Sex shapes gut–microbiota–brain communication and disease Hokanson, Kenton C.; Hernández, Caroline; Deitzler, Grace E. ...
Trends in microbiology (Regular ed.),
February 2024, 2024-02-00, 20240201, Letnik:
32, Številka:
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The microbiota–gut–brain axis (MGBA) plays a crucial role in shaping the development, function, and disease state of biological systems within and beyond the gastrointestinal tract.The historical ...exclusion of females in biomedical research, especially in neuroscience, limits our progress in unraveling disease etiology and the impact of sex on gut and brain function – particularly in neurodevelopmental conditions like autism spectrum disorder (ASD).The influence of microbiota and sex differences on the development and function of the enteric nervous system (ENS), and their combined role in contributing to ASD, is an understudied and potentially groundbreaking field of inquiry.Recent research highlights enteroendocrine cells as pivotal mediators of communication between gut microbes, the host gastrointestinal tract, sex steroids, and the brain, providing exciting avenues for further exploration.
Research into the microbiota–gut–brain axis (MGBA) has entered a golden age, raising the hope that therapeutics acting on it may offer breakthroughs in the treatment of many illnesses. However, most of this work overlooks a fundamental, yet understudied, biological variable: sex. Sex differences exist at every level of the MGBA. Sex steroids shape the structure of the gut microbiota, and these microbes in turn regulate levels of bioactive sex steroids. These hormones and microbes act on gut sensory enteroendocrine cells, which modulate downstream activity in the enteric nervous system, vagus nerve, and brain. We examine recent advances in this field, and discuss the scientific and moral imperative to include females in biomedical research, using autism spectrum disorder (ASD) as an example.
Research into the microbiota–gut–brain axis (MGBA) has entered a golden age, raising the hope that therapeutics acting on it may offer breakthroughs in the treatment of many illnesses. However, most of this work overlooks a fundamental, yet understudied, biological variable: sex. Sex differences exist at every level of the MGBA. Sex steroids shape the structure of the gut microbiota, and these microbes in turn regulate levels of bioactive sex steroids. These hormones and microbes act on gut sensory enteroendocrine cells, which modulate downstream activity in the enteric nervous system, vagus nerve, and brain. We examine recent advances in this field, and discuss the scientific and moral imperative to include females in biomedical research, using autism spectrum disorder (ASD) as an example.
The opioid overdose crisis has continued to increase over the past few years resulting in about 1.7 million people battling substance use disorder related to prescription opioid pain relievers. ...Individual susceptibility to opioid overdose and addiction is largely determined by genetic variation. One gene that shows genetic variation is OPRM1, the gene for the mu‐opioid receptor (MOR), the primary target of all clinically used and abused opioids. OPRM1 is susceptible to several naturally occurring single nucleotide polymorphisms (SNPs), such as A118G (or N40D). N40D is the most prevalent SNP and causes an Asn to Asp switch leading to the removal of an N‐glycosylation site. N40D is associated with various disorders including substance use disorder and alcoholism. However, how N40D and other SNPs change MOR function at molecular and cellular levels are still unknown. To address this gap, we examined the effect of the N40D mutation on two key aspects of receptor function: trafficking and signaling. Our results suggest that N40D variant receptor shows steady state localization and trafficking that is distinct from the MOR, leading to differences in downstream consequences of receptor signaling from the same agonist. These results have profound implications to understanding the pharmacogenetics of opioid physiology and developing personalized care in the future.
Compounding Au-Ni with carbon (C) lubricants is a feasible approach to improve its mechanical properties and wear performance. In this study, 3.5 μm-thick Au-Ni/C nanocomposite coatings with a low ...residual stress on CuCrZr substrates by magnetron sputtering were developed. Face-centered cubic and hexagonal close-packed stacking structures were both confirmed in the composite coatings based on transmission electron microscopy and X-ray diffraction analyses. Amorphous C (a-C) was confirmed to be the structure of C in the composite coatings, and its graphitization transition with an increase in the C content was validated by X-ray photoemission spectra and Raman spectroscopy. By compounding 0.88 wt% a-C, the hardness of the Au-Ni/a-C coating reached 400 HV, which is twice higher than that of the Au-Ni coating. The electrical resistivity of the Au-Ni/a-C coating is relatively stable with an increase in the a-C content. As graphitization occurred on the wear track, the produced composite coatings showed a minimum wear rate of 2.2 × 10−6 mm3/N·m under atmospheric conditions, which is half that of the Au-Ni reference coating. Under vacuum, the wear performance of the produced Au-Ni/a-C composite coatings was similar to that of the Au-Ni reference coating.
