Low OXPHOS is a biomarker and likely cause of inflammatory bowel disease (IBD)
-
The evidence that IBD conditions such as Crohn’s Disease (CD) and ulcerative colitis (UC) are of mitochondrial origin has been accumulating for several decades. As such, the findings of the study below are not necessarily novel per se. However, this is one of the few studies that found evidence for systemic mitochondrial dysfunction (as opposed to just local, in the GI tract) of patients with IBD. Thus, the study indirectly argues (in support of Ray’s writings) that IBD, just like all other chronic diseases, is a systemic and not localized condition. In addition, the study argues that the biomarkers of low OXPHOS in blood (and not just in GI tract) are a reliable predictor of future IBD onset, as well as a biomarker of disease progression. More specifically, despite IBD being inflammatory in origin, the study argues that mitochondrial dysfunction precedes the development of an inflammatory state, and thus is the true cause of IBD. Btw, coincidentally (not!), several recent studies have demonstrated that the same is true for cancer as well. This finding not only suggests that pro-metabolic therapies should be beneficial for IBD, but that also virtually all current “treatments” of IBD are at best masking symptoms and at worse worsening the disease progression in the long run. Namely, virtually all drugs currently used for IBD are immunosuppressve and many of them are also metabolic inhibitors, which is the exact opposite of what a patient needs when diagnosed with a systemic mitochondrial disease, which IBD is now becoming known to be. The study also throws cold water on the usage of glucocorticoids and surgery as established treatments of severe IBD. On one hand, the study argues that long-term glucocorticoid therapy can be pro-inflammatory (something that I have posted about in the past), which obviously exacerbates IBD, while the chronic stress and inflammation induced by major abdominal surgery also have largely the same negative effects.
Speaking of therapies – the study itself states that a combination treatment of B vitamins + vitamin D is a very reasonable approach for actual so-called “disease-modifying treatment” for IBD given the crucial role of the B vitamins in OXPHOS and the systemic anti-inflammatory effects of vitamin D.
“…Here, we show an imbalance in mitochondrial homeostasis and bioenergetics, demonstrated by reduced activity of respiratory complexes and reduced production of TCA intermediates in the plasma of patients with CD and UC. Upon intestinal inflammation, the architecture of mitochondria in intestinal epithelial cells is dysmorphic, with the destruction of the cristae, which leads to increased apoptosis. Changes in mitochondrial morphology and bioenergetics promote metabolic changes in the glycolytic pathway and decrease antioxidant signaling.17 In line with this, in this study, compared to controls, reduced levels of molecules associated with the TCA cycle were observed in the plasma of patients with UC and CD, suggesting that TCA-related molecules are closely linked to the pathogenesis of UC and CD.
Research confirms that the mucosa of the large intestine in the group of patients with UC is in a state of energy deficit and is characterized by a low level of adenosine triphosphate (ATP).9 The results of the study by Hsieh et al show that ultrastructural abnormalities of mitochondria occur even before global changes in colonocytes in the colonic mucosa of patients with UC and long before the onset of mucosal inflammation. Among others, the expression of mitochondrial ATP synthase (ATP5B), a protein responsible for the production of ATP from ADP, is reduced.18 Our study also observed a significant reduction in ATP in the group of IBD patients.
Furthermore, it was shown that damage to mitochondria is an event preceding the development of inflammation in patients with UC. The reason may be increased ROS production in epithelial cell mitochondria in UC patients.19,20 Therefore, preventive measures using antioxidant agents in the group of people genetically predisposed to autoimmune diseases seem reasonable to prevent the development of IBD. For example, Batjargal et al showed that herbal mixtures used in Mongolian traditional medicine activate cell defense mechanisms through anti-inflammatory and antioxidant effects. The action mentioned above was mainly attributed to phenolic components in the mixtures21 and may be relevant for IBD management.
