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Gut Bacteria That Produce BH4, Berberine activated dopa/dopamine biosynthesis, improved brain function in Parkinson's, & Clostridia linked to Parkinson's

This article is not medical or healthcare advice. Before starting any health related regimen you should seek the advice of your Primary Care Physician or an M.D.


One of the biggest sources of oxidative stress is when NOS Uncoupling occurs, a situation where i have written about in several different blog articles. A few key factors proceed this:

1. Upregulation of NOS2

2. Downregulation of NOS3

3. Deficiency in one of the coupling cofactors, BH4, iron, or B6


Once NOS Uncoupling occurs, Super oxide is produced instead of nitric oxide. Super oxide can combine with nitric oxide and form the radical peroxynitrite which leads to protein nitration, mentioned previously in another blog article. According to Pall, 86% of cardiac arrests are preceded by NOS Uncoupling. It appears important.


NOS2 is strongly expressed in the GI tract. In families with NOS2 upregulations, i observe frequent cases of Colon Cancer, and diverticulitis. I know this well, i am worst case, these issues are frequent all through my family tree.


I have covered ways to downregulate NOS2 and upregulate NOS3 before. The only exogenous form of BH4 i am aware of is through RX now, and royal jelly. However it appears certain gut microbiome bacteria can produce BH4!


What is the initial source of these bacteria and where is BH4 found ? Breast Milk!


"Actinobacteria (containing Bifidobacterium longum, Bifidobacterium adolescentis, Collinsella aerofaciens, Aldercreutzia equolifaciens, Microbacterium schleiferi, and Micrococcus luteus) generated total biopterin"[1]


"It is known that the gut microbiota modulates the development of the enteric nervous system in mice. We show in the present study that Bifidobacterium spp., a major group of Actinobacteria within the mammalian gut microbiota, and the predominant intestinal genus in breast-fed infants, express PTPS-2. In addition, we have shown that human breast milk has a high BH4 content and may thus be an important contributor to the endogenous BH4 pool early in life. In fact, idiopathic hypertrophic pyloric stenosis is rarely present in breast-fed infants.

These data together with the present finding that PTPS-2 expressing bacteria were not detected in newborn mice suggest that major contributors to the BH4 endogenous pool are breast milk early in life followed by the intestinal microbiota as it becomes established into adulthood. We anticipate this may be of particular importance in subjects with inborn errors of biopterin metabolism in which BH4 synthesis has been compromised.

Although our screening for the presence of human-derived Actinobacteria spp. with PTPS-2 expression ability was limited, it is important to note that this activity does not seem to be species specific. In three cases, we noted that PTPS-2 expression could be detected for one but not another strain of the same species (Bifidobacterium infantis, Eggerthella lenta and Gordonibacter urolithinfaciens). This suggests that either there are differences in PTPS-2 gene presence among strains of the same species, or that gene expression is limited by environmental conditions. Further work is necessary to definitively delineate the presence of PTPS-2 genes across the Actinobacteria phylum, and to assess whether these genes are active in the mammalian intestine and responsible for BH4 production that can be utilized by the host for metabolic purposes.

This study has some limitations. Our primary goal was to identify specific bacteria capable of BH4 generation. Although we began our studies by assessing BH4 production in a mouse model, we went on to screen defined chemostat-cultured human fecal material for the presence of PTPS-2 expressing bacteria since we considered this translationally relevant to human disease. Indeed, our chemostat bioreactor model is set up to mimic conditions of the human intestine and not easily adaptable for inoculation by mouse fecal pellets. Thus, we have not assessed mouse-derived Actinobacteria in this study beyond our initial screening.

In conclusion, the intestinal microbiota contains BH4 generating bacteria and these likely contribute to the age-dependent rise in tissue levels of this biopterin in hph-1 mice, a BH4 deficient strain. The human gut microbiota additionally contains PTPS-2-expressing bacterial species within the Actinobacteria phylum. Our findings have important translational significance, since manipulation of the intestinal flora may significantly influence the total body BH4 content, and this may be therapeutically useful in cases of BH4 insufficiency."[1]


Berberine

"BBR stimulated intestinal bacteria to produce dopa/dopamine in vitro

Then, we detected the effect of BBR on ten intestinal bacterial strains.......out of the ten strains, four bacterial strains (E. faecalis, E. faecium, Proteus mirabilis, and Lactobacillus acidophilus) showed a significant increase in dopa after BBR treatment (10 and 20 µg/mL for 12 h), three had almost no change in dopa production, and another three strains had dopa concentrations under the detection level, with or without BBR treatment (not detectable, ND). The dopamine profile by BBR in the ten strains was different from that of dopa, three bacterial strains (E. faecalis, E. faecium, and Staphylococcus epidermidis) showed a significant increase in dopamine after BBR treatment (10 µg/mL for 12 h), four had almost no change in dopamine production, and another three strains had a dopamine concentration that was ND, with or without BBR treatment."[4]


Berberine Modulates TH and DDC

"TH and DDC are two key enzymes that respectively convert tyrosine to dopa and then dopa to dopamine. We first determined the activity of TH and level of DDC after exposing the bacteria to BBR for 12 h. Enzyme assays showed that BBR (10 μg/mL) treatment in vitro increased the TH activity in intestinal flora by 23% and DDC level by 28%"[4]


Berberine increases L-Dopa

"Transplantation of E. faecalis and E. faecium in animals increased brain dopa/dopamine and improved brain function"[4]


