCitrate 10 mmol/LTotal osmolarity 245 mOsm/L (the lower-osmolarity solution actually works better)
That is why plain water alone is not enough during diarrhea: without sodium plus glucose, the SGLT1 door stays shut and water is reabsorbed slowly. Sports drinks use the same principle, but they carry too little sodium and too much sugar to replace ORS for dehydration from diarrhea.
The first choice is low-osmolarity ORS from a pharmacy. If you truly cannot get it, WHO has given an emergency recipe: 6 level teaspoons of sugar and half a level teaspoon of salt stirred into 1 L of clean water. If a child with diarrhea is listless or unusually sleepy, is passing much less urine, cannot keep fluids down or vomits everything, or has blood in the stool, seek medical care promptly.
nih-ods-potassiumwho-2012-sodiumwho-2006-orswright-2011-sglt
Chapter 4
Bacteria in the colon
The colon is home to a huge population of bacteria that live on what you cannot digest. Dietary fiber that your teeth cannot break and your own enzymes cannot cut (resistant starch, inulin, pectin, β-glucan and others) travels all the way here before they ferment it. The products are short-chain fatty acids (), and the three main ones go different places:
Acetate: enters the blood and becomes raw material for metabolism throughout the body.Propionate: travels through the portal vein to the liver; animal and cell studies suggest it curbs fat synthesis and takes part in appetite signals.Butyrate: the preferred fuel of colon cells, supplying about 70% of their energy, and it also acts as an anti-inflammatory signal.
In other words, the body has outsourced a stretch of its metabolism to microbes: eat 25–30 g of fiber, and the microbes make about 200–400 mmol of short-chain fatty acids a day.
No fiber, no short-chain fatty acids, and the colon goes hungry. In mouse experiments, microbes deprived of fiber turn to eating the gut's own mucus layer. That is why fiber is not just about regularity.
Acetate: enters the blood and becomes raw material for metabolism throughout the body.Propionate: travels through the portal vein to the liver; animal and cell studies suggest it curbs fat synthesis and takes part in appetite signals.Butyrate: the preferred fuel of colon cells, supplying about 70% of their energy, and it also acts as an anti-inflammatory signal.
In other words, the body has outsourced a stretch of its metabolism to microbes: eat 25–30 g of fiber, and the microbes make about 200–400 mmol of short-chain fatty acids a day.
No fiber, no short-chain fatty acids, and the colon goes hungry. In mouse experiments, microbes deprived of fiber turn to eating the gut's own mucus layer. That is why fiber is not just about regularity.
Numbers · How many residents, and how many genes
Your body has about 30 trillion of its own cells and about 38 trillion gut bacteria. In the revised estimate of Sender 2016, the two are of the same order, close to 1:1 rather than the long-repeated 10:1, and the bacteria together weigh only about 0.2 kg.Compare genes, though, and the gap is large. Humans have about 22,000 genes, while the gut microbiota as a whole carries between 3 million and 10 million — a second genome for the body, 100–500 times larger.
More genes means more things that can be broken down. Your own set of digestive enzymes is actually quite narrow and cannot take apart structures such as plant cell walls; the genes the microbiota brings fill exactly that gap. So fiber is not undigested waste. It is the ration left for them.
Most gut bacteria live in the colon. The two dominant groups (phyla) are Bacteroidetes and Firmicutes, which together make up about 90%.
Evidence · What makes the gut microbiome diverse
Good bacteria versus bad bacteria is an outdated simplification. Today the gut microbiota is judged more by diversity and resilience (whether it can recover after a shock) than by any one particular species.Things that reduce diversity:
Broad-spectrum antibiotics: after one course, diversity drops noticeably, and in some people it takes months or more to partly recover.Some food emulsifiers: in mouse experiments, carboxymethylcellulose and polysorbate 80 changed the microbiota, eroded the mucus layer and triggered gut inflammation (Chassaing 2015); the same has not been shown in people.Low-fiber diets: the bacteria that ferment fiber have nothing to eat and dwindle.Chronic stress and too little sleep: animal studies and small human studies suggest these affect the microbiota too, by how much is unclear.
Hand sanitizer and antibacterial soap mainly affect the microbes of the skin and nose, and have little to do with the gut microbiota.
