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Histidine (symbol His) is one of the 20 amino acids our bodies use to create protein. It was first isolated in 1896 by the Swedish chemist Sven Gustav Hedin. Although it was initially believed to be essential only for infants, we now know that it’s essential for adults as well—meaning we must obtain it from food!
Along with being used for protein biosynthesis, histidine is a precursor for the signaling molecule histamine; this gives it a role in immunity, gastrointestinal function, and neurotransmission. It’s also involved in blood cell production, metal chelation, and proton buffering.
Histidine is found in most protein-rich foods, including red meat, eggs, seafood, poultry, soy, beans, and nuts.
The Biological Roles of Histidine
Broadly, amino acids are molecules with the molecular formula of R-CH(NH2)-COOH-NH2, where -NH2 is the basic amino group, COOH is an acidic carboxyl group, and R represents a molecular unit called a side chain. That side chain is unique for each amino acid, and its chemical properties create different classes of amino acids: nonpolar and neutral, polar and neutral, polar and acidic, and polar and basic.
Although hundreds of amino acids exist, only 20 of them are used for what amino acids are arguably most known for: forming the building blocks of proteins. Proteins are not only an essential macronutrient in the human diet; they’re molecules that perform most of the various functions of life. In addition to being major structural components of cells and tissues, proteins have incredibly diverse roles that range from driving chemical reactions (e.g., enzymes) to signaling (e.g., some types of hormones) to transporting and storing nutrients. Proteins are synthesized within cells through a two-phase process of transcription and translation, during which amino acids get linked together to form long chains (spanning anywhere from 20 to over 2,000 amino acids in length!).
So, while all proteins are made of amino acids, not all amino acids are used for making proteins! We use the term proteinogenic amino acids to refer specifically to the amino acids that get encoded into our DNA and incorporated into proteins. Meanwhile, non-proteinogenic amino acids do neither of these things (although they still have some very important biological roles!).
Amino acids can be further classified based on whether we can create them in our bodies, or need them from our diet. Essential amino acids are amino acids that can only be obtained from foods; these include histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Non-essential amino acids are amino acids our bodies can synthesize metabolically from other molecules; these include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine. And, some amino acids are conditionally essential, meaning our bodies can normally make them, but some circumstances (like illness or stress) can limit their synthesis and create a dietary requirement. These include arginine, cysteine, glutamine, tyrosine, glycine, ornithine, proline, and serine.
Histidine is proteinogenic, meaning it gets incorporated into proteins, and essential, meaning we must obtain it from food! Intriguingly, its essential status was initially missed due to the relatively short duration of the amino acid depletion studies at the time (ranging from six to eight days); it wasn’t until longer studies were performed that histidine deficiency indicators became evident.
One of histidine’s primary jobs is serving as a precursor to histamine—a chemical messenger with important neurological and immune functions. Four different types of histamine receptors exist throughout the body (including in neurons, airway smooth muscle cells, blood vessels, stomach, heart, the central nervous system, and bone marrow), giving histamine regulatory roles in countless body functions.
For example, although it’s most famous for being a player in allergic responses (including itching, food allergies, skin allergies, and even anaphylaxis!), histamine is also involved in regulating the sleep-wake cycle (due to influencing the release of hormones involved in the circadian rhythm), cognitive function (due to its role in neurotransmission), stomach acid secretion, and blood cell formation. The presence of histamine receptors in blood vessels also allows histamine to help regulate microcirculation in muscles during exercise. Via these roles of histamine, the amino acid histidine is involved in local immune reactions, sleep, neurological functioning, digestion, and more!
Histidine also has some unique properties associated with the imidazole side chain in its molecular structure. For one, the imidazole ring contains nitrogen molecules that can bind or release protons, allowing histidine to act as a pH buffer. Histidine is also able to form complexes with metal ions (including iron, copper, cobalt, nickel, cadmium, and zinc), and is responsible for binding iron in the body’s hemoglobin and myoglobin molecules. Histidine’s ability to chelate metal ions also allows it to reduce the toxic effects and free radical production induced by those metals, including zinc and copper neurotoxicity!
Histidine also has notable antioxidant functions. Some of its antioxidant activity is due to its role as a metal chelator, but it’s also able to scavenge reactive oxygen species and nitrogen species (both of which act as free radicals), as well as sequester advanced glycation and advanced lipoxidation end products (which have been linked to health issues like microvascular disease and diabetic retinopathy).
Lastly, histidine is a component of a skin barrier protein called filaggrin, and is released as a natural moisturizing factor during the proteolysis of this protein. This gives it a functional role in skin health!
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Histidine in Health and Disease
Histidine has been studied for potential roles and benefits in a wide variety of conditions—including inflammatory bowel diseases, neurological disorders, inflammation, skin conditions, fatigue, diabetes, obesity!
Histidine and Inflammatory Bowel Disease
Although the research is mostly limited to animal models, some evidence suggests histidine could play a beneficial role in inflammatory intestinal disorders. For example, a 2009 study using a mouse model of colitis found that dietary histidine (but not alanine, the other amino acid tested) was able to reduce intestinal tissue damage and colon weight, as well as reduce the expression of a proinflammatory cytokine called tumor necrosis factor alpha (TNF-α). And, a 2015 analysis of patients with ulcerative colitis found that lower plasma levels of histidine were associated with a higher risk of disease relapse. In vitro experiments have likewise shown that histidine exerts anti-inflammatory effects in ways that might benefit inflammatory bowel diseases.
