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Dectin-1 signaling on colonic γδ T cells promotes psychosocial stress responses.
The intestinal immune system interacts with commensal microbiota to maintain gut homeostasis. Furthermore, stress alters the microbiome composition, leading to impaired brain function; yet how the intestinal immune system mediates these effects remains elusive. Here we report that colonic γδ T cells modulate behavioral vulnerability to chronic social stress via dectin-1 signaling. We show that reduction in specific Lactobacillus species, which are involved in T cell differentiation to protect the host immune system, contributes to stress-induced social-avoidance behavior, consistent with our observations in patients with depression. Stress-susceptible behaviors derive from increased differentiation in colonic interleukin (IL)-17-producing γδ T cells (γδ17 T cells) and their meningeal accumulation. These stress-susceptible cellular and behavioral phenotypes are causally mediated by dectin-1, an innate immune receptor expressed in γδ T cells. Our results highlight the previously unrecognized role of intestinal γδ17 T cells in the modulation of psychological stress responses and the importance of dectin-1 as a potential therapeutic target for the treatment of stress-induced behaviors.
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NOD-like receptors mediate homeostatic intestinal epithelial barrier function: promising therapeutic targets for inflammatory bowel disease.
Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disease that involves host genetics, the microbiome, and inflammatory responses. The current consensus is that the disruption of the intestinal mucosal barrier is the core pathogenesis of IBD, including intestinal microbial factors, abnormal immune responses, and impaired intestinal mucosal barrier. Cumulative data show that nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are dominant mediators in maintaining the homeostasis of the intestinal mucosal barrier, which play critical roles in sensing the commensal microbiota, maintaining homeostasis, and regulating intestinal inflammation. Blocking NLRs inflammasome activation by botanicals may be a promising way to prevent IBD progression. In this review, we systematically introduce the multiple roles of NLRs in regulating intestinal mucosal barrier homeostasis and focus on summarizing the activities and potential mechanisms of natural products against IBD. Aiming to propose new directions on the pathogenesis and precise treatment of IBD.
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Non-Helicobacter pylori Helicobacters, a Treatable Provocateur of Parkinson's Disease: Hypothesis, Evidence and Species Specificity.
Epidemiological and eradication trial evidence indicates that Helicobacter pylori, a major causative factor in peptic ulcer and gastric cancer, is a driver of the hypokinesia of Parkinson's disease (PD). Psychological (cognitive impairment, depression and anxiety) and gastrointestinal (peptic ulceration and constipation) PD features can precede the symptomatic onset of motor features by decades. We hypothesise that the non-H. pylori Helicobacters (NHPH), which have farm, companion and wild animals as their main hosts, can have a role in PD aetiopathogenesis. In those occupationally at risk of NHPH infection, we address whether there is increased mortality with PD, or depression or suicide. Our systematic review gave evidence that occupational exposure to animals/their products is associated with excess mortality with PD. Indeed, whilst livestock farming increased the risk, crop farming decreased it. Moreover, excess mortality from non-Hodgkin lymphoma in livestock farmers is compatible with NHPH being causal. Our scoping review showed that farmers, veterinarians and abattoir workers have an increased risk of depression and suicide; whether their depression is associated with being down the pathway to PD and/or the presence of Helicobacter infection needs investigation. Regarding Helicobacter species specificity, the link between the presence of NHPH in gastric biopsy and PD was described using a ureA polymerase chain reaction (PCR) assay, targeting the most-commonly named NHPH, H. suis. We describe its redesign and optimisation as a probe-based PCR, confirming the exclusion of H. pylori but not H. suis specificity (additionally identifying 6 species of a 22-NHPH-species panel). The exploration of the zoonotic hypothesis requires a non-invasive pan-Helicobacter PCR screen, allowing the detection and molecular grouping of Helicobacter species.
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Dynamic effects of black soldier fly larvae meal on the cecal bacterial microbiota and prevalence of selected antimicrobial resistant determinants in broiler chickens.