Things linked to higher diversity:
Eating many kinds of plants: in American Gut, a citizen-science cohort of more than ten thousand people, those who ate more than 30 kinds of plants a week had a more diverse microbiota than those who ate fewer than 10 (McDonald 2018; an observed association).Fermented foods: in the randomized trial of Wastyk 2021 (from the Sonnenburg lab), with about 18 people per group over 10 weeks, the primary outcome — a combined immune-response score — did not change clearly in either group. In secondary analyses, the high-fermented-food group gained microbiota diversity and several inflammatory markers fell, while diversity in the high-fiber group did not change.Enough dietary fiber, 25–40 g a day.Avoiding antibiotics you do not need.
Fecal microbiota transplantation (moving the gut microbes of a healthy donor into a patient's gut) is now one of the recommended treatments for Clostridioides difficile infection that keeps coming back. In the randomized trial of van Nood 2013, 81% (13/16) were cured after the first transplant, against 31% with vancomycin alone. Other uses (inflammatory bowel disease, irritable bowel syndrome, metabolic syndrome, depression) are still being studied; the evidence is limited and inconsistent, so do not trust the marketing.
Probiotic supplements: only particular strains, for particular uses, have evidence — and new trials can overturn the verdict. Lactobacillus rhamnosus GG (LGG), for example, used to be given to shorten acute diarrhea in children, and newer pooled analyses and guidelines no longer support that use. Broad-spectrum products with vague gut health claims have thin evidence, and many strains do not survive stomach acid and bile.
sonnenburg-2021-cellchassaing-2015-emulsifiers-microbiotamcdonald-2018-americangutvan-nood-2013-nejm-fmt
Chapter 5
How the gut talks to the brain
Your gut has its own nervous system, about 500 million neurons, more than the whole spinal cord holds. It is called the enteric nervous system and is often nicknamed the second brain: even if its connection to the brain is cut, it can still organize the gut's movements, adjust secretion and manage local blood flow on its own.
There are three physical lines between it and the brain. The first is the vagus nerve, a thick cable whose traffic runs mostly upward — the gut reporting to the brain. The second is chemical messengers: many neurotransmitters are made in the gut itself, and the microbes make some as well. The third is immune and endocrine signals: inflammatory factors and fragments of bacterial walls can get into the blood and reach as far as mood.
So the gut affecting mood is not a vague mind-body connection. It is a set of physical pathways you can point to by name. How large their effects are in people is still being studied.
There are three physical lines between it and the brain. The first is the vagus nerve, a thick cable whose traffic runs mostly upward — the gut reporting to the brain. The second is chemical messengers: many neurotransmitters are made in the gut itself, and the microbes make some as well. The third is immune and endocrine signals: inflammatory factors and fragments of bacterial walls can get into the blood and reach as far as mood.
So the gut affecting mood is not a vague mind-body connection. It is a set of physical pathways you can point to by name. How large their effects are in people is still being studied.
Mechanism · The three lines between gut and brain
1. The vagus nerve: cranial nerve X. The most counterintuitive thing about it is the direction: about 80% of its fibers carry signals from gut to brain, not the other way. In other words, this line is mainly the gut reporting upward — fullness, inflammation signals and microbial signals all travel up it. Vagus nerve stimulation (VNS) is now one of the clinical treatments for hard-to-treat depression and for epilepsy.2. Neurotransmitters:
Serotonin (): about 95% of the body's supply is in the gut, made mainly by enterochromaffin cells in the gut wall, where it regulates movement and local signals; the rest sits in platelets, the brain and elsewhere.Dopamine: about 50% is produced in the gut.Gamma-aminobutyric acid (, a neurotransmitter that slows nerves down), short-chain fatty acids and tryptophan metabolites: gut microbes can make these directly.
One common misreading has to be cleared away first: the serotonin in your gut does not travel into your brain; it basically cannot cross the blood-brain barrier. Its job in the gut is regulating movement and local signals. The gut's effect on mood travels along the vagus reporting line, not by shipping the molecule itself into the brain.
3. Immune and endocrine signals:
Cytokines (inflammatory signaling molecules such as and ) can pass signals into the brain and affect mood and energy.Lipopolysaccharide (LPS): fragments of the outer walls of gut bacteria. Trace amounts in the blood are normal; more than that is called metabolic endotoxemia, and its links to depression and metabolic disease come from observational studies.