Histidine and Seizures
Rodent studies have indicated a protective effect of histidine on seizures. For example, in rat models of epilepsy, seizures induced by the drug pentylenetetrazole (a central nervous system stimulant) could be reversed with histidine administration, with higher histidine doses having an increasingly ameliorative effect. Animal models of epilepsy have also suggested that reduced histidine levels promote longer seizure durations. And, in both mice and rats, histidine administration has been shown to enhance the effectiveness of anticonvulsant drugs like carbamazepine and phenytoin. More research is needed in humans to test whether these effects apply to us, too!
Histidine and Cognition
Although research so far is limited, some evidence suggests histidine could benefit cognition—especially when it comes to mental fatigue. A human trial from 2015 found that among people with high fatigue and sleep disruption scores, two weeks of histidine supplementation significantly decreased fatigue scores, significantly shortened working memory reaction time, and significantly increased scores for clear thinking and attentiveness.
Histidine and Atopic Dermatitis (Eczema)
Due to its incorporation into filaggrin in the skin, histidine has a potentially therapeutic role in inflammatory skin conditions, particularly eczema. Several randomized, placebo-controlled pilot trials found that supplementing with oral histidine (4 g daily) reduced eczema disease severity by 34 – 39% in adults, while supplementation with 0.8 g daily reduced eczema area and severity index scores by 49% in children.
Histidine and Obesity
A variety of studies have suggested that histidine could be protective against obesity. In a 2016 cross-sectional study of Northern Chinese adults, for example, dietary histidine intake was higher among people with healthy body weights, compared to those who were overweight or obese. Histidine intake was also inversely associated with waist circumference/abdominal obesity, BMI, and daily calorie intake. Similarly, rodent studies have shown that supplementation with histidine causes a reduction in food intake—likely through its conversion to histamine, which then acts on the hypothalamus to regulate feeding behavior and metabolism. In fact, antihistamine medications (also known as H1 blockers), as well as antipsychotic medications that similarly block histamine, are known to induce weight gain or increase appetite as a side effect.
Histidine and Metabolic Syndrome
Histidine has shown beneficial for some features of metabolic syndrome. For example, in a 2013 trial of 100 women with metabolic syndrome, supplementation with 4 g per day of histidine (for a period of 12 weeks) significantly improved insulin resistance, reduced BMI, reduced fat mass, lowered circulating levels of non-esterified fatty acids, and reduced measures of inflammation and oxidative stress. These effects appeared to be due to histidine’s suppression of pro-inflammatory cytokine expression in fat cells (adipocytes). Likewise, observational studies and mechanistic animal studies have both linked higher histidine intake with lower measures of metabolic syndrome—including fasting blood sugar, insulin resistance, C-reactive protein, and markers of oxidative stress.
Histidine and Type 2 Diabetes
Through its conversion to histamine, histidine plays a role in blood sugar control and may have protective action against diabetes. Higher histidine intake has been associated with improved biomarkers of glucose homeostasis (including fasting blood sugar and HOMA-IR, a measure of insulin resistance). This may be due to histidine increasing brain histamine activity, which in turn signals to the liver to reduce the expression of gluconeogenic enzymes, leading to lower glucose output from the liver. As a result, higher histidine intake could help blood sugar control for diabetics. Its anti-obesity and anti-inflammatory activity further reduce some risk factors for diabetes. More controlled studies are needed in humans to explore histidine’s potential anti-diabetic properties, though!
Histidine and Cancer
Although evidence is still preliminary, some research suggests histidine could have a protective effect against certain types of cancer. In a 2023 analysis of two large prospective cohorts (the European Prospective Investigation into Cancer and Nutrition, and the UK Biobank), higher circulating levels of histidine were associated with a significantly lower risk of colorectal cancer (a 7 – 20% reduction in risk for each standard deviation). And, a 2022 in vitro study of liver cancer cells found that histidine treatment reduced the expression of certain tumor markers (particularly ones related to inflammation, angiogenesis, stem cells, and glycolysis), while also sensitizing cancer cells to sorafenib, a targeted cancer drug. More research in humans will help clarify these potential anti-cancer properties of histidine!
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Health Effects of Histidine Deficiency
Unlike most essential amino acids, histidine deficiency doesn’t immediately induce a negative protein balance. Instead, the body first compensates for inadequate histidine intake by increasing the catabolism of histidine-containing molecules (like hemoglobin or carnosine), leading to a reduction in hemoglobin levels in the blood, and increased breakdown of skeletal muscle tissue.
Problems From Too Much Histidine
Although histidine from food sources is unlikely to cause adverse effects, histidine supplementation may cause problems under certain circumstances—especially at high doses. For example, while histidine supplementation of 4 – 4.5 g daily is generally associated with benefits for insulin sensitivity, inflammation, and body composition, supplementation in excess of 24 g daily has been associated with adverse effects like reduced zinc levels and cognitive impairment. Likewise, animal evidence suggests that in people prone to allergies, a high histidine intake could amplify symptoms; same goes for people susceptible to peptic ulcers (due to the potential of histidine to increase stomach acid secretion). However, these possibilities haven’t been confirmed in humans!
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How Much Histidine Do We Need?
For adults, the recommended dietary allowance (RDA) for histidine is 14 mg per kg of body weight daily, or 6.4 mg per lb. However, different organizations have different recommendations here: the World Health Organization, for example, recommends 8 to 12 mg of histidine per kg of body weight daily.
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