Cocoa: a food with immunoregulatory properties

Author: De Bonis Chiara
Date: 15/04/2014


Chiara De Bonis


Cocoa is a food relatively rich in polyphenols, which makes it a potent antioxidant and so it is beneficial for cardiovascular health, brain functions and cancer prevention.
Furthermore, cocoa has so many effects on immune system (inflammatory innate response and systemic and intestinal adaptive immune response) and it is able to modify T cell functions that conduce to a modulation on the synthesis of systemic and gut antibodies.
It has a great effect on gut associated lymphoid tissue by modulating IgA secretion and intestinal microbiota.

Anti-inflammatory potential of cocoa

Inflammation is the response of tissues to an aggression caused by pathogens, chemicals or wounding; it involves a complex network of reactions in which the activation and migration of leukocytes to the site of the lesion and the release of growth factor, ROS, cytokines and NO play a crucial role.
In general, flavonoids are associated with anti – inflammatory properties and many studies have reported cocoa’s ability to reduce cytokines, ROS, NO, etc. involved in inflammatory response; however, few studies have focused on the in vivo anti – inflammatory activity of cocoa.
Neutrophils and the transcription factor NF-kB also play an important role during inflammation and it has been demonstrated that cocoa has the potential to positively modulate the neutrophil inflammation activity and to modulate TNF-alpha induced NF-kB activation in intestinal epithelial cells.
With regard to studies in human, it has been reported that a supplementation with cocoa products in healthy humans did not affect inflammatory markers; however, the regular intake of dark chocolate by a healthy population in Southern Italy has been reported to be inversely related to serum C-reactive protein concentration.

Cocoa and lymphoid tissues

Primary and secondary lymphoid tissues constitute two major categories of lymphoid organs. The formation of the primary repertoire of lymphocyte takes place in the primary tissues such as thymus and bone marrow. Secondary lymphoid tissues are responsible for the coordination of immune responses by organizing the interaction of immune effector cells.
Studies in rats demonstrate that a cocoa diet can induce changes in the cell composition of both primary and secondary lymphoid organs.
A diet containing 10% of cocoa in rats increases the thymic content of catalase and superoxide dismutase and promotes the progression of immature thymocytes toward more mature T cell stage; a high – cocoa diet also affects the lymphocyte composition of intestinal Peyer’s patches.

Influence of cocoa on adaptive immune response

This type of immune response is a complex reaction of intracellular and intercellular events from the antigen entry until development of effector mechanisms. Dendritic cells, acting as antigen presenting cells, take up, process e and present antigen to TCR - specific Th lymphocytes. Next, Th lymphocytes proliferate and differentiate, becoming effector cells such as Th1, Th2, Th17. Furthermore, cytokines are involved in the activation of Bcells. Activated B cells differentiated into plasma cells, which synthesize antibodies that specifically bind the antigen that has triggered the adaptive immune response.
The first event in adaptive response refers to Th cell activation. Specific recognition of antigenic peptide by TCR together with co-stimulatory molecules causes production of IL-2 which binds to a receptor consisting of three subunits (CD25, CD122 and CD132) to produce cell proliferation.
Cocoa and polyphenols inhibit both IL-2 gene expression and IL-2 secretion in human blood T cells and the inhibition of NF-kB might mediate the downregulation of both Il-2 and CD25 in a similar way to that of the decrease in pro-inflammatory mediators.

Effects of cocoa on intestinal immunity

The GALT (gut-associated lymphoid tissue) receives a huge antigenic load and has to distinguish between invasive pathogens and innocuous antigens from food and commenasal bacteria.
The intestinal immune response is initiated in the M cells from Peyer’s patches (PPs) which uptake luminal antigens and transport them toward dendritic cells, which interact with interfollicular T lymphocytes. This process induces differentiation and maturation of B cells, which become IgA secreting cells (secretory IgA). This immunoglobulin constitutes the first line of non-inflammatory immune protection at mucosal surfaces.
Dietary intervention with cocoa did not morphologically affect the intestinal structure but is capable of modifying some important aspects of the GALT composition and functionality.
The relationship between a cocoa diet and secretory IgA has been demonstrated in different experimental designs using rats; cocoa reduces S-IgA protein and his effect on this type of immunoglobulin might be due to the influence of cocoa on genes related to Th maturation and Th-B cell interactions. Furthermore, there is a lower number of PP cells with a high capacity to secrete IgA.

The GALT maintains also mucosal homeostasis by inducing a state of non-responsiveness to innocuous antigens, such as commensal bacteria, or by responding actively to counteract pathogens. In this regard, toll-like receptors (TLRs), through the recognition of conserved molecular motifs on microorganisms, are important molecules involved in the cross talk between microorganisms and gut epithelial and immune cells.
Cocoa diet in rats have shown differential TLR expression patterns for TLR2, TLR4, TLR7 and TLR9 in PPs, the small intestine and colon. A high (10%) and continuous cocoa diet produced an upregulation of TLR4 and TLR9 and a downregulation of TLR2 and TLR7 in PPs. Conversely, in the small intestine and the colon, cocoa-fed animals shows lower TLR4 and TLR9 and higher TLR2 and TLR7 gene expression.
Cocoa flavonoids reaching the colon can interact with intestinal microbiota; cocoa and flavonoids have particular bacterial metabolism due to the high degree of polymerization of its flavonoids. After the cocoa intake, monomers are rapidly absorbed in the small intestine while the oligomers and polymers pass intact through the gastrointestinal tract, reaching the colon. This fact allows them to be metabolized by the intestinal microbiota and the colon bacterial metabolites are absorbed into the bloodstream. Once absorbed, the microbial metabolites from flavanols are mainly metabolized in the liver by phase II enzymes and then eliminated in urine.
It is known that unabsorbed dietary phenolics and their metabolites can exert significant effects on the intestinal environment by modulation of microbiota.

With regard to human studies, evidence of the effects of cocoa or cocoa products intake on microbiota composition is scarce. It is important to mention that divergence between the animal and human data could be ascribed to several factors, such as cocoa composition, dose and differential composition and distribution ecosystem (rats vs human gut).


A cocoa diet has been shown to influence the immune system in both intestinal and systemic and intestinal compartments. It could be concluded that although cocoa demonstrates clear anti- inflammatory properties in vitro, when tested in vivo results are more controversial; if inflammation is mild and cocoa has a high polyphenol content, it could help in the resolution of inflammatory response and, in any case, due to its antioxidant properties, cocoa can be a complementary anti-inflammatory therapy.


Francisco J. Perez-Cano, Malen Massot-Cladera, Angels Franch, Cristina Castellote and Margarida Castell (2013). The effects of cocoa on the immune system. Pharmacol review article 4, 1-12.

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