Serotonin Activates Bacterial Quorum Sensing and Enhances the Virulence of Pseudomonas aeruginosa in the Host

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899


4. Discussion​

This study establishes serotonin's role as a bacterial quorum sensing molecule. Our cellular system data show that serotonin can activate the LasR QS pathway at μM concentrations (Fig. 3b). This finding is of great interest as physiological levels of serotonin in the digestive tract of healthy and diseased individuals is 10 μM (Erspamer, 1966) and ~ 100 μM (Miwa et al., 2001) respectively. The raised levels of serotonin in patients with Inflammatory Bowel Disease (IBD), combined with the insight that serotonin can activate QS pathways, may allow for better patient care and therapeutics. Additionally, the additive effects of serotonin combined with QSM (Fig. 3c) are relevant as bacteria exist naturally in the gut, thus it is highly likely that serotonin will co-exist with bacterial QSMs.

Previous reports have shown that virulence factor production, such as biofilm formation and protease production, are quorum-dependent (Waters et al., 2008, Valiente et al., 2007), which supports the increase in these factors seen when serotonin was administered in both our in vitro (Fig. 4) and in vivo (Fig. 2, Fig. 5) experiments as serotonin activating the LasR QS system. In vitro, our results show that serotonin mimics the effects of exogenous QSM addition in JP2 cells' biofilm formation (Fig. 4C–D), indicating that serotonin acts as a bacterial signaling molecule that is capable of activating QS-regulated phenotypes. Our developed Pseudomonas infection model demonstrated that serotonin was able to activate Pseudomonas virulence in vivo, within the intestines of the mice (Fig. 2, Fig. 5). Within these experiments, there are two points of particular interest: in the absence of serotonin the JP2 mutant that cannot generate its own QSMs was not able to establish an infection, and the effects of PAO1 infection alone were similar to the effects of JP2 with serotonin. When administered the same CFU of JP2 cells compared to PAO1 cells, the JP2 mutant Pseudomonas did not establish any detectable colonies (Fig. S3B). This lack of infection is supported by the SEM images (Fig. 5A) and histology data (Fig. 5B–C). As the JP2 mutant is only lacking in QSM synthesis, this inability to establish an infection both supports the current literature that Pseudomonas virulence is QS dependent and allows for the assessment of restoration of function, specifically the ability to establish an infection. Thus when we restore the infectivity of JP2 by administering serotonin (Fig. S3B), it indicates that serotonin is fulfilling the role of a QSM. The infection with PAO1 alone and JP2 with serotonin resulted in similar levels of CFUs harvested from the intestines (Fig. S1D, S3B), which further supports serotonin's role as a QSM. This similarity between PAO1 alone and JP2 with serotonin is also noted in the histology data (Figs. 2B–C, 5B–C), with both exhibiting intestinal epithelial damage and villi destruction. These data further demonstrate serotonin's ability to restore function to the JP2 mutant lacking QSMs, providing greater evidence for its role as a QSM.

Our experiments demonstrate that serotonin activates the las quorum sensing pathway, which leads to greater infectivity of P. aeruginosa, however continued experimentation with Pseudomonas infection and serotonin can help to fully elucidate this complex interplay. Our mouse model was limited due to its focus on three day old mouse pups based upon their natural susceptibility to Pseudomonas infection, however, it may be possible to exploit serotonin's enhancement of Pseudomonas virulence to investigate Pseudomonas infections in adult mice. Additionally, there are limitations to current biochemical assays for QSMs, such as a lack of a full crystal structure for LasR. Advancements in this field will allow for binding studies of serotonin with LasR, which would further enhance our findings.

While it is uncertain why Pseudomonas utilizes another organism's molecules to enhance their QS networks, it is not a novel phenomenon. Social cheating by bacteria, where the bacteria exploit sensing molecules produced by other organisms in their vicinity to activate their QS systems, has been observed in many circumstances. Thus serotonin may be a way the opportunistic bacteria P. aeruginosa participates in social cheating to enhance its virulence. While our knowledge of the human microbiome is in its nascent stage, the observed Janus-type behavior of serotonin, acting as both mammalian neurotransmitter and bacterial communication molecule, undoubtedly will contribute to further our knowledge of the complex relationship between the host and its' microbiome. Specifically, these findings could lead to a better understanding of the host regulation of the microbiome, especially during infection, potentially leading to a paradigm shift in the management of intestinal bacterial-related illnesses or disorders of the digestive system that are triggered by bacteria.
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899
Bacteria in humans play an important role in health and disease. ... Specifically, we found that serotonin acts as an interkingdom signaling molecule via quorum sensing and that it stimulates the production of bacterialvirulence factors and increases biofilmformation in vitro and in vivo in a novel mouse infection model
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899
So do bacteria produce serotonin and that some how tricks our immune system or somehow helps bacteria to produce biofilm which helps them prevent out body and antibiotics from killing off the bacteria.

so many complaints in here of intestinal problems and having some relief with suggestions on the ray peat forum but not complete healing.

so would the best way to resolve gut problems is biofilm disrupters combined with serotonin antagonist and antibiotics at the same time to solve gut problems.
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899
Bacteria are not loners

The popular view of bacteria is that they are free-living organisms easily kept in check by antibiotics, Berk said. But scientists now realize that bacteria spend most of their lives in colonies or biofilms, even in the human body. While single bacteria may be susceptible to antibiotics, the films can be 1,000 times more resistant and most can only be removed surgically.
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899

Dr. Marcus Ettinger’s Biofilm Busting Protocol:​

Please Do Not Self Treat! For more information on why I’m suggesting this, read my updated, update below.

