This may be one of the most important Reports that I have placed online;
Plasma D (-)-lactate as a new marker for diagnosis of acute intestinal injury following ischemia-reperfusion;
Ischema of the Gastrointestinal Tract.
I am writing 14 days after Spinal Surgery, so please forgive any errors; I am still in pain and badly fatigued.
This is of direct relevance to how I developed D-Lactic/Bacterial Overgrowth Symptoms; There are many ways to develop Bacterial Overgrowth. But this is of direct relevance to myself and possibly many others; I developed Sepsis due to intestinal injury and was then given repeat antibiotics. This is the first time that I have fully understood the implications of the report below and I believe that it may be relevant to a number of us. I believe that Non-Steroidal Anti-Inflammatories are capable of causing such Gastrointestinal injury and Ischema. I have only realised now that I was given nothing to protect my Gut (just over 20 years ago) while taking prescribed NSAID's at high dosage to stop pain from two shoulder tears and pars defect with collapsed disc, that was all misdiagnosed as Chronic Fatigue Syndrome or Somatization disorder.
NSAID's stop the healing process by inhibiting Cox1, Cox2 enzymes, Proteoglycan and Prostaglandin Synthesis to over 90% which is the cause for damage to the mucosal lining. COX-1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining. NSAIDs block the COX enzymes and reduce production of prostaglandins;''NSAIDs inhibit prostaglandin synthesis, which normally potentiates the pain caused by other inflammatory mediators (such as histamine and bradykinin). NSAIDs work by reversibly inhibiting cyclo-oxygenase (COX) enzymes — the two main types of COX enzyme are COX-1 and COX-2, which have different physiological functions.''
It took from my falling ill in 1999 untill 2003 when Sepsis was first diagnosed; but the infection was never fully eradicated and Sepsis returned and I was given repeat Antibiotics; But the Somatization disorder diagnosis was never rescinded, because I remained ill from undiagnosed D-Lactic acidosis, with repeat bouts of breathing difficulty and abdominal pain and multiple neurological symptoms deemed Somatic. When illness started in 1999, I had such bad abdominal pain that I was frequently in hospital and then a blockage (extreme constipation) and was taken into hospital on holiday when breathing difficulty began.
Prior to falling ill in 1999, I was given high doses of NSAID's (Non-Steroidal Anti-Inflammatory) Drugs for several years at high dosage before becoming unwell, when I developed repeated extreme abdominal pain, pounding abdomen, and illness including breathing difficulty that was just dismissed; when my illness was passed off as 'Chronic Fatigue Syndrome', ME, Anxiety and finally diagnosed as Somatization disorder by a Clinician who only saw me on one short occasion (Doctors are simply not trained to understand Bacterial Overgrowth and the symptoms, including abdominal pain are used to make a psychological diagnosis of Somatization; If you have abdominal pain with seeming no explanation, then you will be blamed as Somatizing, because no one was trained to recognise such a condition that can lead to Bacterial Overgroth or D-Lactic illness; and Doctors have still not been trained to do so). If you develop hyperventilation due to acidosis it will be misunderstood as anxiety, overbreathing or hyperventilation syndrome (when hyperventilation is a natural process to eliminate acidosis and CO2). 4 Doctors requested Arterial Blood Gasses from 2002, which were never performed to date; so my symptoms reamained undiagnosed because normal blood tests were often unremarcable as found for many D-Lactic patients even during exacerbation of symptoms (Oxygen levels can remain normal, but you cannot utilise the Oxygen due to increased CO2 and acidity when Mitochondrial Dysfunction occurs). The only signature for this form of acidosis is a Blood Gas, D-Lactic or Faecal assay (to show specific bacteria in overgrowth). Breathing difficulty feels like being suffocated and you naurally breath faster.
The investigations necessary to make such a diagnosis were never performed for myself. The Doctor who diagnosed Somatization disorder in 1999, wrote to other Doctors urging them not to perform further investigations. The Non-Steroidals were later blamed by two Gastroenterologists as the cause of the Infection that led to Sepsis, Bacterial Overgrowth and D-Lactic symptoms.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4806238/
World J Gastroenterol. 1997 Dec 15; 3(4): 225–227.
Published online 1997 Dec 15. doi:
10.3748/wjg.v3.i4.225
PMCID: PMC4806238
PMID:
27053870
Plasma D (-)-lactate as a new marker for diagnosis of acute intestinal injury following ischemia-reperfusion
Yong-Ming Yao,
Yan Yu,
Ye Wu,
Lian-Rong Lu, and
Zhi-Yong Sheng
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cited by other articles in PMC.