A study by Scoville et al found significant reductions in TCA intermediates, including citrate, aconitate, α-ketoglutarate, succinate, fumarate, and malate in plasma samples of CD patients compared to control and UC patients. Additionally, β-hydroxybutyrate, synthesized from excess acetyl-CoA, was significantly reduced in CD patients compared to healthy controls and UC patients.22 Besides, in mitochondria isolated from the colonic mucosa of patients with UC, it was shown that the respiratory chain II, III, and IV mitochondrial complexes were significantly reduced by approximately 50 to 60% compared to mitochondria isolated from the control mucosa of healthy people, suggesting the involvement of mitochondrial dysfunction in the pathogenesis of UC.7,19 Our studies also confirmed this, as the data shows a reduction in Krebs cycle intermediates in the plasma of IBD patients. Significantly lower concentrations of Cytochrome C Oxidase and Cytochrome C Reductase levels were observed among the patients with CD and UC.
Furthermore, studies confirm that acetyl-CoA concentration in various cellular or pericellular compartments correlates with the severity of pathological conditions. For example, low acetyl-CoA levels play a key role in the pantothenate kinase-related neurodegenerative disease (PKAN). Thus, measuring acetyl-CoA concentration in biological fluids can help monitor the progression of diseases related to acetyl-CoA metabolism and assess the effectiveness of possible new therapies. Although acetyl-CoA concentration in different organs can vary greatly, whole blood levels can represent the accumulated acetyl-CoA in the body. Moreover, blood can be easily collected for clinical trials or therapy monitoring.23
These observations linking Pantothenate regeneration to increased CoA-dependent cell function might also explain the importance of a local Pantothenate supply for colonic homeostasis. Indeed, dietary Pantothenate deficiency alters the intestinal barrier function in the carp. Furthermore, combined supplementation of vitamins B and D in humans mitigates the symptoms associated with IBD. These results suggest that colonocytes might be particularly sensitive to CoA depletion. Indeed, these cells use the butyrate produced by microbiota for energy production through fatty acid β-oxidation and regulation of stem cell renewal.24 In our study, significantly lower Acetyl CoA levels were found in the plasma of IBD patients.
Besides, it has been shown that (IDH2), a mitochondrial NADP+-dependent isocitrate dehydrogenase, is involved in catalyzing the conversion of isocitrate to α-ketoglutarate while producing NADPH from NADP+ in mitochondria. NADPH is an essential factor involved in detoxification, similar to the thioredoxin and glutathione systems. Therefore, IDH2 is a critical antioxidant enzyme in regulating redox status and reducing oxidative stress damage.25 Our results show that patients with IBD had significantly lower NADH2 and IDH2 levels. In the group of patients with CD, treatment with corticosteroids had a significant positive effect, as significantly higher IDH2 and succinate levels were found in patients taking corticosteroids compared to those not.
Glucocorticoids are strong anti-inflammatory and immunomodulatory agents used in moderate to severe IBD, but their use is limited by several important adverse drug effects.26 Additionally, corticosteroids have not been proven effective in maintaining remission in IBD and thus should not be used for this purpose.27 Corticosteroids inhibit the synthesis of pro-inflammatory proteins. In IBD patients treated with corticosteroids, mononuclear cells, and colon epithelium cells down-regulate the production of nuclear factor kappa-B and many pro-inflammatory cytokines compared to untreated patients.28 However, Ding et al showed that glucocorticoids do not have a uniform immunosuppressive effect. Their impact on inflammatory reactions depends partly on the dose and the length of administration. Excess endogenous and exogenous glucocorticoids can even potentially induce inflammatory reactions in the organism.29 Therefore, to avoid potential adverse effects, it is necessary to administer corticosteroids reasonably in IBD patients.27 The results of our research can be explained by the short-term use of corticosteroids, which led to the inhibition of the inflammatory process in patients with CD and, thus, an increase in the level of IDH2 and the level of succinate. In line with this, We have also detected a positive correlation between blood inflammation markers and the TCA cycle. In the group of patients with CD, we observed a correlation with CRP: the higher the CRP, the lower the ATP, and there was a similar trend for succinate levels. Acute inflammation mainly affects cells with mitochondrial impairments, as during inflammation, the intestinal mucosa cells require large amounts of energy to repair the damaged mucosa. Previous reports have shown that active inflammation in cells leads to significantly increased energy expenditure, leading to significant losses of energy and protein.30
In addition, studies of the transcriptional profiles of the colonic mucosa of patients with a first diagnosis of IBD without treatment showed that the inflamed tissue shows an overrepresentation of genes involved in inflammation and an underrepresentation of genes involved in mitochondrial respiration, both in CD and UC. This confirms the vital role of mitochondria in IBD development,31 which can also be confirmed by our research in which we showed the correlation of several mitochondrial function biomarkers with the disease activity scale in CD patients. For example, IDH2, α-ketoglutarate, and succinate levels are significantly lower in patients with higher disease activity.
