Reductions in fecal short-chain fatty acids (SCFAs) but increased plasma SCFAs were observed in patients with Parkinson's disease

Reductions in fecal short-chain fatty acids (SCFAs) but increased plasma SCFAs were observed in patients with #Parkinson disease (PD) and these changes were associated to changes in the gut microbiota and clinical severity.

n.neurology.org/content/98/...

[Bolt_Upright]

Lot's of interesting things in here.

Let's be clear: I am not a smart man. That said, here is my HS Graduate takeaway:

1: SCFAs in PD folks may be escaping the gut through leaky gut.

2: Taking Butyrate to boost SCFAs may just be getting more SCFAs into the plasma and making things worse. Kind of interesting. I posted on this topic 6 months ago: Sodium Butyrate: Conflicting Studies - healthunlocked.com/cure-par...

3: We need to fix the leaky gut. I have a new post on fixing the leaky gut: healthunlocked.com/cure-par....

"Discussion

To our knowledge, this is the first integrated study concomitantly examining both plasma and fecal levels of individual SCFA types and linking to changes in gut microbiota and symptom severity in patients with PD compared with unaffected controls. We found that patients with PD had lower fecal but higher plasma concentrations of SCFAs compared to controls. We further demonstrated that after adjustment for confounders, the reduced fecal levels but increased plasma levels of SCFAs associated with gut microbiota changes and the clinical severity of PD.

In stool, we observed lower levels of SCFAs in patients with PD than controls, in line with several studies that previously found reduced fecal SCFAs levels in patients with PD.8,13,-,15 Similar to the findings of the current study, Tan et al.14 also found an association between reduced fecal SCFAs and worse cognitive and motor outcomes, whereas Aho et al.15 did not find correlations between fecal SCFAs and nonmotor symptom burden in PD. Consistently, recent evidence indicates that SCFAs-producing microbiota are also less abundant in association with PD disease severity, which predicts rapid motor and cognitive deterioration.4,32 In addition, we found that reduced fecal levels of SCFAs could distinguish patients with PD from controls and extend the current knowledge that levels of these SCFAs negatively correlated with motor severity after adjustment for potential confounders. Moreover, cognitive decline is one of the most disturbing nonmotor symptoms of PD. We observed that reduced fecal levels of butyric acid also correlated with cognitive decline in patients with PD. Gut luminal SCFAs are absorbed in colonocytes and are beneficial for maintaining the intestinal barrier and homeostasis.33 Reduced fecal SCFAs, especially butyric acid, are linked to the loss of intestinal tight junctions leading to leaky gut and increased intestinal inflammation, which is associated with aggravating the PD disease process.33 In healthy controls of this study, we found a positive correlation of fecal acetic acid, propionic acid, and butyric acid levels with abundance of Bacteroides sp AM16-15 and Bacteroides sp AM25-34, which are SCFA-producing microbiota.34,35 Notably, this correlation was not present in patients with PD. In line with these findings, in a recent study in a European population, a positive correlation between SCFAs and relative abundance of Bacteroides genera was reported in controls but not in patients with PD. Our results support a previous study that found SCFAs-producing bacteria to be reduced in PD but not REM sleep behavior disorder, suggesting that SCFAs may play a role in the development of PD.36

In plasma, we identified contradictory results that patients with PD had higher plasma concentrations of SCFAs than controls, except acetic acid. Plasma levels of propionic acid correlated with motor symptom severity, whereas butyrate and valerate concentrations associated with cognitive decline. One recent study similarly found plasma propionate level to be higher in patients with PD than controls, while the plasma levels of acetic acid and propionic acid decreased in patients with multiple system atrophy compared to those with PD.17 A case–control study in a Korean population also showed that plasma acetic acid was increased in patients with PD even though the level did not correlate with motor symptom severity.16 Recent evidence also revealed that concentrations of SCFAs are elevated in saliva and urine in patients with PD compared to the general population.15,37 Most of the SCFAs produced in the colon are absorbed and utilized by colonocytes, leaving only a minority entering the peripheral circulation.12 The current findings demonstrate that systemic levels of SCFAs were increased even as fecal levels of SCFAs were consistently reduced in patients with PD. One possible explanation for this divergence may come from increased intestinal permeability that allows SCFAs to enter the systemic circulation, implying an intestinal barrier malfunction. In support of this hypothesis, increased fecal zonulin level, a marker of gut permeability, and increased fecal calprotectin, a marker of gut inflammation, were recently reported in patients with PD compared to controls.15 In vivo rodent model studies also have shown that one of the earliest pathologic changes in PD is intestinal inflammation with impaired intestinal tight junctions that allow for increased infiltration of gut microbial metabolites into the systemic circulation.38 The “leaky gut phenomenon” in patients with PD may lead to a higher penetration of SCFAs from gut to the systemic circulation. However, among the subtypes of SCFAs, plasma level of acetic acid was not significantly increased in patients with PD. In addition to the possible leaky gut phenomenon effect, several conditions may contribute to the plasma levels of acetic acid. Acetic acid can be produced endogenously and the plasma level is influenced by metabolic stress, such as prolonged fasting, lipolysis, and glucagon-like peptide-1concentrations.39 These factors may influence the observed comparable plasma levels of acetic acid between patients with PD and controls in this study. The elevated SCFAs in systemic circulation may cross the BBB and affect the neuron–microglia microenvironment in the CNS. Although accumulating evidence supports the beneficial effects of SCFAs, including maintaining BBB integrity and affecting neurogenesis through epigenetic mechanisms, SCFAs may also exert pathologic effects if the level is over a concentration range that was shown to promote neuroinflammation in a transgenic α-synuclein rodent model.7 Further studies on the molecular mechanisms of different SCFAs at various concentration range in the CNS are warranted. Furthermore, while motor symptom severity positively correlated with plasma propionic acid levels, cognitive dysfunction correlated with circulating butyric acid and valeric acid concentrations. These associations may reflect the diverse pathophysiologic processes of motor and cognitive decline in PD.37 Links between systemic levels of valeric acid and brain pathology also have been reported in patients with Alzheimer disease,40 with higher plasma valeric acid associated with a greater degree of amyloid deposition and circulating inflammatory marker expression. In addition, levels of propionic acid in the systemic circulation correlated with motor symptom severity in the current work. In earlier studies, increased levels of this SCFA were reported to trigger mitochondrial dysfunction, activate T-cell immunity, and increase oxidative stress, especially in the striatum, leading to motor dysfunction in patients with autism spectrum disorder.41 The positive correlations between plasma levels of SCFAs and inflammatory markers in this study could be interpreted as supporting a relevant association between SCFAs and systemic inflammation. Further experimental studies exploring the molecular mechanisms of individual types of SCFAs in promoting neuroinflammation and neurodegeneration are warranted.