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Abstract
AIM: To observe the kinetics of D (-)-lactate alteration in both portal and systemic circulation systems, and its relationship with intestinal injury in rats subjected to acute intestinal ischemia-reperfusion.
METHODS: Anesthetized rats underwent a 75-min superior mesenteric artery occlusion followed by a 6-h reperfusion. Plasma D (-)-lactate levels were measured by an enzymatic spectrophotometric assay.
RESULTS: Intestinal ischemia for 75 min resulted in a significant elevation of D (-)-lactate levels in the portal vein, as compared with the baseline values (
P < 0.05). Plasma D (-)-lactate levels had a tendency to further increase after reperfusion, up to 6 h. Similar alterations in D (-)-lactate were also found in systemic circulation, and there were no significant differences between the portal and systemic circulations at any time point. Moreover, the macropathological evaluation scores were significantly correlated to the portal D (-)-lactate levels in animals at various time points (
r = 0.415,
P < 0.01). In addition, there was a remarkable rise of endotoxin concentration within the portal vein at the end of the 75-min ischemic period (
P < 0.05), reaching a peak at 2 h post-reperfusion.
CONCLUSION: Acute intestinal ischemia is associated with failure of the mucosal barrier resulting in increased plasma D (-)-lactate levels in both portal and systemic blood. The subsequent reperfusion might further increase D (-)-lactate levels, which are correlated to the macropathological alterations. Plasma D (-)-lactate may be a useful marker of intestinal injury following both ischemia and reperfusion insults.
Keywords: D (-)lactate, Endotoxin, Intestinal injury, Reperfusion injury
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INTRODUCTION
Major trauma and shock may initiate a cascade of events leading to sepsis with subsequent multiple organ failure. Gut mucosal barrier dysfunction is assumed to play an important role in causing the septic process[
1]. From our and other studies, it has been suggested that enteric organisms and/or their toxins might translocate across the intestinal mucosa, entering the systemic circulation
via the lymphatic or portal systems and resulting in the development of remote organ damage in animals and patients with shock following hemorrhage, trauma, or burns[
1-
3].
The intestine is one of the most sensitive tissues to ischemia-reperfusion injury. Reperfusion of the intestine is often associated with increased mucosal permeability and ulceration. Mucosal injury has been assessed either morphologically or by measuring the permeability of the mucosal barrier to small or large solutes; however, there exists no reliable serum marker for the early diagnosis of acute intestinal insult in clinical practice.
D (-)-lactate is produced by indigenous bacteria found in the gastrointestinal tract, and mammals do not possess the enzyme systems to rapidly metabolize it[
4]. Therefore, an increase in D (-)-lactate might reflect an efflux of bacteria and/or their products into circulation as a result of mucosal injury. Recently, a report was published showing that serum D (-)-lactate was increased in animal models of acute intestinal ischemia and simple obstruction[
5]; yet, it remains unclear whether this process is associated with a significant dysfunction in mucosal barrier following reperfusion.
The present study was designed to determine the kinetics of plasma D (-)-lactate changes, and to examine whether D (-)-lactate levels are correlated to intestinal damage in rats caused by acute intestinal ischemia-reperfusion injury.
RESULTS
As shown in Figure
Figure1,1, intestinal ischemia for 75 min resulted in a significant elevation in D (-)-lactate levels in portal vein as compared with the baseline values (
P < 0.05). Plasma D (-)-lactate levels had a tendency to further increase after reperfusion, up to 6 h. Similar alterations in D (-)-lactate were also found in systemic circulation (Figure
(Figure1),1), there were no significant differences between the portal and systemic circulations at any time point.
Figure 1
Kinetics of plasma D (-)-lactate alteration in portal and systemic circulation systems. Six to nine animals were assessed for each time point. Data are expressed as x ± sx-. a
P < 0.05 and b
P < 0.01
vs baseline values.
The animals were found to have no abnormal changes in bowel functions before the induction of intestinal ischemia. SMA occlusion for 75 min caused marked intestinal damage, which was much worse upon reperfusion. The macropathological evaluation scores were 2.0 ± 0.2, 2.2 ± 0.2 and 2.7 ± 0.1 at 0.5, 2, and 6 h after reperfusion. The macropathological evaluation scores of intestine were significantly correlated to portal D (-)-lactate levels in animals at various time points (
r = 0.415,
P < 0.01; Figure
Figure22).
Figure 2
Correlation between the macropathological evaluation scores of intestine and the portal D (-)-lactate levels in animals subjected to intestinal ischemia-reperfusion injury.
The endotoxin concentration within portal vein rose remarkably in the control animals, being 9.5-fold over the baseline values at the end of 75-min ischemia (
P < 0.05). It reached a maximum at 2 h after clamp release, and decreased gradually up to the end of the observation period (Figure
(Figure33).
