Psychobiotics and the Microbiota-Gut-Brain Axis: Where Do We Go from Here?

The bidirectional relationship between the gut microbiota and the nervous system is known as the microbiota-gut-brain axis (MGBA). The MGBA controls the complex interactions between the brain, the enteric nervous system, the gut-associated immune system, and the enteric neuroendocrine systems, regulating key physiological functions such as the immune response, sleep, emotions and mood, food intake, and intestinal functions. Psychobiotics are considered tools with the potential to modulate the MGBA through preventive, adjunctive, or curative approaches, but their specific mechanisms of action on many aspects of health are yet to be characterized. This narrative review and perspectives article highlights the key paradigms needing attention as the scope of potential probiotics applications in human health increases, with a growing body of evidence supporting their systemic beneficial effects. However, there are many limitations to overcome before establishing the extent to which we can incorporate probiotics in the management of neuropsychiatric disorders. Although this article uses the term probiotics in a general manner, it remains important to study probiotics at the strain level in most cases.

Inhibition of intestinal FXR activity as a possible mechanism for the beneficial effects of a probiotic mix supplementation on lipid metabolism alterations and weight gain in mice fed a high fat diet.

Supplementation with probiotics has emerged as a promising therapeutic tool to manage metabolic diseases. We investigated the effects of a mix of Bifidobacterium animalis subsp. lactis LA804 and Lactobacillus gasseri LA806 on high-fat (HF) diet -induced metabolic disease in mice. Supplementation with the probiotic mix in HF diet-fed mice (HF-Pr2) reduced weight and fat mass gains, decreased hepatic lipid accumulation, and lowered plasma triglyceride peak during an oral lipid tolerance test. At the molecular level, the probiotic mix protected against HF-induced rise in mRNA levels of genes related to lipid uptake, metabolism, and storage in the liver and white adipose tissues, and strongly decreased mRNA levels of genes related to inflammation in the white adipose tissue and to oxidative stress in the liver. Regarding intestinal homeostasis, the probiotic mix did not prevent HF-induced gut permeability but slightly modified microbiota composition without correcting the dysbiosis induced by the HF diet. Probiotic supplementation also modified the cecal bile acid (BA) profile, leading to an increase in the Farnesoid-X-Receptor (FXR) antagonist/agonist ratio between BA species. In agreement, HF-Pr2 mice exhibited a strong inhibition of FXR signaling pathway in the ileum, which was associated with lipid metabolism protection. This is consistent with recent reports proposing that inhibition of intestinal FXR activity could be a potent mechanism to overcome metabolic disorders. Altogether, our results demonstrate that the probiotic mix evaluated, when administered preventively to HF diet-fed mice could limit obesity and associated lipid metabolism disorders, likely through the inhibition of FXR signaling in the intestinal tract.

Comparing Transgenic Production to Supplementation of ω-3 PUFA Reveals Distinct But Overlapping Mechanisms Underlying Protection Against Metabolic and Hepatic Disorders.

We compared endogenous ω-3 PUFA production to supplementation for improving obesity-related metabolic dysfunction. Fat-1 transgenic mice, who endogenously convert exogenous ω-6 to ω-3 PUFA, and wild-type littermates were fed a high-fat diet and a daily dose of either ω-3 or ω-6 PUFA-rich oil for 12 wk. The endogenous ω-3 PUFA production improved glucose intolerance and insulin resistance but not hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased hepatic levels of ω-3 PUFA-containing 2-monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids with ω-3 PUFA supplementation being more efficacious. Reduced hepatic lipid accumulation associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice supplemented with ω-3 PUFA displayed additional changes in the gut microbiota functions with a significant reduction of fecal levels of the proinflammatory molecules lipopolysaccharide and flagellin. Multiple-factor analysis identify that the metabolic improvements induced by ω-3 PUFAs were accompanied by a reduced production of the proinflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. While endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis.

Milk polar lipids favorably alter circulating and intestinal ceramide and sphingomyelin species in postmenopausal women.