BACKGROUND: We had earlier described the growth-promoting and -depressive effects of replacing soybean meal (SBM) with low (12.5% and 25%) and high (50% and 100%) inclusion levels of black soldier fly larvae meal (BSFLM), respectively, in Ross x Ross 708 broiler chicken diets. Herein, using 16S rRNA gene amplicon sequencing, we investigated the effects of replacing SBM with increasing inclusion levels (0-100%) of BSFLM in broiler diets on the cecal bacterial community composition at each growth phase compared to broilers fed a basal corn-SBM diet with or without the in-feed antibiotic, bacitracin methylene disalicylate (BMD). We also evaluated the impact of low (12.5% and 25%) inclusion levels of BSFLM (LIL-BSFLM) on the prevalence of selected antimicrobial resistance genes (ARGs) in litter and cecal samples from 35-day-old birds. RESULTS: Compared to a conventional SBM-based broiler chicken diet, high (50 to100%) inclusion levels of BSFLM (HIL-BSFLM) significantly altered the cecal bacterial composition and structure, whereas LIL-BSFLM had a minimal effect. Differential abundance analysis further revealed that the ceca of birds fed 100% BSFLM consistently harbored a ~ 3 log-fold higher abundance of Romboutsia and a ~ 2 log-fold lower abundance of Shuttleworthia relative to those fed a BMD-supplemented control diet at all growth phases. Transient changes in the abundance of several potentially significant bacterial genera, primarily belonging to the class Clostridia, were also observed for birds fed HIL-BSFLM. At the finisher phase, Enterococci bacteria were enriched in the ceca of chickens raised without antibiotic, regardless of the level of dietary BSFLM. Additionally, bacitracin (bcrR) and macrolide (ermB) resistance genes were found to be less abundant in the ceca of chickens fed antibiotic-free diets, including either a corn-SBM or LIL-BSFLM diet. CONCLUSIONS: Chickens fed a HIL-BSFLM presented with an imbalanced gut bacterial microbiota profile, which may be linked to the previously reported growth-depressing effects of a BSFLM diet. In contrast, LIL-BSFLM had a minimal effect on the composition of the cecal bacterial microbiota and did not enrich for selected ARGs. Thus, substitution of SBM with low levels of BSFLM in broiler diets could be a promising alternative to the antibiotic growth promoter, BMD, with the added-value of not enriching for bacitracin- and macrolide-associated ARGs.
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Use of Antibiotics and Risk of Psychiatric Disorders in Newly Diagnosed Cancer Patients: A Population-Based Cohort Study in Sweden.
BACKGROUND: Antibiotic-induced dysbiosis is associated with an increased risk of depression and anxiety in the general population. A diagnosis of cancer is associated with an immediately and dramatically elevated risk of psychiatric disorders, but the potential influence of prediagnostic antibiotic-induced dysbiosis is unknown. METHODS: Based on a national cohort of cancer patients in Sweden, we included 309,419 patients who were diagnosed with a first primary malignancy between July 2006 and December 2013. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of first-onset psychosis, depression, anxiety, or stress-related disorders during the first year after cancer diagnosis for antibiotic use during the year before cancer diagnosis. RESULTS: Compared with no antibiotic use, use of antibiotics was associated with a higher rate of the aforementioned psychiatric disorders (HR, 1.23; 95% CI, 1.16-1.30) after adjustment for sociodemographic factors, comorbidity, potential indications for antibiotics, and cancer stage and type. The magnitude of the association was higher for broad-spectrum antibiotics (HR, 1.27; 95% CI, 1.18-1.37), higher doses (HR, 1.32; 95% CI, 1.22-1.44), more frequent use (HR, 1.33; 95% CI, 1.21-1.46), and recent use (HR, 1.26; 95% CI, 1.17-1.35). CONCLUSIONS: Use of antibiotics, especially of broad-spectrum type, of high dose and frequency, with recent use, was associated with an aggravated risk of psychiatric disorders, compared with no antibiotic use. IMPACT: A better understanding of the microbiota-gut-brain axis may open up a wide avenue for the prevention and treatment of psychiatric disorders in cancer patients.
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Chemosensory Impairments and Their Impact on Nutrition in Parkinson's Disease: A Narrative Literature Review.