Put the three lines together — 500 million neurons, about 80% of vagus fibers running upward, 95% of the body's serotonin, plus thousands of bacterial metabolites — and that is what the gut's state affecting the mind looks like in anatomy. It is a circuit, not a metaphor. But the circuit existing does not mean the size of each line's effect in people has been measured.
Evidence · What human studies show on gut and mood
Research on the gut-brain axis is still early in reaching the clinic.Depression and the gut microbiota:
Observational studies find that the microbiota of people with depression differs from that of healthy people. Valles-Colomer 2019, after correcting for antidepressant use, found fewer Coprococcus and Dialister bacteria in people with depression, while the butyrate producers Faecalibacterium and Coprococcus tracked quality of life. These are associations.In mouse experiments, transplanting the gut microbes of people with depression into mice produced depression-like behavior in the mice.A few small randomized trials (such as Akkasheh 2016) saw depression scores fall somewhat with particular probiotic combinations, but the samples were small, the strains all differed, and larger trials are needed to replicate them.
Anxiety and the vagus nerve:
In mice, one strain of Lactobacillus rhamnosus (JB-1) reduced anxiety-like behavior and affected stress hormones through the vagus nerve; cut the vagus and the effect disappeared. In mice, that is a complete causal chain.It gave rise to a research field called psychobiotics, but the human evidence is scarce and weak.
Irritable bowel syndrome is the classic case of disordered gut-brain regulation: the gut is more sensitive, so the same amount of gas hurts much more, and symptoms flare under stress. The ACG 2021 guideline suggests a time-limited trial of a low- diet (cutting a group of short-chain sugars that ferment easily) and also gut-directed psychological therapy; both are conditional recommendations based on very low-quality evidence. It is a real disorder of brain, gut and microbes working together badly, not an imagined illness; the Irritable Bowel Syndrome story covers it in detail.
In practice (the evidence is weak throughout, but the risk is low and there may be a benefit):
Eat a wide variety of plant foods, plus fermented foods.Exercise regularly: in the small trial of Allen 2018, a few weeks of endurance training changed the makeup of the microbiota, and the changes faded after training stopped.Get enough sleep; how too little sleep affects the microbiota is still being studied.Without a clear reason, do not take probiotics on spec.
valles-colomer-2019-neuroactive-microbiotalacy-2021-acg-ibsakkasheh-2016-probiotic-depression-rct
Chapter 6
Where nausea comes from
Nausea is a protective response: the body suspects you have swallowed something harmful, makes you stop, and if needed brings it back up; it also makes you remember the taste so you avoid it next time.
The signal comes in through three doors:
The vestibular system of the inner ear: nausea from motion, such as car sickness, mainly travels this way.The area postrema in the brainstem: this small patch of brain is in direct contact with blood and cerebrospinal fluid and can detect toxins and drugs in the blood; it used to be called the chemoreceptor trigger zone.The vagus nerve in the gut: enterochromaffin cells in the gut wall release serotonin, which directly stimulates vagal nerve endings; most vagal sensory nerves carry 5-HT3 receptors, and one class of anti-sickness drugs blocks the signal right there.
These signals converge in the brainstem, where a group of neurons coordinates each step of vomiting in sequence; there is no single vomiting centre. Stress and anxiety can also trigger nausea directly.
So nausea is not necessarily a stomach problem: stomach bugs, food poisoning, reflux, migraine, inner ear infections, pregnancy, motion sickness, anxiety, alcohol and many medicines can all cause it.
If you suddenly feel sick with chest pain that feels tight or heavy, pain spreading to your arm, back, neck or jaw, or shortness of breath, it could be a heart attack: call emergency services now.
The signal comes in through three doors:
The vestibular system of the inner ear: nausea from motion, such as car sickness, mainly travels this way.The area postrema in the brainstem: this small patch of brain is in direct contact with blood and cerebrospinal fluid and can detect toxins and drugs in the blood; it used to be called the chemoreceptor trigger zone.The vagus nerve in the gut: enterochromaffin cells in the gut wall release serotonin, which directly stimulates vagal nerve endings; most vagal sensory nerves carry 5-HT3 receptors, and one class of anti-sickness drugs blocks the signal right there.
These signals converge in the brainstem, where a group of neurons coordinates each step of vomiting in sequence; there is no single vomiting centre. Stress and anxiety can also trigger nausea directly.
