Pepper, together with foods rich in fiber, is the most cited avoided foods for IBD active and in remission due to the association of such condiment with burning sensation and increased bowel movement 18.

Capsaicin (trans-8-methyl-N-vanillil-6-Nonenamide) and dihydrocapsaicin are the main capsaicinoids from peppers (Capsicum genus), responsible for the pungent flavor that characterize red peppers. Capsaicin, an alkaloid highly volatile and hydrophobic, is the main bioactive and strongest capsaicinoid 1920. The content of capsaicinoids in peppers is about 0.1 to 2.5 mg/g pepper and the consumption of capsaicin in the human diet is estimated at 0.5 to 4 mg/kg/day 21. The Scoville organoleptic test is used to measure the degree of the pungency of several peppers (Figure 1).

Studies in rats showed that the absorption of capsaicin (isolated) occurs mainly in the proximal portion of the gastrointestinal tract. Following intragastric administration, approximately one-third to one half of the capsaicin dose was absorbed from the stomach. The total intestinal absorption amounted to almost 90% 22. After absorption, capsaicin is passively absorbed and metabolized in the liver by cytochrome P450 system, generating metabolites such as vaniline, vanillamine, vanyl alcohol 23. Nonetheless, none of the capsaicin metabolites presented metabolic activity 24.

The amount of capsaicin reaching colon to be absorbed is not well known. It is possible that pure capsaicin has a faster and more proximal absorption than capsaicin contained in the spicy foods. It is well known that interactions with other food components such as dietary fibers can slow the absorption rate of some nutrients. In this way, a more significant portion of capsaicin from natural food could reach the colon compared to pure capsaicin. Some individuals allege that capsaicin containing foods induce an anal sensation of burning, suggesting that capsaicin reaches the distal parts of the colon. Nonetheless, studies with healthy individuals receiving capsaicin capsules showed that burning sensation during bowel movements was not related during the experiment 25.

Capsaicin has been related to several biological effects, including reduction of body fat 262728, anti-inflammatory, anticarcinogenic, antioxidant activites and modulator of intestinal motility 29303132333435. Most of the capsaicin actions are due to its role as TRPV1 agonist. TRPV1 can be activated by acidity and high temperatures and is described as a molecular integrator of chemical and physical stimuli that provoke pain. In the inflammatory process, the stimulation of sensory neurons leads to a response in peripheral tissues and transmission of nociception to the central nervous system. In this context, TRPV1 mediates the transmission of sensory neuron signaling involved in thermal hyperalgesia and visceral sensitivity. In the human colon, TRPV1 is overexpressed in the epithelial cells and afferent nerves during inflammation 36.

TRPV1 activation leads to the release by sensory fibers of neuropeptides such as substance P (SP) and the calcitonin gene-related peptide (CGRP). These neuropeptides, besides their vasodilator effects, drive the transmission of nociception in the colonic mucosa. In this way, activation of TRPV1 contributes to the generation of inflammatory responses through the recruitment and migration of leukocytes to the site of inflammation, a process that is accompanied by visceral hypersensitivity 3738.

The transient activation of TRPV1 leads to the influx of calcium ions, leading to the membrane depolarization that results in an action potential that propagates the signaling to the brain. However, when a stable and persistent agonist, such as capsaicin, is present, TRPV1 significantly increases the influx of calcium to the intracellular environment of sensitive fibers. Organelles expressing TRPV1 also release calcium into the intracellular environment. The persistently elevated levels of intracellular calcium cause dysfunctionality of nerve fibers due to temporary loss of membrane potential. In this way, chronic capsaicin exposition results in inhibition of pain transmission by inducing persistent calcium influx and nerve fiber dysfunctionality. Capsaicin also downregulates the synthesis, storage, transport, and release of SP and CGRP, both messengers of peripheral pain impulses to the central nervous system (Figure 2). The depletion of SP in nerve terminals reduces or blocks the propagation of pain impulses toward the brain 31. In summary, although in short‐term capsaicin can excite afferent neurons and induce burn sensation (by stimulating TRPV1), chronic exposure causes a block of sensory neurons, attenuating the noxious stimuli 25.