Parkinson's disease (PD) is a neurological disorder characterized by heterogeneous symptomatology, in which the classical motor features of Parkinsonism are associated with clinically significant non-motor symptoms. Olfactory alteration, as a manifestation of PD's premotor or prodromal phase, is well known. These impairments can lead to malnutrition, decreased appetite, and depression, thereby worsening patients' quality of life. However, only a few studies clarify the mechanisms, characteristics, and clinical diagnostic and therapeutic implications of impaired taste perception. Moreover, unlike most motor features of PD, non-motor symptoms often have limited treatment options or responses. The purpose of this review is to collate and describe all relevant studies on taste and smell alterations in patients with PD and how these alterations could affect nutritional status. Our search aimed to identify English-language research articles and reviews published in peer-reviewed journals over the past two decades (2004-2024), while also including older foundational studies when relevant. Several studies show that hyposmia in PD worsens over time, potentially linked to structural changes in the brain's basal ganglia and piriform cortex. Severe hyposmia is also associated with a higher risk of dementia in PD patients and can negatively influence quality of life, affecting social interactions and nutrition. Regarding taste perception, recent studies have suggested that hypogeusia may occur even in the prodromal stage of PD, such as in patients with REM sleep disorder, although the exact mechanisms remain unclear. Additionally, research has explored the role of bitter taste receptors and their possible involvement in inflammation and α-synuclein misfolding, suggesting a link between taste dysfunction and immune system changes in PD. Attention was then focused on the gut microbiota's link to the central nervous system and its contribution to gustatory dysfunctions, as well as how the nasal microbiome influences PD progression by altering the olfactory system. Nowadays, the primary role of a correct diet in the overall treatment of PD patients is becoming increasingly important for practitioners. Diet should be included among the available aids to counteract some aspects of the pathology itself. For all these reasons, it is also crucial to determine whether these chemosensory impairments could serve as disease markers, helping to better understand the underlying mechanisms of the disease.
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Prospective study of an amino acid-based elemental diet in an eosinophilic gastritis and gastroenteritis nutrition trial.
BACKGROUND: Eosinophilic gastritis/gastroenteritis (EoG/EoGE) are rare disorders with pathologic gastric and/or small intestinal eosinophilia lacking an approved therapy. An allergic mechanism is postulated but underexplored mechanistically and therapeutically. OBJECTIVE: We evaluated the effectiveness of a food allergen-free diet (elemental formula) in controlling gastrointestinal eosinophilia in adult EoG/EoGE. METHODS: Adults aged 18 to 65 years with histologically active EoG/EoGE (≥30 eosinophils per high-power field) in the stomach and/or duodenum and gastrointestinal symptoms within the month preceding enrollment were prospectively enrolled onto a single-arm clinical trial to receive elemental formula for 6 consecutive weeks. The primary end point was percentage of participants with complete histologic remission (<30 eosinophils per high-power field in both stomach and duodenum). Exploratory outcomes were improvement in symptoms, endoscopy results, blood eosinophilia, quality of life, Physician Global Assessment score, and EoG-relevant gastric transcriptome and microbiome. RESULTS: Fifteen adults (47% male, average age 37.7 years, average symptom duration 8.8 years) completed the trial. Multi-gastrointestinal segment involvement affected 87%. All subjects had complete histologic remission in the stomach (P = .002) and duodenum (P = .001). Scores improved in overall PhGA (P = .002); EGREFS (P = .003); EGDP (P = .002); SODA pain intensity (P = .044), non-pain (P = .039), and satisfaction (P = .0024); and PROMIS depression (P = .0078) and fatigue (P = .04). Food reintroduction reversed these improvements. The intervention was well tolerated in 14 subjects, with 1 serious adverse event reported in 1 subject. CONCLUSION: An amino acid-based elemental diet improves histologic, endoscopic, symptomatic, quality-of-life, and molecular parameters of EoG/EoGE; these findings and disease recurrence with food trigger reintroduction support a dominant role for food allergens in disease pathogenesis. CLINICALTRIALS: gov Identifier: NCT03320369.
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Intestinal colonization of germ-free mice with indole-producing E. coli modulates the central and peripheral endocannabinoidome.
