The root vegetable Beta vulgaris rubra has attracted lately much attention as health promoting food. It’s well known for it’s powerful antioxidant, anti-inflammatory and vascular-protective effects, which have been clearly demonstrated by several in vitro and in vivo human and animal studies.

Especially as a nutritional approach to help manage cardiovascular disease and cancer it has increasing popularity. In human studies, beetroot supplementation reduced blood pressure, attenuate inflammation, avert oxidative stress, preserve endothelial function and restore cerebrovascular haemodynamics. Furthermore, several studies have now established beetroot supplementation as effective of enhancing athletic performance. (1)

Especially the reduction of inflammation might be a huge opportunity to extend the use of red beet in the fields of prevention and modulation.

This article elucidates the beneficial health effects of beetroot on the human body, and the incredible potential it might have in several disease, caused by chronic inflammation.

2.1 Potentially bioactive compounds

The beneficial health effects of Beta vulg. is largely attributed to it’s bioactive compounds.

Especially to its high inorganic nitrate content. Nitrate itself isn’t considered to mediate any specific physiological function, the beneficial effects are rather related to it’s redution to nitric oxid (NO). Reduction to Nitrite happens after absorption and entering the entero-salivary cycle, we assume that 25% of Nitrate enters this cycle. Salivary bacteria reduce salivary Nitrate to NO. However, salivary nitrite is re-absorbed into the circulation via the stomach and there metabolised to NO. (1)

Beetroot is one of the few vegetables that contain a group of highly bioactive pigments, known as Betalains. A number of studies reported a high antioxidant and anti-inflammatory capability in vitro and in vivo animal models, sparking interest in a possible use for beetroot in clinical pathologies characterised by oxidative stress and chronic inflammation (in IBD/IBS, asthma, chronic fatigue syndrome, liver disease, arthritis, Alzheimers, Parkinson, CVD, DM, CKD)

Betalains can be separated into Betacyanins, as Betanin and Isobetanin, and Betaxanthins, as Vulgaxanthin I &II and Indicaxanthin. (1)

Additionally we see a certain amount of Cartenoids, Ascorbic acids and Phenolics, as Flavinoids, Phenolic acid and Penolic amides, in Beta vulg. (1)

2.2. Benefits of Betalains

Betalains presented in in vitro models a significant downregulation of inflammatory molecules such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and inflammatory cytokines IL-6 and IL-8. (7)

In vivo models showed a reduction in brain apoptosis in individuals, who have been under high-fat diet, after four weeks of oral treatments with Indicaxanthin. This effect can be explained by the downregulation of the expression of proapoptotic and upregulating antiapoptotic genes, by reduced neuroinflammation via decreasing the expression of proinflammatory genes and proteins, and by mitigated oxidative stress via reducing reactive oxygen species (ROS) and nitrogen species.

Taken together, betalains, particularly betanin and indicaxanthin, exhibit potent antioxidant and anti-inflammatory effects, targeting key mechanisms like ROS reduction, pro-inflammatory cytokine suppression, and the modulation of apoptosis-related pathways. (7)

2.3 Chemical structure of beet compounds

The anti-free radical capacity of betanin is explained with its chemical structure containing sets of hydroxyls and unsaturations in the benzene ring. Betanin prevents oxidative damage to proteins by inhibiting the nitration of the amino acid tyrosine. (7)

3.1 Antioxidant

It’s proven, that beet is a functional food with antioxidative biological function, due to it’s betalain (betain) and other phenolic components. The anti-free radical capacity of betanin is explained with it’s chemical structure (7)

Studies provide evidence that beetroot is an outstanding source of antioxidants. Which show significant protection ability of cellular components from oxidation in vitro and more important, also in vivo. (1)