A.
Biofilm Busting Products. This is just a partial list of the products that can be used, and not all of these products will be, or should be, used at the same time. Additional nutraceuticals may be needed, based on each individual’s unique situation and genetics.

  1. Monolaurin or Lauricidin [AKA Glyceryl laurate or glycerol monolaurate] (monolaurin information).
  2. Nattokinase (a potent oral fibrinolytic enzyme supplement) Some prefer Boluoke Lumbrokinase.
  3. InterFase Plus™ (broad-spectrum enzyme formula w/EDTA – The non-EDTA version can be used by those who can’t tolerate that ingredient)
  4. NAC (N-Acetyl-Cysteine)
  5. Lactoferrin (I like Nutricillin by Ecological Formulas) Dr. Anju Usman of Illinois states, “Our bodies make proteins, transferrin and lactoferrin, which mop up iron and block the ability of biofilm to form,” she said. “But pathogenic bacteria secrete iron chelators to snatch up iron and thus compete with the transferrin and lactoferrin for what they need to survive.”
  6. Xylitol (sugar alcohol)
  7. Nutiva Extra-Virgin Coconut Oil (42-52% Medium Chain Fatty Acids [MCFA], lauric acid, by volume)
  8. Serrapeptase (a potent oral fibrinolytic enzyme supplement)
  9. Guaifenesin
  10. Turmeric, Neem oil, Reishi Mushroom
  11. BFB-1™ & BFB-2™
  12. Smilax Officinalis
  13. Carbonized Bamboo
  14. Bladderwrack
  15. Bioperine
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899


The present study was mainly performed to assess the in vitroand in vivo effects of a natural herbal compound, dihydrotanshinone I (DHT), against standard and clinical H. pylori strains. DHT demonstrated effective antibacterial activity against H. pylori in vitro (MIC50/90, 0.25/0.5 μg/ml), with no development of resistance during continuous serial passaging. Time-kill curves showed strong time-dependent bactericidal activity for DHT. Also, DHT eliminated preformed biofilms and killed biofilm-encased H. pylori cells more efficiently than the conventional antibiotic metronidazole. In mouse models of multidrug-resistant H. pylori infection, dual therapy with DHT and omeprazole showed in vivo killing efficacy superior to that of the standard triple-therapy approach. Moreover, DHT treatment induces negligible toxicity against normal tissues and exhibits a relatively good safety index. These results suggest that DHT could be suitable for use as an anti-H. pylori agent in combination with a proton pump inhibitor to eradicate multidrug-resistant H. pylori.
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899


In vitro anti-Candida activity of selective serotonin reuptake inhibitors against fluconazole-resistant strains and their activity against biofilm-forming isolates​

 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899

Reserpine is an ancient tranquilizer, derived from a plant used in India for centuries. It has a powerful tranquilizing action, has been used to treat hypertension, and was found to be an antidepressant (Davies and Shepherd, 1955). It lowers the concentration of serotonin in the brain and other tissues. Isoniazid, an antidepressant that came into use in the 1950s, is effective, but it probably has no effect on serotonin. When those drugs were popular, serotonin wasn’t recognized as a “neurotransmitter.” It wasn’t until the 1960s that our present set of doctrines regarding serotonin’s effects on mood and behavior came into being.

Antibacterial effectsEdit

Reserpine inhibits formation of biofilms by Staphylococcus aureus and inhibits the metabolic activity of bacteria present in biofilms.[32]
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899

The inhibition of biofilm formation is viewed as a new strategy for the prevention of S. aureus infections. Here, we demonstrated that minimum inhibitory concentrations (MICs) of aloe-emodin exhibited no bactericidal activity against S. aureus but affected S. aureus biofilm development in a dose-dependent manner. Further studies indicated that aloe-emodin specifically inhibits the initial adhesion and proliferation stages of S. aureus biofilm
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899

Antimicrobial resistance in bacteria, such as Staphylococcus aureus, has been the subject of many assistance studies of alternatives for the treatment of infections. These studies aim to solve this problem for bacteria, such as biofilm formation. Aiming to control the emergence of the problem or enhance antibiotic activity, the data sources are inserted into new therapeutic alternatives for the treatment of infections. β-Lapachone and Lapachol Oxime are semi-synthetic derivatives of Lapachol with antimicrobial potential. Clinical isolates from human blood cultures were used in this study. Scanning electron microscopy (SEM) was performed following the glutaraldehyde fixation protocol. The presence of β-Lapachone and Lapachol Oxima interfered in the biofilm formation state. In the MEV, the effect was observed in the reduction of the population of biofilm-forming cells. Therefore, it was possible to conclude the promising potential of the anti-biofilm of substances, justifying the nature of the natural products as agents of inspiration for the detection of new compounds with the biological function.
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899
Objective: ?To investigate the effect of the estradiol hormones on biofilm formati on and structure of Staphylococcus epidermidis after breast implant surgery.

