The microbiota-gut-brain axis: pathways to better brain health. Perspectives on what we know, what we need to investigate and how to put knowledge into practice.

The gut and brain link via various metabolic and signalling pathways, each with the potential to influence mental, brain and cognitive health. Over the past decade, the involvement of the gut microbiota in gut-brain communication has become the focus of increased scientific interest, establishing the microbiota-gut-brain axis as a field of research. There is a growing number of association studies exploring the gut microbiota's possible role in memory, learning, anxiety, stress, neurodevelopmental and neurodegenerative disorders. Consequently, attention is now turning to how the microbiota can become the target of nutritional and therapeutic strategies for improved brain health and well-being. However, while such strategies that target the gut microbiota to influence brain health and function are currently under development with varying levels of success, still very little is yet known about the triggers and mechanisms underlying the gut microbiota's apparent influence on cognitive or brain function and most evidence comes from pre-clinical studies rather than well controlled clinical trials/investigations. Filling the knowledge gaps requires establishing a standardised methodology for human studies, including strong guidance for specific focus areas of the microbiota-gut-brain axis, the need for more extensive biological sample analyses, and identification of relevant biomarkers. Other urgent requirements are new advanced models for in vitro and in vivo studies of relevant mechanisms, and a greater focus on omics technologies with supporting bioinformatics resources (training, tools) to efficiently translate study findings, as well as the identification of relevant targets in study populations. The key to building a validated evidence base rely on increasing knowledge sharing and multi-disciplinary collaborations, along with continued public-private funding support. This will allow microbiota-gut-brain axis research to move to its next phase so we can identify realistic opportunities to modulate the microbiota for better brain health.

A taxonomic note on the genus Lactobacillus: Description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and Leuconostocaceae.

The genus Lactobacillus comprises 261 species (at March 2020) that are extremely diverse at phenotypic, ecological and genotypic levels. This study evaluated the taxonomy of Lactobacillaceae and Leuconostocaceae on the basis of whole genome sequences. Parameters that were evaluated included core genome phylogeny, (conserved) pairwise average amino acid identity, clade-specific signature genes, physiological criteria and the ecology of the organisms. Based on this polyphasic approach, we propose reclassification of the genus Lactobacillus into 25 genera including the emended genus Lactobacillus, which includes host-adapted organisms that have been referred to as the Lactobacillus delbrueckii group, Paralactobacillus and 23 novel genera for which the names Holzapfelia, Amylolactobacillus, Bombilactobacillus, Companilactobacillus, Lapidilactobacillus, Agrilactobacillus, Schleiferilactobacillus, Loigolactobacilus, Lacticaseibacillus, Latilactobacillus, Dellaglioa, Liquorilactobacillus, Ligilactobacillus, Lactiplantibacillus, Furfurilactobacillus, Paucilactobacillus, Limosilactobacillus, Fructilactobacillus, Acetilactobacillus, Apilactobacillus, Levilactobacillus, Secundilactobacillus and Lentilactobacillus are proposed. We also propose to emend the description of the family Lactobacillaceae to include all genera that were previously included in families Lactobacillaceae and Leuconostocaceae. The generic term 'lactobacilli' will remain useful to designate all organisms that were classified as Lactobacillaceae until 2020. This reclassification reflects the phylogenetic position of the micro-organisms, and groups lactobacilli into robust clades with shared ecological and metabolic properties, as exemplified for the emended genus Lactobacillus encompassing species adapted to vertebrates (such as Lactobacillus delbrueckii, Lactobacillus iners, Lactobacillus crispatus, Lactobacillus jensensii, Lactobacillus johnsonii and Lactobacillus acidophilus) or invertebrates (such as Lactobacillus apis and Lactobacillus bombicola).

Autophagy: A Novel Mechanism Involved in the Anti-Inflammatory Abilities of Probiotics.

