Gut-brain signaling peptide PHI-27 (Peptide histidine isoleucine-27)
A natural 27-amino-acid peptide released alongside VIP in the gut and brain, helping regulate digestion, immunity, and lung function; used as a lab research tool, not an approved drug.
- Class
- Endogenous neuropeptide / VIP–secretin family member
- Status
- No approved therapeutic status identified
- Best-supported effect
- Characterized as a bovine intestinal peptide belonging to the glucagon-secretin family; no biological or therapeutic effect is supported by evidence attached to this card
- Main caveat
- Single vendor-catalog source entry with sequence and one isolation reference; no efficacy, mechanism, or safety data are attached
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
What this is
Peptide histidine isoleucine-27 (PHI-27) is a naturally occurring 27-amino-acid gut-brain peptide found in mammals including humans, pigs, and cattle. It is co-released with a close relative, vasoactive intestinal peptide (VIP), from the same gene — the two peptides are encoded on adjacent exons of the prepro-VIP gene and are processed from the same precursor protein (Bodner and colleagues, PNAS 1985). PHI was first isolated from porcine upper intestinal tissue by Tatemoto and Mutt (PNAS 1981), who identified it using a chemical screen for peptides with a C-terminal amide structure. The name reflects its endpoints: a histidine at the N-terminus and an isoleucine-amide at the C-terminus. The stored sequence (HADGVFTSDYSRLLGQLSAKKYLESLI) is the bovine form, confirmed by Carlquist and colleagues (European Journal of Biochemistry 1984); the active peptide carries a C-terminal amide (-NH₂) on the final isoleucine that is not visible in the raw single-letter sequence. In humans, the equivalent peptide is called PHM-27 (peptide histidine methionine-27), where a methionine replaces the C-terminal isoleucine (Bodner and colleagues 1985).
History
Tatemoto and Mutt reported the isolation of PHI-27 from porcine intestine in 1981 in the Proceedings of the National Academy of Sciences, identifying it as a new member of the glucagon-secretin peptide family with notable sequence homology to VIP, secretin, and glucagon. Shortly after, Carlquist and colleagues (1984) isolated the bovine form in substantially higher yield from bovine upper intestine — forty times more peptide per gram of tissue than the porcine preparation — and confirmed the full amino acid sequence. The human gene structure was mapped in 1985, when Bodner, Fridkin, and Gozes showed that the coding sequences for VIP and PHM-27 sit on two adjacent exons separated by a 0.75-kilobase intronic stretch, with each exon encoding both the hormone residues and the post-translational processing signals. This architecture suggested the possibility of alternative RNA processing generating different proportions of the two peptides from a single gene locus.
What it does
PHI-27 acts on many of the same tissues as VIP, to which it is structurally related and with which it is co-released. In the gut, PHI triggers intestinal secretion: Moriarty and colleagues (Gut 1984) showed that intravenous infusion of PHI in healthy volunteers caused significant inhibition of net water, sodium, potassium, and bicarbonate absorption in the jejunum, with induction of net chloride secretion — effects that reversed after the infusion stopped. Anagnostides and colleagues (Gut 1984) similarly demonstrated secretagogue activity in the human jejunum, with plasma PHI rising to supraphysiological concentrations during infusion. In the brain, PHI acts at thalamic relay neurons, where Lee and Cox (Neuropharmacology 2008) found it produces membrane depolarisation by enhancing the hyperpolarisation-activated cation current (Ih), effectively increasing the excitability of relay cells and suppressing slow oscillatory activity. In the nervous system, PHI is co-stored and co-released with VIP from the same neurons across the central and peripheral nervous system. PHI also modulates prolactin secretion — intravenous PHI raises plasma prolactin levels in rats and stimulates prolactin release from cultured pituitary cells — as well as insulin and glucagon release. Beyond the gut and endocrine tissues, PHI is present in respiratory tract nerve fibres and has been found in intrathyroid nerve fibres from laryngeal ganglia, where it co-exists with VIP.
Evidence
- Human: Moriarty and colleagues (Gut 1984) demonstrated that intravenously infused PHI alters water and electrolyte transport in the human jejunum, producing net chloride secretion and inhibiting sodium and water absorption. Anagnostides and colleagues (Gut 1984) confirmed secretagogue activity in the human jejunum. These studies used pharmacological infusion doses; no randomised controlled trials have been conducted with PHI-27 as a therapeutic agent. No registered trials appear on ClinicalTrials.gov for peptide histidine isoleucine.
- Animal: Lee and Cox (Neuropharmacology 2008) demonstrated that PHI depolarises thalamic relay neurons in rat brain slices via the VPAC2 receptor; PHI required an EC50 of approximately 0.048 µM to produce half-maximum depolarisation versus approximately 0.13 µM for VIP, making PHI more potent than VIP at this site. Goursaud and colleagues (FASEB Journal 2011) reported that PHI upregulates the glutamate transporter GLT-1a in the corpus callosum of an ALS rat model (hSOD1^G93A) by inhibiting caspase-3-mediated inactivation of the transporter, acting via VPAC2 receptors.
- In vitro: PHI activates adenylyl cyclase via Gs-coupled VPAC receptors, raising intracellular cAMP. Tse and colleagues (Endocrinology 2002) identified a goldfish receptor selectively responsive to PHI and its extended form PHV (EC50 ~133 nM for human PHI) that does not respond to VIP or PACAP, suggesting a PHI-specific signalling pathway distinct from the VPAC1/VPAC2 axis.
