Your Constipation Is Getting Worse. Your Genes May Be Why.

Your gut produces roughly 95% of your body’s serotonin, and this serotonin doesn’t circulate in your bloodstream like brain serotonin does. Instead, it acts locally on nerve endings in your intestinal wall, telling your muscles when to contract. SLC6A4 is the serotonin transporter, the protein that recycles serotonin back into nerve cells after it does its job. If serotonin isn’t recycled efficiently, your gut muscles don’t get the signal to contract.

The 5-HTTLPR short allele variant of SLC6A4 impairs serotonin recycling by roughly 40%. About 40% of people carry at least one copy of this short allele. If you have this variant, your gut receives fewer serotonin signals telling it to move food along, which means your intestines contract less frequently and less forcefully. Your food moves through your digestive tract more slowly, water is reabsorbed back into your bloodstream more completely, and your stool becomes harder and more difficult to pass.

You might notice that your bowel movements are infrequent (three or fewer per week), that you need to strain significantly to have a bowel movement, or that you feel like you can’t fully empty your bowels. You might feel bloated after eating because food isn’t moving out of your stomach quickly enough. Stress makes this worse because stress suppresses serotonin production even further. You might also have IBS, anxiety, or mood changes because the same serotonin recycling problem affects your brain.

COMT breaks down catecholamines like dopamine and norepinephrine, the chemicals that control your stress response and pain perception. If COMT works too slowly (because of a variant called Val158Met), these stress chemicals build up in your brain and gut. If COMT works too fast, you don’t produce enough dopamine and norepinephrine, which affects motivation and pain relief.

The Val158Met variant can cause slow COMT activity in roughly 25% of people, particularly those of European ancestry. When COMT works slowly, stress chemicals accumulate, which heightens your pain perception and makes your gut more sensitive to discomfort. Your constipation feels worse because every intestinal movement, every bit of pressure in your abdomen, registers as pain. Your gut also becomes more reactive to stress because your stress system can’t turn off efficiently. This creates a vicious cycle: stress makes constipation worse, constipation causes pain, pain causes more stress, which makes constipation even worse.

You might notice that your constipation is dramatically worse during stressful periods, that you’re very sensitive to pain or discomfort in your abdomen, or that you have anxiety or mood swings. You might be very sensitive to caffeine, which adds to the buildup of these stress chemicals. You might find that you feel overwhelmed easily or that you have difficulty shifting focus away from worries about your digestion.

MTHFR converts folate into its active form, 5-methyltetrahydrofolate, which your cells use to make methyl groups. These methyl groups are used throughout your body to regulate gene expression, produce neurotransmitters, and repair damaged tissue. Your intestinal lining constantly regenerates itself: your intestinal cells are replaced every 3 to 5 days. If you can’t convert folate efficiently, your gut cells can’t regenerate properly, which makes your intestinal wall more fragile and permeable.

The C677T variant of MTHFR, carried by roughly 40% of the population, reduces enzyme efficiency by 40 to 70%. If you have this variant, your intestinal cells regenerate more slowly, your gut lining becomes more permeable, and your intestines are more prone to inflammation and dysfunction. Your gut is also less able to produce the compounds it needs to heal itself, which means any inflammation or irritation becomes chronic.

You might notice that your constipation is accompanied by bloating, abdominal pain, or mucus in your stool. Your constipation might alternate with diarrhea (because your intestines are trying to push out material they’re not properly handling). You might have chronic fatigue or brain fog because of the same methylation problem affecting your cells throughout your body. You might find that certain foods trigger stronger reactions than they used to, suggesting that your gut barrier is more permeable.

VDR is the protein that lets your cells actually use vitamin D. Vitamin D is not just about bone health: it’s a critical regulator of immune function in your gut. Your intestinal lining contains roughly 70% of your immune system, and vitamin D controls whether those immune cells remain calm or become hyperactive and inflammatory. VDR variants affect how efficiently your cells can bind to vitamin D and use it.

Roughly 30 to 50% of people carry VDR variants that reduce vitamin D sensitivity, particularly Fok1 and Bsm1 variants. If you have these variants, your gut immune system becomes overactive even when your vitamin D blood levels look normal, which means your intestines stay inflamed and your motility stays impaired. This is one reason standard vitamin D supplementation doesn’t always help people with constipation: the problem isn’t vitamin D deficiency, it’s that your cells can’t use vitamin D efficiently.

You might notice that your constipation worsens during winter months when sun exposure is lower, or that vitamin D supplementation doesn’t seem to help. You might have a history of gut infections or food sensitivities that never fully resolved. You might get constipation along with loose stools or urgency (because your inflamed intestines are dysmotile and unpredictable). You might notice that your immune system in general is reactive: you catch colds easily or take a long time to recover from infections.

TNF stands for tumor necrosis factor, a powerful inflammatory signaling molecule that your immune system releases when it detects a threat. In the right amounts, TNF helps protect you. In high amounts, TNF increases intestinal permeability, damages the tight junctions that hold your intestinal wall together, and triggers chronic inflammation. The -308G>A variant of TNF increases your baseline TNF production.

Roughly 30% of people carry the A allele of this variant. If you have this variant, your gut constantly produces more TNF than normal, which keeps your intestinal lining inflamed and increases intestinal permeability. Your intestines are in a chronic state of irritation, which impairs normal motility. Constipation in this context is often accompanied by abdominal pain, bloating, and a feeling that your gut never quite feels normal.

You might notice that your constipation comes with persistent abdominal discomfort or cramping. You might have a history of food reactions or sensitivities that seem to be getting worse over time. You might notice that your constipation is worse after eating certain foods, or that your gut always feels inflamed. You might have other signs of chronic inflammation: joint pain, brain fog, or a persistent sense of being unwell despite normal bloodwork.

TRPV1 is a pain receptor protein in your gut. It senses temperature, capsaicin (the hot compound in chili peppers), and other irritants, and tells your brain that your intestines are being threatened. This is protective in small amounts, but if your TRPV1 is hyperactive, your intestines become hypersensitive. You feel pain from normal intestinal movements, normal food, and normal pressure.

Roughly 25 to 30% of people carry variants in TRPV1 that increase its activity. If you have this variant, your intestines perceive normal sensations as painful or irritating, which slows down gut motility because your gut’s defense system is constantly triggered. Your intestines tense up in response to perceived threats, which physically prevents food from moving along normally. This creates painful constipation.

You might notice that your constipation is primarily characterized by pain and discomfort rather than just infrequency. You might feel like your intestines are very reactive, that you’re constantly aware of your gut, or that even small amounts of food cause significant bloating and pain. You might find that spicy foods, fatty foods, or certain vegetables cause sharp pain or cramping. You might have a history of being told you have IBS because your symptoms seem to be about pain and sensitivity rather than just slow movement.