Colonization of germ-free (GF) mice with indole-producing E. coli exacerbates anxiety- and depression-like behaviors. Lack and subsequent reintroduction of gut microbiota in mice alter in opposing ways the brain and intestinal levels of the lipid mediators of the expanded endocannabinoid system, or endocannabinoidome (eCBome), which controls affective behaviors. By using LC/MS-MS-based targeted lipidomics and qPCR, we investigated the effect of GF mouse colonization with E. coli strains capable (wild-type, I+) or not (knock-out, I-) of producing indole, on the brain and intestinal eCBome. Compared to untreated GF mice, and unlike the I- strain, the I+ strain reduced the levels of 2-monoacylglycerols (2-MAGs), and 2-arachidonoylglycerol in particular, in the amygdala, and of 2-MAGs and NAEs in the hippocampus. Moreover, it elevated 2-MAGs in the ileum and reduced NAEs in the cecum. The mRNA expression of some eCBome receptors was also selectively altered by the I+ strain, including Gpr55 (upregulated in the amygdala), Gpr18 (downregulated in the ileum), Cnr2 (upregulated in the colon), and Gpr119 (downregulated in the cecum). LC/MS-MS-based targeted metabolomics detected the indole metabolite indoxyl-3-sulfate in the plasma and liver, but not brain, of I+-colonized mice. Our data pinpoint the eCBome as a potential mediator of the effects of indole.
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Probiotic, prebiotic, synbiotic and fermented food supplementation in psychiatric disorders: A systematic review of clinical trials.
The use of probiotics, prebiotics, synbiotics or fermented foods can modulate the gut-brain axis and constitute a potentially therapeutic intervention in psychiatric disorders. This systematic review aims to identify current evidence regarding these interventions in the treatment of patients with DSM/ICD psychiatric diagnoses. Forty-seven articles from 42 studies met the inclusion criteria. Risk of bias was assessed in all included studies. Major depression was the most studied disorder (n = 19 studies). Studies frequently focused on schizophrenia (n = 11) and bipolar disorder (n = 5) and there were limited studies in anorexia nervosa (n = 4), ADHD (n = 3), Tourette (n = 1), insomnia (n = 1), PTSD (n = 1) and generalized anxiety disorder (n = 1). Except in MDD, current evidence does not clarify the role of probiotics and prebiotics in the treatment of mental illness. Several studies point to an improvement in the immune and inflammatory profile (e.g. CRP, IL6), which may be a relevant mechanism of action of the therapeutic response identified in these studies. Future research should consider lifestyle and dietary habits of patients as possible confounders that may influence inter-individual treatment response.
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The Add-On Effect of Lactobacillus plantarum PS128 in Patients With Parkinson's Disease: A Pilot Study.
Background: Lactobacillus plantarum PS128 (PS128) is a specific probiotic, known as a psychobiotic, which has been demonstrated to alleviate motor deficits and inhibit neurodegenerative processes in Parkinson's disease (PD)-model mice. We hypothesize that it may also be beneficial to patients with PD based on the possible mechanism via the microbiome-gut-brain axis. Methods: This is an open-label, single-arm, baseline-controlled trial. The eligible participants were scheduled to take 60 billion colony-forming units of PS128 once per night for 12 weeks. Clinical assessments were conducted using the Unified Parkinson's Disease Rating Scale (UPDRS), modified Hoehn and Yahr scale, and change in patient "ON-OFF" diary recording as primary outcome measures. The non-motor symptoms questionnaire, Beck depression inventory-II, patient assessment of constipation symptom, 39-item Parkinson's Disease Questionnaire (PDQ-39), and Patient Global Impression of Change (PGI-C) were assessed as secondary outcome measures. Results: Twenty-five eligible patients (32% women) completed the study. The mean age was 61.84 ± 5.74 years (range, 52-72), mean disease duration was 10.12 ± 2.3 years (range, 5-14), and levodopa equivalent daily dosage was 1063.4 ± 209.5 mg/daily (range, 675-1,560). All patients remained on the same dosage of anti-parkinsonian and other drugs throughout the study. After 12 weeks of PS128 supplementation, the UPDRS motor scores improved significantly in both the OFF and ON states (p = 0.004 and p = 0.007, respectively). In addition, PS128 intervention significantly improved the duration of the ON period and OFF period as well as PDQ-39 values. However, no obvious effect of PS128 on non-motor symptoms of patients with PD was observed. Notably, the PGI-C scores improved in 17 patients (68%). PS128 intervention was also found to significantly reduce plasma myeloperoxidase and urine creatinine levels. Conclusion: The present study demonstrated that PS128 supplementation for 12 weeks with constant anti-parkinsonian medication improved the UPDRS motor score and quality of life of PD patients. We suggest that PS128 could serve as a therapeutic adjuvant for the treatment of PD. In the future, placebo-controlled studies are needed to further support the efficacy of PS128 supplementation. Clinical Trial Registration: https://clinicaltrials.gov/, identifier: NCT04389762.