So nausea is not necessarily a stomach problem: stomach bugs, food poisoning, reflux, migraine, inner ear infections, pregnancy, motion sickness, anxiety, alcohol and many medicines can all cause it.
If you suddenly feel sick with chest pain that feels tight or heavy, pain spreading to your arm, back, neck or jaw, or shortness of breath, it could be a heart attack: call emergency services now.
In practice · What to do with nausea and vomiting
First try these:Get some fresh air, and distract yourself with music or a film.Take small, regular sips of a cold drink; try ginger or peppermint tea, or foods containing ginger.Eat smaller, more frequent meals, eat slowly, and don't have a large drink with a meal.Avoid cooking or eating strong-smelling food, and go easy on hot, fried or greasy food.Don't lie down soon after eating, and avoid clothes that are tight around your waist or tummy.
If it isn't better in a few days, or keeps coming back, see a doctor to find the cause.
If you're vomiting, prevent dehydration first. If you keep being sick and can't keep fluids down, still have signs of dehydration after oral rehydration sachets, or have been vomiting for more than 2 days, contact a doctor the same day. Children need help sooner: a baby under 12 months who is vomiting, a child who stops breast or bottle feeding while ill, or a child under 5 with signs of dehydration (such as fewer wet nappies) needs medical advice now.
Go to the emergency department now (don't drive yourself) if you vomit blood or something like coffee grounds, have green vomit, may have swallowed something poisonous, have a stiff neck and pain looking at bright lights, a sudden severe headache or severe tummy pain, blue or grey skin or lips, severe difficulty breathing, or confusion.
nhs-diarrhoea-and-vomiting
Chapter 7
The one-cell-thick gut wall
Your gut wall is only one cell thick. That single layer separates two worlds: on one side the inside of the gut, with food residue and trillions of bacteria; on the other, the blood and the immune system.
It is not a solid wall. Neighboring gut cells are stitched together by a ring of proteins, and that stitching can loosen or tighten. Loosened, it lets water and small ions through; tightened, it keeps large molecules, bacteria and toxins out. So permeability is never a yes-or-no question but a matter of how far it is open right now.
The tightness is regulated by a signal molecule called zonulin. According to the work of Fasano's group (mostly experiments on cells and gut tissue samples), fragments of gliadin from gluten loosen the stitching a little in everyone's gut lining, and people with celiac disease have more trouble closing it again. But the real root of celiac disease is in the immune system: an enzyme called tissue transglutaminase reshapes gluten into a form the immune system has never seen, which sets off a sustained attack. The loosened barrier is only one link in that chain.
It is not a solid wall. Neighboring gut cells are stitched together by a ring of proteins, and that stitching can loosen or tighten. Loosened, it lets water and small ions through; tightened, it keeps large molecules, bacteria and toxins out. So permeability is never a yes-or-no question but a matter of how far it is open right now.
The tightness is regulated by a signal molecule called zonulin. According to the work of Fasano's group (mostly experiments on cells and gut tissue samples), fragments of gliadin from gluten loosen the stitching a little in everyone's gut lining, and people with celiac disease have more trouble closing it again. But the real root of celiac disease is in the immune system: an enzyme called tissue transglutaminase reshapes gluten into a form the immune system has never seen, which sets off a sustained attack. The loosened barrier is only one link in that chain.
Mechanism · Four defenses and the proteins that seal cells
The gut barrier is one of the thinnest, longest and hardest-hit borders in the body: that layer of gut cells is about 25 μm tall, 4 times thinner than a hair.It is really not one layer but four lines of defense nested one inside the next:
Mucus layer: goblet cells secrete mucin (mainly MUC2), forming a physical and chemical buffer. For a bacterium to reach a cell, it first has to get through this gel.Antimicrobial peptides: Paneth cells secrete defensins, cathelicidin and other antimicrobial peptides — like scattering chemical mines through the gel.Gut cells and tight junctions: proteins such as claudin, occludin and ZO-1 stitch neighboring cells tightly together; these are the stitching described earlier.Gut-associated lymphoid tissue (GALT) beneath the lining: a large share of the body's immune cells are stationed here, and if something does leak through, they clean up.
Tight junctions are not welded shut; they are adjustable. Opened, they let water, ions and small molecules through selectively; closed, they block large molecules, bacteria and toxins.