The plasma-to-fecal ratio of individual types of SCFAs could provide a better landscape of individual SCFAs in the leaky gut condition of PD process. We observed that the plasma-to-fecal ratios of separated SCFAs types were linked to the respective abundance of specific gut microbiota. For example, Bifidobacteria and Bacteroides spp produce acetate, whereas microbes from the Firmicutes phylum (Roseburia, Eubacterium, and Lachnospira) actively produce butyrate.42 The Bacteroides spp are Gram-negative Bacteroidetes and predominate in the human gut. Acetic acid is the most abundant SCFA and acts in maintenance of the normal structure, integrity, and function of the intestines.34 The absence of positive correlations between Bacteroides spp abundance and fecal levels of all types of SCFAs in patients with PD may suggest a dysbiosis state that leads to impaired intestinal barrier function in the disease process of PD.34 In addition, among patients with PD, we found that abundance of the proinflammatory Clostridiales bacterium correlated with the plasma-to-fecal ratio of propionic acid, whereas the abundance of another proinflammatory microbe, Ruminococcus sp AM28-29B, correlated with an increased plasma level of butyric acid. Clostridiales bacterium and Clostridiaceae taxa, such as Clostridium spp, are also associated with inflammatory bowel disease.43 The abundance of members of the Clostridiales order correlates positively with the regulatory T-cell transcription factor Foxp3, as does abundance of members of the phylum Verrucomicrobia.44 We therefore speculate that Clostridiales bacterium and Ruminococcus sp AM28-29B may be able to induce intestinal regulatory immune responses leading to intestinal inflammation and possibly explain the increased plasma-to-fecal ratios of propionic acid and butyric acid. Of note, the abundance of Prevotella spp P3-122 correlated with reduced plasma-to-fecal ratios of all SCFAs. Several studies, including our previous work, have shown a decreased abundance of Prevotellaceae and Prevotella genera in patients with PD.6,19 As commensals, Prevotellaceae bacteria are involved in mucin synthesis in the gut mucosal layer and in production of neuroactive SCFAs through fiber fermentation.45 The Prevotella sp P3-122 may partially explain the decreased plasma-to-fecal ratio of all SCFAs in patients with PD. Finally, although numerous studies have shown that propionic acid and butyric acid have anti-inflammatory effects, results conflict.7,13 Both pro- and anti-inflammatory activities of SCFAs have been documented, and dietary supplementation with SCFAs produces variable effects on inflammation that appear to be strongly influenced by SCFA concentration. Our further analysis showed plasma levels of SCFAs, especially propionic acids, positively correlated with peptidoglycan maturation pathway and glycolysis IV. Peptidoglycan is one of the pathogen-associated molecular patterns and has been shown to enhance proinflammatory cytokine secretion from activated microglia.46 Glycolysis is the conversion of glucose to pyruvate or lactate, which results in the generation of ATP and has been shown to be abnormally regulated in neurons in patients with PD.47 An in vivo model of zebrafish deficient in the familial PD–associated protein PTEN-induced kinase 1 observed an upregulation of TigarB, the ortholog of human TP53 induced glycolysis regulatory phosphatase (TIGAR).48 Further investigation is needed into how different concentrations of individual SCFA types affect immune responses in the context of PD pathology.