3.2 Anti-Inflammatory

Data of several studies demonstrat with in vivo models, that betalain-rich dye, made out of Beta vulgaris, reduces the production of the inflammatory mediators TNF-a and IL-1ß. Betalains also limit the effects of lipopolysaccharide in bone marrowed-derived macrophages. LPS activates NF-kB and increases levels of IL-1ß and TNF-a. (7)

In conclusion betalains in red beet, especially Betanin may blunt inflammation via the inhibition of the NF-kB signal pathway and by reducing ROS via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. (8)

Pietrzkowski et al. showed in their study, that betalain-rich oral capsules, in a therapeutic setting, reduce pain and inflammation in osteoarthritic patients. After a period over 10 days and daily supplementation of at least 35mg twice a day, patients showed lower serum levels of Interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-a) and markedly inhibited the activity of two chemokines; regulated oncogene-alpha (GRO-alpha) and regulated upon activation normal T-cell growth (RANTES). (9)

The anti-inflammatory capacity of beetroot also seems to improve endothelium-dependent and -independent vasodilation in the forearm of patients with Raynaud-syndrome. (11)

3.3 Gut Microbiome

Calvani et al. showed, that ingestion of red beetroot juice had a greater abundance of bacteria with well-known beneficial effects, including Akkermansia, Oscillospira, Prevotella, Roseburia, Ruminococcaceae, and Turicibacter, compared with placebo. They also showed significantly higher levels of fecal nicotinate and trimethylamine. (6)

4.1 Irritable bowel SYNDROME (IBS)

IBS is a functional disorder of the gastrointestinal system, caused by alteration of the gut-brain pathways. 

Possible mechanisms for gut-brain dysfunction suggest primary gut disturbance as underlying cause in some of the subgroups. 

Underlying mechanisms that could lead to irritable bowel syndrome include genetic factors, post-infectious changes, chronic infections and disturbances in the intestinal microbiota. Disturbance of the intestinal microbiome often lead to low-grade mucosal inflammation, immune activation, and altered intestinal permeability. Abnormalities in serotonin metabolism and alterations in brain function could be primary or secondary factors. (4)

Other evidence also implicates intestinal inflammation, the cytokine response, and the gut microbiome affecting first the gut and then lead to brain alterations in IBS.(4)

But also some studies have shown that psychosocial factors like childhood abuse and posttraumatic stress disorder are associated with the development of IBS in adulthood. Stress is known to increase immune activation through proinflammatory cytokines and NF-kB. 

Both psychosocial factors are also known to promote a proinflammatory phenotype by sensitizing the corticotropin-releasing factor systems and dysregulating the HPA axis. Also a hyperresponsive HPA axis could contribute to visceral hypersensitivity, also commonly seen in IBS patients. (5)

Anxiety and mood disorders are also well-established risk factors for developing postinfectious IBS, showing a similar risk to a severe infective gastroenteritis episode. Further research of mood disorders pointed out the persistence of systemic and neuroinflammation. 

Functional magnetic resonance imaging studies of IBS patients have shown elevated visceral stimuli response, with increased activation of the anterior cingulate cortex, prefrontal cortex, and thalamus in response to rectal distention. These responses also seem to be modulated by anxiety and depression. (5)

The elevated levels of Interleukin-6 (IL-6) and Interleukin (IL-8), which have been found in IBS patients are affecting the tryptophan metabolism and leading to abnormal serotonergic (5-HT) functioning. Abnormal 5-HT functioning is associated with altered gut mobility and higher nociceptive pain sensitivity, symptoms we commonly see in IBS patients. (5)

Also fecal samples of IBS patients with diarrhoea showed an increased amounts of the cytokines interleukin 1β, interleukin 10, TNFα, and interleukin 6. Also the concentration of these cytokines appeared to associate with the frequency and severity of pain. (5)

We also see an overlap of IBS with ulcerative colitis and Crohn’s disease, in which treatment with anti-TNFa has been shown to improve visceral sensory function and positive attribution biases. This is further evidence that inflammatory processes of the gut affect central processing of information. (5)