Conclusions: ?High level estradiol can promote bacteria growth, biofilm formation, and biofilm maturity of Staphylococcus epidermidis.
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899

The scientists analyzed the samples for two classes of endocrine-disrupting chemicals—hormones (such as 17β-estradiol, estrone, and 17a-ethynylestradiol), and nonylphenols (detergent degradation products such as 4-nonylphenol, 4-nonylphenolmonoethoxylate, and 4-nonylphenoldiethoxylate). The scientists detected minimal levels of these compounds in biofilms in Boulder Creek upstream of the wastewater discharge. In contrast, many of the compounds downstream of the wastewater outlet were detected at much higher levels. It is interesting to note that many of the hormones were not detected in any of the water samples, both upstream and downstream, but were detected in the biofilms. This shows that the biofilms efficiently accumulate hormones from water and can play a major role in understanding the impact of these chemicals on aquatic organisms.
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899
Biofilm formation and dipeptidyl peptidase IV (DPPIV) enzyme activity contribute to the virulence of oral bacteria, and these virulence factors are partly regulated by quorum sensing signaling system. We recently demonstrated that estradiol regulates growth properties and DPPIV activity of Prevotella intermedia, Prevotella nigrescens, and Prevotella pallens. Here, we examined the DPPIV dependency of biofilm formation of Prevotella aurantiaca. Three strains (two clinical strains AHN 37505 and 37552 and the type strain CCUG 57723) were incubated in three estradiol concentrations (30, 90, and 120 nmol/L). Regulation of DPPIV activity, biofilm and fimbria formation, and coaggregation of bacterial strains were analyzed after incubation with four concentrations (10 nM, 100 nM, 1 μM, 10 μM) of dihydroxy-2,3-pentaedione (DPD), the universal precursor of autoinducer -2 (AI-2), and analogs (ethyl-DPD, butyl-DPD, and isobutyl-DPD) for 24 h. Estradiol enhanced the planktonic growth, coaggregation, and biofilm formation of P. aurantiaca strains. The whole cell extract of AHN 37505 had the highest DPPIV activity, followed by CCUG 57723 and AHN 37552. Inhibition of DPPIV activity with di-isopropylfluorophosphate suppressed the effect of estradiol on biofilm formation. At 100 nM and 10 μM concentrations of DPD, butyl DPD, and isobutyl DPD, biofilm formation of P. aurantiaca was significantly inhibited. Fimbriae formation was enhanced up to concentrations of 100 nM and 1 μM followed by a significant inhibition at higher concentrations of DPD and all analogs. A slight but significant inhibitory effect of DPD and analogs on DPPIV activity was observed. Our results indicate that DPPIV plays a key role in the estradiol-regulated biofilm formation of P. aurantiaca. Quorum sensing autoinducer DPD and C1-alkyl analogs could inhibit biofilm-related virulence of P. aurantiaca.
 
OP
A

area51puy

Member
Forum Supporter
Joined
Mar 21, 2021
Messages
899


Conclusions and Future Directions​

Studies explicitly linking the crosstalk between hormones, P. aeruginosa and the host immune response are limited. Most currently available studies either focus on the influence of hormones on the host, or on P. aeruginosa. It is worthwhile considering that both these hormonal influences occur concurrently in vivo and where studied together will better frame our understanding of the extent to which hormones modulate Pseudomonaspathogenesis and infection outcomes, especially clinically. Human hormones can directly modulate both the innate and adaptive arms of immunity while hormonal-rich environments account for phenotypic P. aeruginosa change, particularly in the context of its growth and virulence. This has clear influence on the host immune response, disease progression and infection outcome.
The study and understanding of the microbial endocrinology of P. aeruginosa, particularly its relationship to sex hormones, may help narrow observed gender gaps in infection and disease dichotomy. Manipulating hormones with antagonists or analogues could potentially be studied for their abilities to alter bacterial growth, quorum sensing and biofilm formation for therapeutic benefit. Understanding specific factors may provide possible avenues toward sex-specific therapeutic strategies that in turn result in better clinical outcomes for patients both acute and/or chronically infected with P. aeruginosa. The wider implications of current therapeutic uses of steroids, such as fluticasone or budesonide in COPD for instance, must also be considered in the context of microbial endocrinology and infection, and necessitates future work. Further developments in this fledgling field can serve to improve clinical strategies toward better patient outcomes especially in the current era of emerging antimicrobial resistance. Altering pathways associated with microbial endocrinology such as that described for P. aeruginosa may well represent an alternative to antibiotics in the treatment of such infection and reduce the pressure now conferred toward the development of new antibiotics to tackle emerging global resistance patterns.
 

Similar threads

Back
Top Bottom