BACKGROUNDHigh circulating levels of ceramides (Cer) and sphingomyelins (SM) are associated with cardiometabolic diseases. The consumption of whole fat dairy products, naturally containing such polar lipids (PL), is associated with health benefits, but the impact on sphingolipidome remains unknown.METHODSIn a 4-week randomized controlled trial, 58 postmenopausal women daily consumed milk PL-enriched cream cheese (0, 3, or 5 g of milk PL). Postprandial metabolic explorations were performed before and after supplementation. Analyses included SM and Cer species in serum, chylomicrons, and feces. The ileal contents of 4 ileostomy patients were also explored after acute milk PL intake.RESULTSMilk PL decreased serum atherogenic C24:1 Cer, C16:1 SM, and C18:1 SM species (Pgroup < 0.05). Changes in serum C16+18 SM species were positively correlated with the reduction of cholesterol (r = 0.706), LDL-C (r = 0.666), and ApoB (r = 0.705) (P < 0.001). Milk PL decreased chylomicron content in total SM and C24:1 Cer (Pgroup < 0.001), parallel to a marked increase in total Cer in feces (Pgroup < 0.001). Milk PL modulated some specific SM and Cer species in both ileal efflux and feces, suggesting differential absorption and metabolization processes in the gut.CONCLUSIONMilk PL supplementation decreased atherogenic SM and Cer species associated with the improvement of cardiovascular risk markers. Our findings bring insights on sphingolipid metabolism in the gut, especially Cer, as signaling molecules potentially participating in the beneficial effects of milk PL.TRIAL REGISTRATIONClinicalTrials.gov, NCT02099032, NCT02146339.FUNDINGANR-11-ALID-007-01; PHRCI-2014: VALOBAB, no. 14-007; CNIEL; GLN 2018-11-07; HCL (sponsor).

Dietary lipids and cardiometabolic health: a new vision of structure-activity relationship.

PURPOSE OF REVIEW: The impact of dietary lipids on cardiometabolic health was mainly studied considering their fatty acid composition. This review aims to present the recent change in paradigm whereby the food matrix, the molecular and supramolecular structures of dietary lipids modulate their digestive fate and cardiometabolic impact. RECENT FINDINGS: Epidemiological studies have reported that the metabolic impact of full-fat dairy products is better than predictable upon saturated fatty acid richness. Milk polar lipid supplementation reduced adiposity and inflammation in rodents by modulating gut microbiota and barrier, and decreased lipid markers of cardiovascular disease risk in humans by lowering cholesterol absorption. The metabolic importance of the structure of lipid molecules carrying omega-3 (molecular carrier) has also been documented. Plant lipids exhibit specific assemblies, membrane and molecular structures with potential health benefits. Lipid emulsifiers used to stabilize fats in processed foods are not mere bystanders of lipid effects and can induce both beneficial and adverse health effects. SUMMARY: These findings open new clinical research questions aiming to further characterize the cardiometabolic fate of lipids, from digestion to bioactive metabolites, according to the food source or molecular carrier. This should be useful to elaborate food formulations for target populations and personalized dietary recommendations.

Milk polar lipids reduce lipid cardiovascular risk factors in overweight postmenopausal women: towards a gut sphingomyelin-cholesterol interplay.

OBJECTIVE: To investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health. DESIGN: A double-blind, randomised controlled 4-week study involving 58 postmenopausal women was used to assess the chronic effects of milk PL consumption (0, 3 or 5 g-PL/day) on lipid metabolism and gut microbiota. The acute effects of milk PL on intestinal absorption and metabolism of cholesterol were assessed in a randomised controlled crossover study using tracers in ileostomy patients. RESULTS: Over 4 weeks, milk PL significantly reduced fasting and postprandial plasma concentrations of cholesterol and surrogate lipid markers of cardiovascular disease risk, including total/high-density lipoprotein-cholesterol and apolipoprotein (Apo)B/ApoA1 ratios. The highest PL dose preferentially induced a decreased number of intestine-derived chylomicron particles. Also, milk PL increased faecal loss of coprostanol, a gut-derived metabolite of cholesterol, but major bacterial populations and faecal short-chain fatty acids were not affected by milk PL, regardless of the dose. Acute ingestion of milk PL by ileostomy patients shows that milk PL decreased cholesterol absorption and increased cholesterol-ileal efflux, which can be explained by the observed co-excretion with milk sphingomyelin in the gut. CONCLUSION: The present data demonstrate for the first time in humans that milk PL can improve the cardiometabolic health by decreasing several lipid cardiovascular markers, notably through a reduced intestinal cholesterol absorption involving specific interactions in the gut, without disturbing the major bacterial phyla of gut microbiota. TRIAL REGISTRATION NUMBER: NCT02099032 and NCT02146339; Results.

Alterations of endogenous sphingolipid metabolism in cardiometabolic diseases: Towards novel therapeutic approaches.

The increasing prevalence of obesity and metabolic diseases is a worldwide public health concern, and the advent of new analytical technologies has made it possible to highlight the involvement of some molecules, such as sphingolipids (SL), in their pathophysiology. SL are constituents of cell membranes, lipoproteins and lipid droplets (LD), and are now considered as bioactive molecules. Indeed, growing evidence suggests that SL, characterized by diverse families and species, could represent one of the main regulators of lipid metabolism. There is an increasing amount of data reporting that plasma SL profile is altered in metabolic diseases. However, less is known about SL metabolism dysfunction in cells and tissues and how it may impact the lipoprotein metabolism, its functionality and composition. In cardiometabolic pathologies, the link between serum SL concentrations and alterations of their metabolism in various organs and LD is still unclear. Pharmacological approaches have been developed in order to activate or inhibit specific key enzymes of the SL metabolism, and to positively modulate SL profile or related metabolic pathways. Nevertheless, little is known about the long-term impact of such approaches in humans and the current literature still focuses on the decomposition of the different parts of this complex system rather than performing an integrated analysis of the whole SL metabolism. In addition, since SL can be provided from exogenous sources, it is also of interest to evaluate their impact on the homeostasis of endogenous SL metabolism, which could be beneficial in prevention or treatment of obesity and related metabolic disorders.