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•Low residual stress Au-Ni/a-C composite coating was developed by magnetron sputtering method.•The deposited Au-Ni base alloy is composed of FCC and HCP two phases.•No adhesion degradation observed on the Au-Ni/a-C coating compared with the Au-Ni reference coating.•The hardness of the Au-Ni/a-C coating is improved from 200 HV (Au-Ni reference) to 400 HV.•The wear rate of the Au-Ni/a-C coating in the atmosphere is less than half of the Au-Ni reference coating.
Introduction: high dose chemotherapy (HDT) and autologous stem cell transplantation (ASCT) is an effective treatment in relapsed follicular lymphoma (FL). Alternative regimens including bendamustine ...based conditioning (BeEAM) had been developed to improve lymphoma outcome. Visani et al. showed in a phase I/II for relapsed aggressive lymphomas and relapsed Hodgkin lymphomas that bendamustine used at a dose of 200mg/m2, 2 days in combination with cytarabine (400 mg/m2, day-5 to day-2), etoposide (200 mg/m2, day-5 to day-2) and melphalan (140 mg/m2, day-1) was well tolerated with promising efficacy results. We designed a single arm, multicenter, phase II study for first and second chemosensitive relapses in FL patients (pts) evaluating this conditioning regimen.
Methods: The primary endpoint is the efficacy of BeEAM by measuring the 2-year event-free survival (2-year EFS) rate defines by relapse, progression, death from any cause and initiation of a new therapy. The hypothesis was the improvement of 2-year EFS rate from 70% (H0) to 85% (H1). Based on a Fleming-A'Hern single-stage design, 50 pts are needed. Secondary endpoints are: overall response rate (ORR) at day 100 according to 2007 Cheson criteria; progression-free survival (PFS); overall survival (OS) and safety profile of BeEAM. Main eligible criteria are: histologically confirmed FL relapsed (WHO grade 1, 2, 3a); aged 18-65 years; first or second chemosensitive relapses after salvage immunochemotherapy based on 2007 Cheson criteria with a complete (CR) or a partial response (PR) before the BeEAM; eligibility for ASCT; signed informed consent. This trial was funded by the French government PHRC program 2012.
Results: Twenty-one pts were included between July 2014 and November 2016 in 7 LYSA centers. One patient did not receive the treatment. The final analysis was based on 20 pts. Inclusion were performed for 16 (80%) and 3 (15%) pts at 1st and 2nd relapses, respectively. One patient (5%) was included at 3rd relapse and is considered as protocol minor deviation. The median time between the initial diagnostic and the 1st relapse was 3.6 years (0.7-12.9). In first-line therapy, 17/20 pts (85%) were treated with immunochemotherapy. At the relapse allowing inclusion, the FLIPI score were 0-1, 2, ≥3 for 6 (32%), 7 (36%), 6 (32%) pts, respectively. Salvage treatments were rituximab (R) associated with, dexamethasone, cytarabine, and platin in 19 pts and R-CHOP in one patient. The median age at inclusion was 57 years (range, 39-63); 16 (80%) and 4 (20%) pts were in CR and PR before BeEAM. After 18 included pts, the protocol was amended due to unexpected toxicities especially two hepatic veino-occlusive diseases (VOD), leading to the reduction of bendamustine dosage. Finally, 17 and 3 pts were respectively treated at 200mg/m2, 2 days and 160mg/m2, 2 days. The median time for neutrophil>0.5 G/L and platelet recoveries>20 G/L were 7.5 (0-11) and 7 (2-18) days. Patients received a median of 4 (0-12) packed red blood cell units and 6 (3-21) platelet units until J100. The median duration of hospital stay duration was 27 days (20-50). Response evaluation at J100 showed 19 CR pts and one patient in progressive disease. The ORR was 95.0% (95%CI, 75.1-99.9). Six pts progressed with two deaths of the FL (Figure 1A). With a median follow-up of 31 months (16-42), the 2-year EFS rate was 59.6% (95%CI, 35.1-77.4) but two events correspond to unplanned rituximab maintenance in two CR pts (Figure 1B). The PFS and OS rates were 69.6% (95%CI, 44.5-85.1) and 90% (95%CI, 65.6-97.4), respectively (Figure 1C). Fifteen pts (75%) had infectious complications until J100 that needed treatments for more than 7 days. Grade ≥3 toxicities were infections (N=18, 90%), gastrointestinal disorders (N=14, 70%), mucositis (N=12, 60%); atrial flutter (N=1, 5%); acute renal failure (N=2, 10%); HHV6 reactivation (N=3, 15%). In total, 29 serious adverse events (SAE) were declared for 16 pts. Two pts experienced VOD classified as unexpected SAE; one of them needed a hepatic transplantation. No patient presented toxic death.