4.2 Mental Health Conditions

Osimo et al. found significantly elevated blood levels of CRP, IL-3, IL-6, IL-12, IL-18, sIL-2R and TNF-a in patients with depression with medium-large effect sizes. These results survived sensitivity analyses for psychiatric and lifestyle predictors, influence of skew, influence of poor-quality studies and publication bias. (13)

Also Li et al. identified in their latest systematic review and meta-analysis a range of various inflammatory and immunological biomarkers. Those are significantly different in depressed adolescents as compared to healthy controls. (16)

CRP is one of the best studied inflammatory markers in the field of medicine. Higher levels of CRP have been consistently found in several, even longitudinal, studies of depression.

It’s often preceding the onset of illness, suggesting that inflammation could be a cause rather than simply a consequence of the illness.

Supporting this hypothesis, a Mendelian randomization analyses of the UK Biobank sample found that IL-6 and CRP are likely to be causally linked with depression. 

Furthermore, elevated peripheral CRP levels have been found to correlate with its level in the central nervous system, with a strong correlation between plasma and CSF CRP. (13)

TNF-α is one of the major pro-inflammatory cytokines.

It is produced by dendritic cells and macrophages, which produce during acute infection IL-6 and IL-12. The increase of TNF-α, IL-6 and IL-12 in current depressive episodes elucidate the systemic nature of the inflammatory status, as it’s showing similarity to the immune reaction to an active infection. (13)

Several studies on IL-6 and CRP/hsCRP did find predictive associations between marker levels and treatment response. Studies found that baseline levels were associated with better response to compounds with known anti-inflammatory characteristics, such as infliximab and ketamine.

Also different subtypes of major depressive disorder show differences in their inflammatory profiles, like IL-6 and IL-1β for melancholic depression and CRP for non-melancholic depression. (14)

Studies also showed, that increased inflammation in children and adolescents is associated with greater future depression. Evidence suggests that inflammatory cytokines in the brain can change the structure and function of the brain by altering neurotransmission, hippocampal, hypothalamic-pituitary-adrenal axis and sympathetic system Function. 

These may lead to changes in cognition and can lead to depressive symptoms. (15)

These results confirm that acute depression is a pro-inflammatory state and support the hypothesis that inflammatory marker elevations in depression are due to a right shift of the immune marker distribution. (13)

And they show a bidirectional association between depression and pro-inflammatory states that is detectable early in the life course. (15)

For a food component to be considered beneficial for health it must be bioavailable in vivo.

We see a high bioavailability of inorganic dietary nitrate in red beet and there are reports of close to 100% absorption following digestion. (1)

As reduction of nitrate to Nitrite is mediated to specific salivary bacterias, spitting out saliva or taking oral anti-bacterial treatments, as dental mouthwash, can diminish nitrate-nitrite conversation. (1)

The extent of betalain absorption is less clear. The extent to which betalains are metabolised and structurally transformed to secondary metabolites is yet to be characterized, but should be taken into consideration when examining their bioavailability. (1)

Studies suggest, that some of the active compounds in beetroot are lost or perhaps degraded during cooking and processing. Conceptually, thermal treatment, exposure to bacterial agents, acidification, storage conditions, and modified atmospheric treatment could affect phytochemical composition. (3)

There are several factors, which negatively impact betalain stability, including elevated temperature, light, oxygen, extreme pHs, metal ions, and high-water activity. 

Especially the thermal degradation is a huge challenge for working with betalain-based products. Betacyanins los stability above 60°C, while betaxanthins already do above 40°C. Room temperature seems to exhibit greater stability for betalain-based products, during storage.

In terms of pH, betalains are generally stable within the 3 to 7 range. Alkaline conditions impact them negatively.

The main challenge for betalains’ application in the industry is their instability to these environmental factors.