In vivo screening of multiple bacterial strains identifies Lactobacillus rhamnosus Lb102 and Bifidobacterium animalis ssp. lactis Bf141 as probiotics that improve metabolic disorders in a mouse model of obesity.

Given the growing evidence that gut dysfunction, including changes in gut microbiota composition, plays a critical role in the development of inflammation and metabolic diseases, the identification of novel probiotic bacteria with immunometabolic properties has recently attracted more attention. Herein, bacterial strains were first isolated from dairy products and human feces and then screened in vitro for their immunomodulatory activity. Five selected strains were further analyzed in vivo, using a mouse model of diet-induced obesity. C57BL/6 mice were fed a high-fat high-sucrose diet, in combination with 1 of 3 Lactobacillus strains (Lb38, L. plantarum; L79, L. paracasei/casei; Lb102, L. rhamnosus) or Bifidobacterium strains (Bf26, Bf141, 2 different strains of B. animalis ssp. lactis species) administered for 8 wk at 109 colony-forming units/d. Whereas 3 strains showed only modest (Lb38, Bf26) or no (L79) effects, Lb102 and Bf141 reduced diet-induced obesity, visceral fat accretion, and inflammation, concomitant with improvement of glucose tolerance and insulin sensitivity. Further analysis revealed that Lb102 and Bf141 enhanced intestinal integrity markers in association with selective changes in gut microbiota composition. We have thus identified 2 new potential probiotic bacterial strains with immunometabolic properties to alleviate obesity development and associated metabolic disturbances.-Le Barz, M., Daniel, N., Varin, T. V., Naimi, S., Demers-Mathieu, V., Pilon, G., Audy, J., Laurin, E., Roy, D., Urdaci, M. C., St-Gelais, D., Fliss, I, Marette, A. In vivo screening of multiple bacterial strains identifies Lactobacillus rhamnosus Lb102 and Bifidobacterium animalis ssp. lactis Bf141 as probiotics that improve metabolic disorders in a mouse model of obesity.

Treatment with camu camu (Myrciaria dubia) prevents obesity by altering the gut microbiota and increasing energy expenditure in diet-induced obese mice.

OBJECTIVE: The consumption of fruits is strongly associated with better health and higher bacterial diversity in the gut microbiota (GM). Camu camu (Myrciaria dubia) is an Amazonian fruit with a unique phytochemical profile, strong antioxidant potential and purported anti-inflammatory potential. DESIGN: By using metabolic tests coupled with 16S rRNA gene-based taxonomic profiling and faecal microbial transplantation (FMT), we have assessed the effect of a crude extract of camu camu (CC) on obesity and associated immunometabolic disorders in high fat/high sucrose (HFHS)-fed mice. RESULTS: Treatment of HFHS-fed mice with CC prevented weight gain, lowered fat accumulation and blunted metabolic inflammation and endotoxaemia. CC-treated mice displayed improved glucose tolerance and insulin sensitivity and were also fully protected against hepatic steatosis. These effects were linked to increased energy expenditure and upregulation of uncoupling protein 1 mRNA expression in the brown adipose tissue (BAT) of CC-treated mice, which strongly correlated with the mRNA expression of the membrane bile acid (BA) receptor TGR5. Moreover, CC-treated mice showed altered plasma BA pool size and composition and drastic changes in the GM (eg, bloom of Akkermansia muciniphila and a strong reduction of Lactobacillus). Germ-free (GF) mice reconstituted with the GM of CC-treated mice gained less weight and displayed higher energy expenditure than GF-mice colonised with the FM of HFHS controls. CONCLUSION: Our results show that CC prevents visceral and liver fat deposition through BAT activation and increased energy expenditure, a mechanism that is dependent on the GM and linked to major changes in the BA pool size and composition.

Arctic berry extracts target the gut-liver axis to alleviate metabolic endotoxaemia, insulin resistance and hepatic steatosis in diet-induced obese mice.