One signal molecule that regulates them is zonulin, discovered by Alessio Fasano's group in the 2000s. It is the body's own molecule, named after a toxin of the cholera bacterium (zonula occludens toxin, Zot), because the two open tight junctions in similar ways. Gliadin, a protein in gluten, is one of the strongest known triggers of zonulin release. In Fasano's model, gliadin sets off this pathway in everyone's gut lining; the difference lies in closing it again — most people can, people with celiac disease have more trouble. The model comes mainly from experiments on cells and tissue samples, and celiac disease also requires a particular immune susceptibility; the barrier is only one link.
Evidence · What is real about leaky gut
Leaky gut syndrome is overused in alternative-medicine circles and often dismissed in mainstream medicine. But the underlying science of intestinal permeability is real; how to use it clinically is still at an early stage.Conditions with a fairly clear link to raised barrier permeability:
Celiac disease: the clearest link.Type 1 diabetes: some studies have found raised gut permeability in some patients before diagnosis.Inflammatory bowel disease (Crohn's disease, ulcerative colitis): raised permeability may be both a result and a driver.Metabolic dysfunction-associated steatotic liver disease, or (formerly NAFLD): one hypothesis under study is that a leaky barrier raises LPS in the portal vein and worsens inflammation in the liver.
Possibly related, but with limited and inconsistent evidence: food allergy and intolerance, irritable bowel syndrome, autoimmune diseases (thyroid disease, rheumatoid arthritis, lupus), depression, anxiety.
How it is measured:
The lactulose/mannitol test: drink the two sugars and measure the proportion excreted in urine; a classic research tool.Serum zonulin: commercially available, but unreliable, with many false positives.LPS and LPS-binding protein (LBP): indirect markers.None is accepted by mainstream consensus as a diagnostic standard for leaky gut syndrome.
What helps the barrier: enough fiber and short-chain fatty acids (butyrate fuels gut cells directly, and in cell experiments raises the activity of tight-junction genes); zinc, vitamin A, vitamin D and glutamine, the basic raw materials of the barrier; fewer non-steroidal anti-inflammatory drugs (long-term, high-dose ibuprofen or aspirin raises small-intestine permeability — the evidence here is clear); less alcohol (acetaldehyde disrupts tight junctions in cell experiments); regular sleep and managing chronic stress (animal studies suggest that daily rhythms and stress hormones both regulate the gut barrier).
Claims with no evidence behind them: leaky gut detox supplements, teas and enemas; collagen or bone broth heals a leaky gut (the products are fine in themselves, but the effect is exaggerated); and treating Helicobacter pylori or candida overgrowth as the root of all disease.
References · 12
- National Institutes of Health, Office of Dietary Supplements. (2024). Iron — Fact Sheet for Health Professionals. Fact sheet (updated September 4, 2025; Wayback snapshot 21 September 2026): RDAs 8 mg/day for men and for women 51+, 18 mg women 19-50, 27 mg pregnancy; UL 45 mg/day from age 14; bioavailability about 14%-18% from mixed diets with meat, seafood and vitamin C and 5%-12% from vegetarian diets; serum ferritin below 30 mcg/L suggests iron deficiency and below 10 mcg/L IDA, but inflammation can raise ferritin; supplemental iron of 45 mg/day or more may cause nausea and constipation; people with hereditary hemochromatosis are at risk of iron overload (fact sheet). Heme vs nonheme: heme iron (lean meat and seafood are the richest sources) has higher bioavailability than nonheme iron, and other dietary components affect it less; calcium might reduce the bioavailability of both forms; heme iron is about 10%-15% of total iron intake in western populations. The sheet gives no separate heme and nonheme absorption percentages (fact sheet, Wayback 2026 snapshot). ods.od.nih.gov/factsheets/Iron-HealthProfessional