Our results also show a significant correlation between UC patients’ albumin levels and IDH2, α-ketoglutarate, succinate, and NADH2 levels. The results of our analysis may indicate the effects of albumin as an antioxidant and protein protecting against chronic inflammation. Albumin is the main component of plasma proteins responsible for approximately 80% of the antioxidant effect of thiol in the body.32 In an experimental study of liver inflammation, the protective effect of albumin on mitochondria against TNFα damage was demonstrated. In the presence of albumin, liver cells showed decreased production of mitochondrial ROS and fatty acid β-oxidation, which was explained by restoring the breakpoint between isocitrate and α-ketoglutarate in the TCA. These findings demonstrate that albumin is necessary to protect hepatocyte cells from mitochondrial oxidative stress.33
The role of oxidative stress in IBD is unquestionable, and the implementation of antioxidant therapies seems rational. However, IBD patients show significant heterogeneity in response to treatment, inhibiting the formation of reactive oxygen species. In the case of 5-aminosalicylic acid (5-ASA), commonly used in the treatment of IBD, which exerts its therapeutic effects mainly through antioxidant mechanisms, it has been shown that the effects of the drug are not the same in all patients. Therefore, it should not be assumed that all patients’ treatment with antioxidants will provide clear health benefits. Antioxidant therapies in IBD should be selected individually for each patient, considering the pathological overproduction of selected reactive species and careful monitoring of redox signaling.34
Importantly, cell biosynthesis of thiol compounds (eg, glutathione, lipoic acid, albumin, coenzyme A) decreases with age.35 CD patients showed a correlation between the length of illness and mitochondrial function biomarkers: the length of the illness significantly affected the levels of NADH2, with levels lower in patients with longer durations. A similar but insignificant trend can be seen for Acetyl CoA and IDH2 levels. No correlation was found between the length of illness and other biomarker levels (Supplementary figure S1B). For patients with UC, we detected an effect of age on the levels of IDH2 as a trend and a significant effect on NADH2 levels. Thus, energy metabolism, age, and length of illness are closely related. Studies of animal models and people confirm that ATP levels fall linearly with age and, thus, length of illness. A critical relationship was also observed, where the bioenergetic failure of the cell is often associated with such variables as cumulative DNA damage, stem cell exhaustion, oxidative stress, and inflammation. Understanding these mechanisms can help prevent many diseases associated with lowering ATP in cells, for example, by using adequately adapted preventive measures.36
The correlation between CD patients and RBC is also interesting: the higher the RBC, the higher the fumarate levels. Carboxylic acid intermediates of the Krebs cycle, such as succinyl-CoA, are involved in erythropoiesis by driving heme synthesis. Additionally, small molecule dicarboxylates in this pathway (eg, fumarate) maintain erythropoiesis through the mechanism of stabilizing hypoxia-inducible factor 1α (HIF1α) after exposure to hypoxia, which is otherwise degraded by hydroxylation by alpha-ketoglutarate-dependent prolyl hydroxylases.37,38 Therefore, our results suggest a coordinated regulation that occurs in mitochondria: We demonstrate that mitochondrial metabolites influence erythropoiesis and may regulate specific aspects of the systemic inflammatory response in the intestinal epithelium. Therefore, the development of effective drugs affecting the interactions of Krebs cycle intermediates is a promising area of new therapeutic opportunities in IBD.
Finally, our data shows the effect of surgical treatment on CD patients: patients with surgical treatment have significantly lower NADH2 levels. A similar situation occurred in UC patients taking biological treatments with significantly lower plasma NADH2 levels. The indication of surgical treatment and biological treatments is usually the final solution when conservative treatment is ineffective. Surgical treatment is necessary when there is an urgent situation that threatens the patient’s life or the development of cancer.39 Exacerbating the disease process (biological treatments), the condition after major surgery, which involves a lengthy recovery process, and the presence of severe forms of IBD in those undergoing surgery and requiring biological treatments may be reflected by the particularly low NADH2 levels in that group of patients.”