AIMS/HYPOTHESIS: There is growing evidence that fruit polyphenols exert beneficial effects on the metabolic syndrome, but the underlying mechanisms remain poorly understood. In the present study, we aimed to analyse the effects of polyphenolic extracts from five types of Arctic berries in a model of diet-induced obesity. METHODS: Male C57BL/6 J mice were fed a high-fat/high-sucrose (HFHS) diet and orally treated with extracts of bog blueberry (BBE), cloudberry (CLE), crowberry (CRE), alpine bearberry (ABE), lingonberry (LGE) or vehicle (HFHS) for 8 weeks. An additional group of standard-chow-fed, vehicle-treated mice was included as a reference control for diet-induced obesity. OGTTs and insulin tolerance tests were conducted, and both plasma insulin and C-peptide were assessed throughout the OGTT. Quantitative PCR, western blot analysis and ELISAs were used to assess enterohepatic immunometabolic features. Faecal DNA was extracted and 16S rRNA gene-based analysis was used to profile the gut microbiota. RESULTS: Treatment with CLE, ABE and LGE, but not with BBE or CRE, prevented both fasting hyperinsulinaemia (mean ± SEM [pmol/l]: chow 67.2 ± 12.3, HFHS 153.9 ± 19.3, BBE 114.4 ± 14.3, CLE 82.5 ± 13.0, CRE 152.3 ± 24.4, ABE 90.6 ± 18.0, LGE 95.4 ± 10.5) and postprandial hyperinsulinaemia (mean ± SEM AUC [pmol/l × min]: chow 14.3 ± 1.4, HFHS 31.4 ± 3.1, BBE 27.2 ± 4.0, CLE 17.7 ± 2.2, CRE 32.6 ± 6.3, ABE 22.7 ± 18.0, LGE 23.9 ± 2.5). None of the berry extracts affected C-peptide levels or body weight gain. Levels of hepatic serine phosphorylated Akt were 1.6-, 1.5- and 1.2-fold higher with CLE, ABE and LGE treatment, respectively, and hepatic carcinoembryonic antigen-related cell adhesion molecule (CEACAM)-1 tyrosine phosphorylation was 0.6-, 0.7- and 0.9-fold increased in these mice vs vehicle-treated, HFHS-fed mice. These changes were associated with reduced liver triacylglycerol deposition, lower circulating endotoxins, alleviated hepatic and intestinal inflammation, and major gut microbial alterations (e.g. bloom of Akkermansia muciniphila, Turicibacter and Oscillibacter) in CLE-, ABE- and LGE-treated mice. CONCLUSIONS/INTERPRETATION: Our findings reveal novel mechanisms by which polyphenolic extracts from ABE, LGE and especially CLE target the gut-liver axis to protect diet-induced obese mice against metabolic endotoxaemia, insulin resistance and hepatic steatosis, which importantly improves hepatic insulin clearance. These results support the potential benefits of these Arctic berries and their integration into health programmes to help attenuate obesity-related chronic inflammation and metabolic disorders. DATA AVAILABILITY: All raw sequences have been deposited in the public European Nucleotide Archive server under accession number PRJEB19783 ( https://www.ebi.ac.uk/ena/data/view/PRJEB19783 ).

Erratum: Figure Correction: Probiotics as Complementary Treatment for Metabolic Disorders.

[This corrects the article on p. 291 in vol. 39, PMID: 26301190.].

Gut Microbiota Dysbiosis in Obesity-Linked Metabolic Diseases and Prebiotic Potential of Polyphenol-Rich Extracts.

Trillions of microorganisms inhabit the human body, strongly colonizing the gastro-intestinal tract and outnumbering our own cells. High-throughput sequencing techniques and new bioinformatic tools have enabled scientists to extend our knowledge on the relationship between the gut microbiota and host's physiology. Disruption of the ecological equilibrium in the gut (i.e., dysbiosis) has been associated with several pathological processes, including obesity and its related comorbidities, with diet being a strong determinant of gut microbial balance. In this review, we discuss the potential prebiotic effect of polyphenol-rich foods and extracts and how they can reshape the gut microbiota, emphasizing the novel role of the mucin-degrading bacterium Akkermansia muciniphila in their metabolic benefits.

Probiotics as Complementary Treatment for Metabolic Disorders.

Over the past decade, growing evidence has established the gut microbiota as one of the most important determinants of metabolic disorders such as obesity and type 2 diabetes. Indeed, obesogenic diet can drastically alter bacterial populations (i.e., dysbiosis) leading to activation of pro-inflammatory mechanisms and metabolic endotoxemia, therefore promoting insulin resistance and cardiometabolic disorders. To counteract these deleterious effects, probiotic strains have been developed with the aim of reshaping the microbiome to improve gut health. In this review, we focus on benefits of widely used probiotics describing their potential mechanisms of action, especially their ability to decrease metabolic endotoxemia by restoring the disrupted intestinal mucosal barrier. We also discuss the perspective of using new bacterial strains such as butyrate-producing bacteria and the mucolytic Akkermansia muciniphila, as well as the use of prebiotics to enhance the functionality of probiotics. Finally, this review introduces the notion of genetically engineered bacterial strains specifically developed to deliver anti-inflammatory molecules to the gut.