BACKGROUND/AIMS: Deregulation of the complex interaction among host genetics, gut microbiota and environmental factors on one hand and aberrant immune responses on the other hand, are known to be associated with the development of inflammatory bowel disease. Recent studies provided strong evidence that autophagy plays a key role in the etiology of Crohn's disease (CD). Probiotics may exhibit many therapeutic properties, including anti-inflammatory abilities. While successful results have been obtained in ulcerative colitis patients, probiotics remain inefficient in CD for unknown reason. It remains therefore important to better understand their molecular mechanisms of action. METHODS: The activation of autophagy was examined by stimulating bone marrow-derived dendritic cells by the bacteria, followed by confocal microscopy and western blot analysis. The impact of blocking in vitro autophagy was performed in peripheral blood mononuclear cells using 3-methyl adenine or bafilomycin followed by cytokine secretion measurement by ELISA. The role of autophagy in the anti-inflammatory capacities of the bacterial strains was evaluated in vivo using an acute trinitrobenzene sulfonic acid-induced murine model of colitis. The impact of BMDC was evaluated by adoptive transfer, notably using bone marrow cells derived from autophagy-related 16-like 1-deficient mice. RESULTS: We showed that selected lactobacilli and bifidobacteria are able to induce autophagy activation in BMDCs. Blocking in vitro autophagy abolished the capacity of the strains to induce the release of the anti-inflammatory cytokine interleukin-10, while it exacerbated the secretion of the pro-inflammatory cytokine interleukin-1ß. We confirmed in the TNBS-induced mouse model of colitis that autophagy is involved in the protective capacity of these selected strains, and showed that dendritic cells are involved in this process. CONCLUSION: We propose autophagy as a novel mechanism involved in the regulatory capacities of probiotics.

Commercial Probiotic Products: A Call for Improved Quality Control. A Position Paper by the ESPGHAN Working Group for Probiotics and Prebiotics.

Probiotics have been proposed for a number of indications ranging from the hypothetical long-term immunomodulatory effects to proven benefits in the management of different clinical conditions.An increasing number of commercial products containing probiotics are available. In those products, irrespective if it is food, food supplement, medical food, or drug, the probiotic microorganisms have to be present in a sufficient number by the end of the shelf-life, to pass through the gastrointestinal tract resisting acid and bile, to colonize the gut, and to retain functional properties required to obtain the suggested beneficial effect. Finally, it should be contamination-free.Studies organized worldwide and summarized in this article have shown that inconsistencies and deviations from the information provided on the product label are surprisingly common. Frequently strains are misidentified and misclassified, products are occasionally contaminated, sometimes with even facultative or obligatory pathogens, strains are not viable, the labeled number of colonies cannot be verified, or the functional properties are diminished to the extent that preclude the proposed health benefit. As the probiotic preparations are commonly used for a wide range of conditions, the aim of the Working Group was to summarize results of the studies looking into the quality of the probiotic products and to raise the awareness of the important issue of their quality control.Based on the results obtained, we strongly suggest a more stringent quality control process. This process should ensure that the probiotic content as mentioned on the label meets the actual content throughout the shelf life of the product, while no contamination is present.

Beneficial metabolic effects of selected probiotics on diet-induced obesity and insulin resistance in mice are associated with improvement of dysbiotic gut microbiota.

Alterations in gut microbiota composition and diversity were suggested to play a role in the development of obesity, a chronic subclinical inflammatory condition. We here evaluated the impact of oral consumption of a monostrain or multi-strain probiotic preparation in high-fat diet-induced obese mice. We observed a strain-specific effect and reported dissociation between the capacity of probiotics to dampen adipose tissue inflammation and to limit body weight gain. A multi-strain mixture was able to improve adiposity, insulin resistance and dyslipidemia through adipose tissue immune cell-remodelling, mainly affecting macrophages. At the gut level, the mixture modified the uptake of fatty acids and restored the expression level of the short-chain fatty acid receptor GPR43. These beneficial effects were associated with changes in the microbiota composition, such as the restoration of the abundance of Akkermansia muciniphila and Rikenellaceae and the decrease of other taxa like Lactobacillaceae. Using an in vitro gut model, we further showed that the probiotic mixture favours the production of butyrate and propionate. Our findings provide crucial clues for the design and use of more efficient probiotic preparations in obesity management and may bring new insights into the mechanisms by which host-microbe interactions govern such protective effects.

Analysis of the complete genome sequence of the archaeon Pyrococcus chitonophagus DSM 10152 (formerly Thermococcus chitonophagus).

Here we analyze the first complete genome sequence of Pyrococcus chitonophagus. The archaeon was previously suggested to belong to the Thermococcus rather than the Pyrococcus genus. Whole genome phylogeny as well as whole proteome comparisons using all available complete genomes in Thermococcales clearly showed that the species belongs to the Pyrococcus genus. P. chitonophagus was originally isolated from a hydrothermal vent site and it has been described to effectively degrade chitin debris, and therefore is considered to play a major role in the sea water ecology and metabolic activity of microbial consortia within hot sea water ecosystems. Indeed, an obvious feature of the P. chitonophagus genome is that it carries proteins showing complementary activities for chitin degradation, i.e. endo- and exo-chitinase, diacetylchitobiose deacetylase and exo-ß-D glucosaminidase activities. This finding supports the hypothesis that compared to other Thermococcales species P. chitonophagus is adapted to chitin degradation.