Encapsulation and adsorption techniques are promising alternatives to overcome these limitations and improve the stability of bioactive compounds. (7)

Factors improving betalain stability include ascorbic acid, isoascorbic acid, chelating agents like citric acid and EDTA. Also ß-cyclodextrin and glucose oxidase might be effective, by absorbing free water and removing dissolved oxygen. (12)

Also generated betanin derivatives might have a strong influence on the bioactivities of B. vulgaris products and can be used for various food applications with new health-promoting potentials and colorant properties. (12)

Studies showed a lower absorption rate, due to lower epithelial transport, of betalains from red beet in comparsion to betalains from other sources, as cactus pear fruit. A recent work suggest lower absorption rates are caused by differences in the food matrix. This suggests that the bioavailability of betanin may be lower after beetroot consumption compared to other sources of betanin. (3)

Although betalains have evidence of biological efficacy in vivo, they seem to have a very low bioavailability in general, which might affect the therapeutic potential. So it’s essential to consider that the interactions between the substances that constitute the natural matrix may influence the bioavailability of betalains from red beet. (7)

An in vitro study using Caco-2 cell showed that indicaxanthin and betanin are absorbed through the intestinal epithelium but in a different way. While Indicaxanthin follows a route without relying on membrane transporters, betanin is limited to them, which reduces its absorption. Indicaxanthin’s absorption is more efficient, and its bioavailability is higher. The absorption of indicaxanthin wasn’t affected by the food matrix, in comparsion to betanin. (7)

A studie on human volunteers showed that betalains peaked in plasma after the first week of fermented beetroot juice intake and in urine after the second week of juice intake. This might suggest that betalains are possibly going through a sequential biotransformation. (7)

Another study observed that a large proportion of betacyanins from beetroot underwent fragmentation, including deglucosidation and decarboxylation, in the gastrointestinal tract. Furthermore, it seems like diverse gut bacteria are involved in the intestinal transformation and so there might be a huge individual variation. (7)

In vivo and in vitro evidence demonstrates that betalains can reduce inflammation. As they are successfully targeting different pathways in the inflammatory process, they exhibit potential in treating various diseases linked to inflammatory pathophysiologies, as IBS.

Based on the collected data beetroot seems to be a health promoting food with various benefical effects. Although the data are promising, we still need to explore via large clinical studies the effect of redbeet on chronic inflammatory diseases like IBS, arthritis, etc. Nevertheless, the collected data highly indicates that beetroot supplemenation is an economic, powerful and natural dietary intervention in a clinical setting.

Regarding the bioavailibility it seems to be quiet essential to create an encapsuled product for supplementation under a critical observed production process, especially regarding the applied heat during production. Also it seems highly important to evaluate factors, which might affect absorption in a postive or negative way and try to exlude or add them to the supplemation progress.

If the product is prepared in the right way under strict conditions and administered to the patient in a proper way, I see a great possibility in betalain supplemention in a clinical setting, which might impact and influence the modern medicine in a sustainable way, as we could treat the cause of the disease, not just the symptoms, and also prevent it in an economic and absolutely low-risk way.

Red beet als contains FODMAPs, which can increase the symptoms in some IBS subgroups, but its questionable, if the amount contained in a red beet extract has any effect of IBS symptoms. But it might be beneficial to evaluate the potential of co-supplements to ease digestion and improve absorption of the bioactive compounds.

Furthermore there might be a potential field in preventing mental health disorders or reduce the symptoms.

The main reason for the high potential in beet root supplementation is the lack of medication to treat chronic inflammatory disorders successfully and prevent them. So far there are none or just a few possibilities to treat the underlying cause or mechanisms of those diseases. Usually therapy depends on reducing symptoms in a more or less effective way.

As the incidence of mental health disorders and other inflammatory disorders like IBS is continuing to rise and is leading so far to an enhanced interest in sustainable and natural nutrition and medicine, it seems to be the perfect time to come up with promising solutions for the medical needs of a certain percentage of the human population.