"These results demonstrated that BBR was an agonist of TH in Enterococcus and could lead to the production of L-dopa in the gut. Furthermore, a study of 28 patients with hyperlipidemia confirmed that oral BBR increased blood/fecal L-dopa by the intestinal bacteria. Hence, BBR might improve the brain function by upregulating the biosynthesis of L-dopa in the gut microbiota through a vitamin-like effect."[4]


"BBR increased blood dopa/dopamine in clinical subjects

This study discovered first that the gut microbiota is a new source of dopa/dopamine in the body, and second, BBR enhanced TH to produce L-dopa by triggering the biosynthesis of BH4 in the gut microbiota. As BBR has been an OTC drug for many years, it might have immediately applicable potential in regulating gut–brain dialog and improving brain function in humans."[4]


"This review examines the relationship between key genera of gut microbiota such as Prevotella, Bacteroides, Lactobacillus, Bifidobacterium, Clostridium, Enterococcus, and Ruminococcus and their effects on dopamine. The effects of gut dysbiosis on dopamine bioavailability and the subsequent impact on dopamine-related pathological conditions such as Parkinson’s disease are also discussed. Understanding the role of gut microbiota in modulating dopamine activity and bioavailability both in the periphery and in the central nervous system can help identify new therapeutic targets as well as optimize available methods to prevent, delay, or restore dopaminergic deficits in neurologic and metabolic disorders."[5]


High Ruminococous (Clostridia) and Low Prevotella in Parkinson's

"Substantial evidence supports the involvement of microbiota-gut-brain signaling in dopamine release, synthesis, and bioavailability. In this review, we focused on key microbial genera, Prevotella, Bacteroides, Lactobacillus, Bifidobacterium, Clostridium, Enterococcus, and Ruminococcus, that are intricately intertwined with dopaminergic pathways via myriad effects on dopamine precursors, enzymes, receptors, transporters, and metabolites. States of intestinal dysbiosis involving these key genera disrupt microbiota-gut-brain signaling, leading to dopaminergic deficits that manifest in neuropathological conditions like PD. Overall, the literature continues to support the notion that pathophysiological effects in PD begin within the GI system. Notable pathological markers in the GI tract that are attributed to gut microbial changes include increased intestinal inflammation, mucin-layer degradation, LPS secretion, and α-synuclein accumulation and decreased butyrate synthesis and neuroprotective bile acid production. Vagus-mediated pathways communicate these pathological manifestations to the CNS, leading to neurodegenerative effects on dopaminergic neurons. Consequently, expression of BDNF, MAO-B, and tyrosine hydroxylase is negatively affected by decreased BBB integrity and increased neuroinflammation through microglial activation and ROS production. Although significant advances have been made to elucidate the associations between gut microbiota, dopamine, and related pathophysiology, there remains much to be learned. Many studies have been conducted in animal models that have been developed to mimic a parkinsonian patient through MPTP or rotenone-induced neurotoxicity. PD etiology is a progressive neurodegenerative disease that involves contributory lifestyle, genetic, and socioeconomic factors which are difficult to replicate in animal studies. Food consumption and environmental variability are associated with differing gut microbiomes worldwide. For example, consumption of the Western diet has been associated with specific microbial enterotypes that can predispose individuals to various pathologies. Elevated Ruminococcus resulting from a Western diet results in pro-inflammatory behavior underlying the pathophysiology seen in neurodegenerative disorders such as PD. Metagenomic sequencing of gut microbiota following Western diets also reveals a limited prevalence of Prevotella that is associated with decreased DAT binding affinity. Further, the results from twin studies demonstrate how gut microbiome composition is largely connected to non-genetic factors. Thus, it is plausible that individuals from different communities are more susceptible to developing dopamine-related pathologies based on their gut microbial makeup shaped by diet and environment. Controlling for these variables in future studies is critically important and will help in our understanding of gut microbiota involvement in neurodegenerative etiology. Furthermore, some animal studies did not consider the different time points and progression of the parkinsonian state when measuring dopaminergic changes. Early PD and late PD have different clinical manifestations and may reflect the various effects on the dopaminergic pathways and other pathological changes detailed in this review. Nevertheless, the progress thus far establishing the link between gut microbiota and neurodegenerative disorders is a step forward in our understanding of the complex mechanisms underlying these pathologies."[5]




Please explore the references listed below if you have further interest in this subject. There is a world of information in them.


References:

  1. Intestinal microbiota as a tetrahydrobiopterin exogenous source in hph-1 mice

  2. Neuromicrobiology, an emerging neurometabolic facet of the gut microbiome?

  3. The microbiota–gut–brain axis and neurodevelopmental disorders. Qinwen Wang, Qianyue Yang, Xingyin Liu. Protein & Cell, Volume 14, Issue 10, October 2023, Pages 762–775, https://doi.org/10.1093/procel/pwad026

  4. Oral berberine improves brain dopa/dopamine levels to ameliorate Parkinson’s disease by regulating gut microbiota. Yan Wang, Qian Tong. Published: 24 February 2021. Signal Transduction and Targeted Therapy volume 6, Article number: 77 (2021).

  5. Role of Microbiota-Gut-Brain Axis in Regulating Dopaminergic Signaling. by Sevag Hamamah, Armin Aghazarian, et. al. Biomedicines 2022, 10(2), 436; https://doi.org/10.3390/biomedicines10020436. Submission received: 16 January 2022 / Revised: 6 February 2022 / Accepted: 11 February 2022 / Published: 13 February 2022



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