Conclusions: the prospective evaluation of BeEAM conditioning in FL pts with a chemosensitive relapses showed excessive toxicities especially infectious complications, cases of VOD leading to premature termination of the trial. Based on the 20 treated pts, the outcome seems not improve with the use of BeEAM. Our study does not encourage the use of BeEAM conditioning in relapsed FL pts.
Ghesquieres:Sanofi: Consultancy; Gilead: Consultancy; Celgene: Consultancy. Le Bras:Amgen: Consultancy. Le Gouill:Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria. Cartron:Celgene: Consultancy, Honoraria; Gilead Sciences: Honoraria; Sanofi: Honoraria; Janssen: Honoraria; Roche: Consultancy, Honoraria.
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Eating high fat chow increases sensitivity of rats to drugs that act indirectly on dopamine receptors (e.g., cocaine). This effect is greatest in female adolescent rats. Eating high fat ...chow also enhances sensitivity of adult male rats to the behavioral effects of drugs that act directly on dopamine receptors (e.g., the dopamine D
2
/D
3
receptor agonist quinpirole); however, it is not known if this effect is greater in adolescents. It is also not known if there are sex differences in this diet‐induced enhancement that mirror those previously demonstrated with cocaine. To test the hypothesis that females are more sensitive than males to the diet‐induced effects on quinpirole‐induced yawning, male and female Sprague‐Dawley rats (postnatal day 25) eating either standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat), were tested once per week with quinpirole (0.0032–0.32 mg/kg) for 8 weeks. Eating high fat chow increased sensitivity to the behavioral effects of quinpirole in male rats. Specifically, quinpirole induced more yawning in male rats eating high fat chow, (e.g., an increase in the maximal effect) as compared to standard chow fed controls. In comparison, female rats yawned significantly less than their male counterparts, and eating high fat chow did not increase the frequency of yawning. These data suggest that alternative behavioral assays should be considered to measure sensitivity to the behavioral effects of dopamine receptor agonists in female rats. For example, other directly observable behaviors, such as locomotion or rearing, might provide a way to measure drug sensitivity in female rats. These results further demonstrate the importance of studying drug sensitivity in both male and female subjects.
Eating a high fat laboratory chow enhances sensitivity of rats to the behavioral effects of drugs that act on dopamine systems (e.g., cocaine). Further, in male rats, eating high fat chow impairs ...expression of insulin signaling phosphorylated protein kinase B (pAkt), which is vital for maintaining dopamine homeostasis. Eating high fat chow enhances sensitivity of female rats to drugs that act indirectly on dopamine receptors (e.g., cocaine); however, less is known about sensitivity of females to drugs that act directly on dopamine receptors (e.g., quinpirole). Further, it is not known if pAkt expression is impaired in female rats eating high fat chow. Some quinpirole-induced behaviors (e.g., penile erections and yawning) are either absent or occur at very low frequency in adult female rats. It is not known if quinpirole sensitivity in adolescent rats is more comparable between sexes. The present report examined another unconditioned behavioral effect (i.e., rearing) induced by once-weekly cumulative doses of quinpirole (0.0032-0.32mg/kg) in male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat), for several weeks throughout development, (spanning adolescence and early adulthood). Following behavioral assessments, pAkt expression was examined using western blot protein analysis. Eating high fat chow increased sensitivity of male rats to the quinpirole-induced yawning, as compared to male rats eating standard chow. However, other unconditioned behavioral effects of quinpirole (yawning and hypothermia) remained unchanged. Female rats yawned significantly less than male rats, and eating a high fat chow had no effect on any quinpirole-induced unconditioned behavioral effect in female rats. Eating high fat chow also reduced pAkt levels in male, but not female rats. Taken together, these data suggest that alternative behavioral and biochemical assays should be considered to measure sensitivity of female rats to the behavioral effects of dopamine receptor agonists, and further demonstrate the importance of studying drug sensitivity in both male and female subjects.