- National Institutes of Health, Office of Dietary Supplements. (2024). Vitamin B12 — Fact Sheet for Health Professionals. Fact sheet (updated July 2, 2025; Wayback snapshot 20 September 2026): multivitamin/mineral supplements typically contain 5 to 25 mcg B12, B-complex products 50 to 500 mcg, B12-only supplements typically 500 to 1,000 mcg; absorption is only about 2% at 500 mcg and 1.3% at 1,000 mcg; a 2018 Cochrane review of 3 RCTs (153 participants) compared very high oral doses (1,000-2,000 mcg) with intramuscular B12; high oral doses (e.g. 1,000 mcg/day) might be equally effective in Crohn's disease and appear as effective as hydroxocobalamin injections after Roux-en-Y bypass. These are product contents and trial doses; the sheet gives no recommended daily supplement range (fact sheet). ods.od.nih.gov/factsheets/VitaminB12-HealthProfessional
- National Institutes of Health, Office of Dietary Supplements. (2023). Omega-3 Fatty Acids — Fact Sheet for Health Professionals. ods.od.nih.gov/factsheets/Omega3FattyAcids-HealthProfessional
- National Institutes of Health, Office of Dietary Supplements. (2022). Zinc — Fact Sheet for Health Professionals. ods.od.nih.gov/factsheets/Zinc-HealthProfessional
- Sender, R., Fuchs, S., & Milo, R. (2016). Revised estimates for the number of human and bacteria cells in the body. PLoS Biology, 14(8), e1002533. 10.1371/journal.pbio.1002533
- Koh, A., De Vadder, F., Kovatcheva-Datchary, P., & Bäckhed, F. (2016). From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell, 165(6), 1332–1345. 10.1016/j.cell.2016.05.041
- Lozupone, C. A., et al. (2012). Diversity, stability and resilience of the human gut microbiota. Nature, 489(7415), 220–230. 10.1038/nature11550
- Cryan, J. F., O'Riordan, K. J., Cowan, C. S. M., Sandhu, K. V., Bastiaanssen, T. F. S., Boehme, M., et al. (2019). The microbiota-gut-brain axis. Physiological Reviews, 99(4), 1877-2013. 10.1152/physrev.00018.2018
- Hu, S., Loureiro, A., & Zhang, C. (2025). Sensory signals for nausea. Trends in Neurosciences, 48(10), 780–791. Nausea is a protective response to harmful ingested material that promotes avoidance learning of associated cues; stress and anxiety can also trigger it, and it is a common side effect of cancer and obesity medicines. Apart from motion, sensed mainly through the vestibular pathway, most nausea signals are detected by the area postrema (a brainstem circumventricular organ with direct access to blood and cerebrospinal fluid, historically the chemoreceptor trigger zone) and by vagal afferents; gut enterochromaffin cells release serotonin that directly stimulates vagal sensory terminals, most of which express 5-HT3 receptors; in mice, area postrema neurons carrying GLP-1 receptors are needed for the avoidance induced by a GLP-1 receptor agonist (full text PMC12506644). 10.1016/j.tins.2025.08.003
- Hornby, P. J. (2001). Central neurocircuitry associated with emesis. The American Journal of Medicine, 111(Suppl 8A), 106S–112S. Toxins, trauma, drug reactions and motion cause nausea and vomiting; chemosensitive neurons in the area postrema detect emetic agents in the blood and relay to the nucleus tractus solitarius, where abdominal vagal afferents sensing gut contents and gastric tone also end; a central pattern generator in the medulla coordinates the sequence of vomiting, so there is no isolated vomiting centre; 5-HT3 receptor antagonists act mainly on vagal afferents (abstract, PMID 11749934). 10.1016/s0002-9343(01)00849-x
- NHS. (2023). Feeling sick (nausea). Usually goes away on its own. Do: get fresh air, distract yourself, take regular sips of a cold drink, ginger or peppermint tea, ginger foods, smaller more frequent meals. Don't: eat or cook strong-smelling food, eat hot, fried or greasy food, eat too quickly, have a large drink with meals, lie down soon after eating, wear clothes tight around the waist. See a GP if not better in a few days or it keeps coming back. Call 999 if you suddenly feel sick with chest pain that feels tight or heavy, pain spreading to the arms, back, neck or jaw, or shortness of breath: this could be a heart attack. Causes include norovirus or food poisoning, infections such as flu, acid reflux, migraine, labyrinthitis or vertigo, pregnancy, motion sickness, anxiety, alcohol, medicines and recent surgery (page last reviewed 17 November 2023). www.nhs.uk/symptoms/feeling-sick-nausea
- Fasano, A. (2012). Zonulin, regulation of tight junctions, and autoimmune diseases. Annals of the New York Academy of Sciences, 1258(1), 25–33. 10.1111/j.1749-6632.2012.06538.x