Our study has several limitations. First, we did not directly measure colonic SCFA concentrations but used fecal SCFA levels as a surrogate for colonic SCFA production and absorption. Second, we did not examine intestinal barrier function using a gut permeability assay in our participants, although one recent study has demonstrated gut hyperpermeability in patients with PD compared to controls.15 Third, cognitive function was assessed using MMSE. Further detailed neuropsychological tests are needed for assessing the correlation between SCFA levels and individual cognitive domain decline in patients with PD. Fourth, dietary intake pattern assessed by FFQ was comparable between patients with PD and controls, while some other studies reported between-group differences.49,50 As some controls enrolled in this study were spouses of the patients with PD, we speculate the common environment shared between spouse controls and patients with PD may contribute to the comparable dietary intake pattern between patients with PD and controls in this study. In addition, constipation and use of laxatives and anticholinergic agents or cholinesterase inhibitors may influence the results of gut microbiota and gut metabolites. Studies enrolling healthy controls from general populations and considering these potential confounders should be taken into account in the future. Furthermore, the diagnosis of PD was based on clinical diagnostic criteria in this study and lacks neuropathology confirmation. Finally, the cross-sectional study design precludes any inferences of a causal relationship between SCFAs and the disease process in PD. Further longitudinal follow-up studies with serial measurements of both fecal and plasma SCFAs are warranted.

Our findings suggest that gut metabolite SCFAs may serve as surrogate gut-oriented markers for distinguishing patients with PD from controls and reflecting disease severity. Further studies of the exact mechanisms of different SCFAs at neurons and microglia in experimental models should help to elucidate the complex gut–brain interactions in PD."

[rescuema in reply to Bolt_Upright]

1. yes

2. not necessarily as it depends on the concentration. See below.

3. yes leaky gut is a big issue, but the problem may include inappropriate diets/conditions promoting the gut permeability such as branched hyphal form candida amongst growth of other glyphosate(or other toxins)-resistant opportunistic pathogens that choke out the beneficial microbe diversity such as mucin synthesizing Prevotellaceae and Prevotella genera found to be lacking in PWP. Antinutrients such as lectin are not necessarily the culprit but the outcome of the proinflammatory cascade due to compromised gut barrier. This includes high SCFA in plasma which is a derivative of differing microbiota compositions. Always question chicken or the egg.

"SCFAs may also exert pathologic effects if the level is over a concentration range that was shown to promote neuroinflammation in a transgenic α-synuclein rodent model....Both pro- and anti-inflammatory activities of SCFAs have been documented, and dietary supplementation with SCFAs produces variable effects on inflammation that appear to be strongly influenced by SCFA concentration."

[Hidden]

Butyrate combined with TUDCA extends the lifespan in ALS patients. They used sodium phenylbutyrate. How is that different from just sodium butyrate?

Much more info online about this.

Dr. Rudolph Tanzi of Harvard is involved.

onlinelibrary.wiley.com/doi...

[Ghmac]

so I am confused here - is adding butyrate a good idea or not?

[Bolt_Upright in reply to Ghmac]

Sadly, nobody seems to know if butyrate is good or not. Just that SCFAs seem to be in the plasma of people with PD. There are conflicting reports on Butyrate.

[Hidden in reply to Bolt_Upright]

MICE! Mice are not humans. In the absence of SCFA, the MICE had no PD. When the SCFA was reintroduced in the MICE , they were more prone to PD. Then it states, THIS CONFLICTS WITH THE HUMAN DATA. Focus on the human data unless you are deeply concerned about the well-being of the rodents.

Butyrate reduces neuro inflammation. Combined with TUDCA it even reduces ALS.

Butyrate is extremely important and “good.” Too much butyrate is not but that is true of just about everything.

My take away from this; once again, mouse data should be bypassed as we seek out in human data.

pubmed.ncbi.nlm.nih.gov/341...

[Bolt_Upright in reply to Hidden]

Not so simple. But you are entitled to your opinion (and may be correct). Please see my post "Sodium Butyrate: Conflicting Studies" healthunlocked.com/cure-par...

[Hidden in reply to Bolt_Upright]

I edited my response to better explain. You are giving too much credence to mouse data. It even stated that the mouse data conflicted with the human data. I don’t form any opinions based off of mice data.

[Hidden in reply to Bolt_Upright]

Bolt, a theory….Decreased SCFA in feces but increased in plasma. Could this be related to slow gut motility and or IBS which is common in PD? Are we maybe blaming SCFA when the problem could be the underlying cause of the increased plasma levels of SCFA? I think slow motility and IBS causes worse PD symptoms and the increased SCFA in plasma is involved but not the source of the problem.

Thoughts on my theory?

[Hidden in reply to Bolt_Upright]

Me again , my theory led me to this.

onlinelibrary.wiley.com/doi...

Quotes:

Regarding fecal Butyric acid level

“The Butyric acid level was inversely correlated with IBS,”

And

“Fecal Butyric acid level lower in IBS patients.”

I think the study from which you are concluding “butyrate bad” is a very flawed study. Butyrate is not the problem. IBS is! That is my theory. Why the reduced fecal butyrate correlates with worse PD is not the fault of the butyrate but the IBS. 🤓💩

And then there is this:

bmcgastroenterol.biomedcent...

But I’m pooped so not more of this butyrate in 💩 research.