Eating a diet high in fat can lead to several negative health consequences, including obesity, type 2 diabetes and dopamine system dysfunction. For example, rats eating high fat laboratory chow are ...more sensitive to the behavioral effects of drugs acting on dopamine systems, including direct‐(e.g., quinpirole) and indirect‐acting (e.g., cocaine) dopamine receptor agonists. Dietary supplementation with omega‐3 fatty acids, such as fish oil, can successfully prevent and treat this high fat chow‐induced enhanced sensitivity to dopaminergic drugs. Fish oil contains two omega‐3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), therefore the relative contribution of each fatty acid to the beneficial effects of fish oil are not known. To test the hypothesis that daily injections of DHA will prevent high fat diet‐induced enhanced sensitivity to the behavioral effects of cocaine (1.0–17.8 mg/kg), adolescent female rats ate standard laboratory chow (17% kcal from fat), or high fat chow (60% kcal from fat) in combination with daily injections of DHA or vehicle. Eating high fat chow enhanced sensitivity of female rats to cocaine‐induced locomotion as compared to rats eating standard chow alone. That is, the cocaine‐induced locomotion dose‐response curve was shifted upward in rats eating high fat chow, as compared to rats eating standard chow. Daily injections of DHA did not prevent this effect. Rats receiving daily injections of DHA (regardless of type of chow) gained significantly more weight than rats eating standard chow alone or high fat chow alone. While these results might suggest that EPA, rather than DHA, is the likely omega‐3 fatty acid driving the aforementioned effects of fish oil, only one dose of DHA has been examined thus far. Future experiments will focus on examining different doses of DHA alone and in combination with various doses of EPA to determine the relative contribution of each omega‐3 fatty acid in mediating the beneficial effects of fish oil. These data add to a growing literature regarding the health benefits of fish oil and omega‐3 fatty acids.
Support or Funding Information
Research reported in this was supported by the National Institute of General Medical Sciences of the National Institute of Health under linked Award Numbers RL5GM118969, Tl4GM118971, and UL1GM118970.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat laboratory chow are more sensitive than rats eating standard chow to ...the behavioral effects of the dopamine receptor D2/D3 receptor agonist quinpirole. Specifically, quinpirole induces yawning in rats, and quinpirole‐induced yawning is enhanced in rats eating high fat chow as compared to rats eating standard chow. Daily dietary supplementation with 20% (w/w) fish oil prevents this high fat diet‐induced effect; however, for beneficial effects of fish oil in humans, doctors recommend that patients take fish oil only 2–3 times a week. To test the hypothesis that intermittent (e.g., 2/7 days per week) dietary supplementation with fish oil prevents high fat diet‐induced effects (e.g., weight gain and enhanced sensitivity to the behavioral effects of dopaminergic drugs) rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), and rats eating standard or high fat chow with 20% (w/w) intermittent (e.g., 2/7 days per week) dietary fish oil supplementation were tested once weekly with quinpirole (0.0032–0.32 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole. That is, the quinpirole‐induced yawning dose‐response curve was shifted significantly to the left for rats eating high fat chow as compared to rats eating standard chow. Intermittent access to fish oil prevented this effect, since quinpirole‐induced yawning was not different among rats eating standard chow and rats eating high fat chow supplemented with fish oil. Future experiments will examine other dopaminergic drugs (e.g., cocaine) and will focus on understanding the mechanism by which fish oil produces these beneficial effects, by examining the specific omega‐3 polyunsaturated fatty acids found in fish oil.
Support or Funding Information
A portion of this project was supported by R25 GM069621.
This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
Abstract only
Eating a high fat diet can lead to negative health consequences, such as obesity and insulin resistance. Eating a high fat diet also enhances sensitivity of rats to the behavioral ...effects of drugs acting on dopamine systems, including the dopamine D
2
/D
3
receptor agonist, quinpirole. To test the hypothesis that dietary supplementation with fish oil prevents high fat diet‐induced enhanced sensitivity to the behavioral effects of quinpirole (0.0032–0.32 mg/kg), adolescent male rats ate standard laboratory chow (17% kcal from fat), high fat chow (60% kcal from fat), standard chow supplemented with fish oil or high fat chow supplemented with fish oil. Similar to previous reports, after 5 weeks, rats eating high fat chow were more sensitive (e.g., leftward shift of the quinpirole dose‐response curve) than rats eating standard chow, to yawning induced by quinpirole. Dietary supplementation with 20% (w/w) fish oil prevented this effect. That is, quinpirole dose‐response curves were not different between rats eating high fat chow supplemented with fish oil and standard chow‐fed controls. These results suggest that although a high fat diet causes enhanced drug sensitivity to the behavioral effects of quinpirole, fish oil supplementation can prevent this. Further research is being conducted to understand the mechanisms underlying this effect, and to examine whether fish oil will reverse the effects of eating a high fat diet once they have already developed.
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