Figure 3
Changes in plasma endotoxin concentration in portal vein following acute intestinal ischemia-reperfusion injury. Six to nine animals were assessed for each time point. Data are expressed as x ± sx-. a
P < 0.05 and b
P < 0.01
vs baseline values.
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DISCUSSION
In the present experiment, we observed that ischemia-reperfusion of the small bowel resulted in a significant elevation in D (-)-lactate levels in both portal and systemic blood. This was potentially associated with failure of the intestinal mucosal barrier leading to the subsequent escape of indigenous endotoxin/bacteria to the circulation systems. Our data also suggested that an early and sustained rise in systemic D (-)-lactate might occur during mesenteric ischemia, even without further reperfusion injury[
5].
The normal gut epithelium provides an anatomical and physiological barrier to the toxic intestinal contents. Conditions which lead to mesenteric hypoperfusion, such as those seen in hemorrhage and other shock states, have been shown to cause breakdown of the intestinal mucosal barrier[
1-
3,
9]. In this study, the status of the mucosal barrier was assessed quantitatively using a plasma marker, namely D (-)-lactate. D (-)-lactate is strictly a product of bacterial fermentation, and it is known to be produced by many species of bacteria found in the gut flora[
4,
5], while mammalian tissue does not produce D-lactic acid, which may not or only slowly be metabolized. D-lactic acid accumulating in the blood can generally be considered as a result of active bacterial metabolism due to systemic infections or some gastrointestinal disorders. In fact, D-lactate acidosis has been described in humans with short bowel syndrome, as well as bacterial infections[
10]. More recently, in a clinical study, Murray et al[
11]demonstrated that patients found to have mesenteric ischemia at laparotomy had significantly elevated D (-)-lactate levels in peripheral blood as compared with the patients with other acute or normal abdominal conditions. Thus, circulating D (-)-lactate could aid in diagnosing acute mesenteric ischemia[
5]. From the current experiment, it is clearly revealed that marked elevation in plasma D (-)-lactate occurred during the occlusive episode, which had a tendency to further increase after release of the clamp and was correlated with a progressive disintegration in the histology of the small bowel in response to reperfusion injury. Therefore, plasma D (-)-lactate appears to be a useful marker reflecting gut barrier damage in the setting of acute ischemia-reperfusion insult.
The mechanisms by which intestinal ischemia-reperfusion leads to a sustained elevation in plasma D (-)-lactate are not entirely understood from this experiment; although, it is possible that acute intestinal insult might cause substantial mucosal injury and increase permeability, thereby inducing an efflux of bacteria and their metabolic products into the portal circulation. In this study, the pathological examination showed marked intestinal lesions during ischemia, which became worse upon reperfusion. Another possible explanation would be that an increased gut permeability might attribute to release of inflammatory mediators, particularly tumor necrosis factor, which is considered to be induced by gut-derived endotoxin/bacteria, as well as hypoxia. These mediators may directly damage the mucosal barrier function[
6]. In addition, it has been reported that ischemia-reperfusion injury to the intestine is associated with overgrowth of the residing microbial flora, and normally low plasma D (-)-lactate levels could be elevated markedly as a result of increased release of D-lactate by bacterial proliferation concomitant to increased mucosal permeability. Our previous observation that the overgrowth of Gram-negative bacteria in the intestinal tract was associated with an increase in intraluminal bacterial products, such as endotoxin following hemorrhage and resuscitation[
3], gives further support to this opinion. Finally, since D-lactate is not metabolized in the liver; persistent elevation of D-lactate level in both portal and systemic circulation systems following intestinal ischemia-reperfusion injury resulted in similar D (-)-lactate concentration in the peripheral and portal vein throughout the observation period. Therefore, our data might be of potential importance, serving as the experimental basis for the favorable clinical use of D (-)-lactate in the diagnosis of acute intestinal disorders related to ischemia-reperfusion injury.
In summary, these data suggest that acute intestinal ischemia is associated with failure of the mucosal barrier resulting in increased plasma D (-)-lactate levels in both portal and systemic blood, and it is also remarkably enhanced by the subsequent reperfusion. Plasma D (-)-lactate may be a useful marker of intestinal injury following both ischemia and reperfusion insult.
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ACKNOWLEDGMENTS
The authors express their gratitude to all colleagues who have been of considerable help in the realization of this study, in particular to Dr. Zhou Bao-Tong, Dr. S Bahrami, and Dr. G Schlag.
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Footnotes
S- Editor: A L- Editor: Filipodia E- Editor: Li RF
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