Some studies have shown that TRPV1 channels are involved in the induction and progression of colitis in humans and experimental models 394041. However, the participation of TRPV1 channels in inflammatory bowel diseases is still controversial, showing evidence of pro-inflammatory or anti-inflammatory stimuli 42134445.

Utsumi et al. (2018) investigated the contributions of TRPV1 and TRPA1 in a model of sodium dextran sulfate (DSS) induced colitis. They observed that pretreatment with high doses of capsaicin (100 mg/kg), worsened rectal bleeding, and other inflammatory signs of colitis. In agreement, DSS-induced colitis in TRPV1 KO mice was less intense than in wild-type controls, suggesting that TRPV1 is associated for the colitis progression 46.

However, previous studies of Massa and colleagues showed that colitis induced by dinitrobenzene sulfonic acid was aggravated in TRPV1KO mice 36, suggesting that these receptors could be protective against colon inflammation. Studies with sensory deafferentation induced by high doses capsaicin also exacerbated the inflammation in trinitrobenzene sulfonic acid - induced colitis 47. In contrast with high doses, chronic administration of lower doses of capsaicin attenuated intestinal inflammation in several studies 484950.

Few studies have evaluated the role of TRPV receptors in human colitis. A study comparing colon biopsies of patients with active IBD and healthy controls showed that TRPV1 was increased in IBD patients. TRPV1 was also highly expressed in infiltrating inflammatory cells of patients with active disease. Nonetheless, TRPV1 expression was not associated with the disease severity 51. Another clinical study evaluated the expression of TRPV1 to TRPV4 in colonic mucosa biopsies of patients with UC or healthy controls 52. Interestingly, unlike the previous study, patients with UC had a lower expression of TRPV1 channels in colon epithelial cells, suggesting different associations between TRPV1 and colon inflammation. Once again, TRPV1 expression was not associated with IBD clinical manifestation or with the disease severity 52.

The reduction of proinflammatory cytokines, chemokines, and adhesion molecules related to capsaicin activity seem to involve pathways not mediated by TRPV1. Capsaicin is also an agonist of the peroxisome proliferator-activated receptor (PPAR), especially of PPAR-γ 1415195354. PPAR-γ is part of the nuclear hormone receptor superfamily and expressed in epithelial cells, macrophages and lymphocytes, and other immune cells and plays an essential role in the homeostasis of the intestinal mucosa 15. PPAR γ regulates colon inflammation, as demonstrated by animal and clinical studies 55. To exert its action, PPAR-γ binds another nuclear receptor such as retinoid X receptor (RXR)-α, forming a heterodimer that binds to PPAR response elements (PPRE) in DNA 5356. As a result of PPAR γ action, the expression of proteins codified by the target genes will be up or downregulated 57. PPAR-γ can also regulate gene expression by interacting with other transcription factors such as activator protein (AP)-1, STAT (signal transducers and activators of transcription), and NF-κB, all factors that also regulate gene expression 57 (Figure 2).

Although there are no specific studies with IBD patients or colitis models, the participation of PPARγ in the capsaicin actions was confirmed by studies with macrophages cell line (RAW) that do not express TRPV1. In this cell line, capsaicin inhibited the lipopolysaccharide (LPS) induced production of pro-inflammatory cytokines (TNF, IL-6, and IL-1β). The mechanism was dependent on PPARγ since a PPARγ agonist intensified the cytokine inhibition, and PPARγ antagonist reverts the inhibition caused by capsaicin 53. The anti-inflammatory effect of capsaicin is possibly the consequence of PPARγ interaction with the transcription factor NF-κB. The NF-κB is closely related to the production of inflammatory cytokines, and it is the primary target for PPAR-γ to suppress inflammatory cytokine production 57 (Figure 2).

In conclusion, studies suggest that capsaicin containing foods unlikely aggravate the symptoms or the severity of inflammatory bowel diseases. On the opposite, some studies in animal models show promising results with the use of capsaicin in the control of intestinal inflammation by a mechanism that could involve not only the TRPV1 receptor but also PPARγ. However, clinical studies are still scarce, and data regarding capsaicin concentrations, routes of administration, and long-term side-effects need to be better understood before its use.