Known effects
- Intestinal secretion — increases chloride secretion and reduces sodium/water absorption in the human jejunum (Moriarty and colleagues 1984; Anagnostides and colleagues 1984); Gut pharmacology studies
- Thalamic excitation — depolarises relay neurons and suppresses slow oscillatory thalamic rhythms via VPAC2 (Lee & Cox 2008); rat brain slice electrophysiology
- Prolactin stimulation — raises plasma prolactin in conscious rats and stimulates release from cultured pituitary cells; animal studies
- Glutamate transport preservation — upregulates GLT-1a in white matter via VPAC2 in an ALS model (Goursaud and colleagues 2011); rodent in vivo/ex vivo
- Vasodilation — produces vasodilation, though less potently than VIP; animal pharmacology
Mechanism
PHI-27 is a class B GPCR agonist that activates VPAC1 and VPAC2 receptors — the same two receptor subtypes targeted by VIP (Couvineau and colleagues, British Journal of Pharmacology 2012). Both receptors are primarily coupled to Gs proteins and signal through elevation of intracellular cAMP, with downstream activation of PKA and EPAC pathways. Although PHI binds both receptor subtypes, its affinity for VPAC1 and VPAC2 is generally considered lower than that of VIP or PACAP under standard binding conditions; however, Lee and Cox (2008) found PHI to be more potent than VIP at VPAC2-expressing thalamic relay neurons (EC50 ~0.048 µM vs ~0.13 µM), suggesting that the relative potency of PHI versus VIP may depend on the receptor context and tissue environment. Evidence from VPAC2 knockout mice confirmed that PHI's thalamic excitatory effects are fully dependent on VPAC2 receptors: neurons from knockout animals showed no membrane depolarisation in response to PHI (Lee & Cox 2008). PHI's C-terminal isoleucine-amide (not encoded in the stored raw sequence) is part of the structural pharmacophore conserved across this peptide family; loss of the amide cap typically reduces biological activity.
Related peptides
- Vasoactive intestinal peptide (VIP) — the co-encoded sibling peptide, processed from the same prepro-VIP precursor; shares most of PHI's receptor targets and many biological effects, generally with higher potency at VPAC1 and VPAC2
- See also: PACAP (pituitary adenylate cyclase-activating polypeptide), the third major VPAC receptor agonist family member, and PHM-27, the human-sequence counterpart to PHI-27 in which isoleucine is replaced by methionine at the C-terminus
Research directions for this peptide, selected from the current sources — hypotheses you can explore and model. None of it is proven yet; tap any one to see the full thinking.
Could PHI-27 independently reduce gut inflammation, or does it only matter as VIP's traveling companion?
If PHI-27 has its own anti-inflammatory role in the gut, it could become a separate drug target for Crohn's disease or ulcerative colitis. Because PHI-27 is smaller than VIP and varies between species, it might be easier to engineer into a drug that patients could eventually take orally.
Could the non-amidated form of PHI-27 act as a blocker rather than an activator of its receptor?
If true, scientists could use simple chemical modification to switch PHI-27 from stimulating to blocking gut-brain signals. This could benefit people with conditions where the VIP/PHI signaling system is overactive, such as certain inflammatory bowel diseases or hormone-secreting tumors.
Could combining the unique front end of PHI-27 with the back end of VIP produce a hybrid peptide that hits one receptor more precisely than either natural peptide does alone?
If this hybrid worked, researchers would have a finely tuned tool to study gut-brain and immune circuits with fewer off-target effects. In the longer term, such a hybrid could become a starting point for more targeted treatments for gut disorders, inflammation, or metabolic disease.
Does PHI-27 linger on the receptor longer than VIP, stretching the nerve signal even after VIP has let go?
If PHI-27 naturally prolongs VIP signaling through a kinetic mechanism, it could explain why the two are always released together. This knowledge could help design better drugs for gut motility disorders or neuroinflammation by mimicking or blocking this prolonged signaling window.
Does swapping the last amino acid (Ile vs Met) shift the peptide's preference between two closely related receptors?
If confirmed, this could guide the design of new drugs that precisely target either the gut-immune axis (VPAC1) or the circadian-metabolic axis (VPAC2) without cross-activating the other. Patients with inflammatory bowel disease or sleep-metabolic disorders could benefit from more selective therapies.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.854060709476471 | openfold3-mlx |
| ranking score | 0.9234389066696167 | openfold3-mlx |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.803 | global PDE — lower = better |
| disorder | 0.194 | fraction disordered |
| chain pair ipTM (A, B) | 0.854 | interface quality |
▸3-letter notation
▸recipeopenfold3-mlx 0.3.1
| parameter | value |
|---|---|
| model | openfold3-mlx 0.3.1 |
| weights | aedd8f3eb814e392… |
| hardware | apple_m4_base_16gb |
| mlx version | 0.31.1 |
| python | 3.14.3 |
| random seed | 42 |
| msa strategy | colabfold |
| diffusion samples | 1 |
| runtime | 404s |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
python3 openfold3/run_openfold.py predict --query_json {query.json} --runner_yaml examples/example_runner_yamls/mlx_runner.yml --output_dir {output_dir} --num_diffusion_samples 1 ▸citationbibtex
@peptide{pep10574,
sequence = {HADGVFTSDYSRLLGQLSAKKYLESLI},
target = {vpac1},
author = {peptidemodel},
year = {2026},
status = {synthesized}
}