Dual-Color Bioluminescence Imaging for Simultaneous Monitoring of the Intestinal Persistence of Lactobacillus plantarum and Lactococcus lactis in Living Mice.

Lactic acid bacteria are found in the gastrointestinal tract of mammals and have received tremendous attention due to their health-promoting properties. We report the development of two dual-color luciferase-producing Lactobacillus (Lb.) plantarum and Lactococcus (Lc.) lactis strains for noninvasive simultaneous tracking in the mouse gastrointestinal tract. We previously described the functional expression of the red luciferase mutant (CBRluc) from Pyrophorus plagiophthalamus in Lb. plantarum NCIMB8826 and Lc. lactis MG1363 (C. Daniel, S. Poiret, V. Dennin, D. Boutillier, and B. Pot, Appl Environ Microbiol 79:1086-1094, 2013, http://dx.doi.org/10.1128/AEM.03221-12). In this study, we determined that CBRluc is a better-performing luciferase for in vivo localization of both lactic acid bacteria after oral administration than the green click beetle luciferase mutant construct developed in this study. We further established the possibility to simultaneously detect red- and green-emitting lactic acid bacteria by dual-wavelength bioluminescence imaging in combination with spectral unmixing. The difference in spectra of light emission by the red and green click beetle luciferase mutants and dual bioluminescence detection allowed in vitro and in vivo quantification of the red and green emitted signals; thus, it allowed us to monitor the dynamics and fate of the two bacterial populations simultaneously. Persistence and viability of both strains simultaneously administered to mice in different ratios was studied in vivo in anesthetized mice and ex vivo in mouse feces. The application of dual-luciferase-labeled bacteria has considerable potential to simultaneously study the interactions and potential competitions of different targeted bacteria and their hosts.

Comparative genomics of the dairy isolate Streptococcus macedonicus ACA-DC 198 against related members of the Streptococcus bovis/Streptococcus equinus complex.

BACKGROUND: Within the genus Streptococcus, only Streptococcus thermophilus is used as a starter culture in food fermentations. Streptococcus macedonicus though, which belongs to the Streptococcus bovis/Streptococcus equinus complex (SBSEC), is also frequently isolated from fermented foods mainly of dairy origin. Members of the SBSEC have been implicated in human endocarditis and colon cancer. Here we compare the genome sequence of the dairy isolate S. macedonicus ACA-DC 198 to the other SBSEC genomes in order to assess in silico its potential adaptation to milk and its pathogenicity status. RESULTS: Despite the fact that the SBSEC species were found tightly related based on whole genome phylogeny of streptococci, two distinct patterns of evolution were identified among them. Streptococcus macedonicus, Streptococcus infantarius CJ18 and Streptococcus pasteurianus ATCC 43144 seem to have undergone reductive evolution resulting in significantly diminished genome sizes and increased percentages of potential pseudogenes when compared to Streptococcus gallolyticus subsp. gallolyticus. In addition, the three species seem to have lost genes for catabolizing complex plant carbohydrates and for detoxifying toxic substances previously linked to the ability of S. gallolyticus to survive in the rumen. Analysis of the S. macedonicus genome revealed features that could support adaptation to milk, including an extra gene cluster for lactose and galactose metabolism, a proteolytic system for casein hydrolysis, auxotrophy for several vitamins, an increased ability to resist bacteriophages and horizontal gene transfer events with the dairy Lactococcus lactis and S. thermophilus as potential donors. In addition, S. macedonicus lacks several pathogenicity-related genes found in S. gallolyticus. For example, S. macedonicus has retained only one (i.e. the pil3) of the three pilus gene clusters which may mediate the binding of S. gallolyticus to the extracellular matrix. Unexpectedly, similar findings were obtained not only for the dairy S. infantarius CJ18, but also for the blood isolate S. pasteurianus ATCC 43144. CONCLUSIONS: Our whole genome analyses suggest traits of adaptation of S. macedonicus to the nutrient-rich dairy environment. During this process the bacterium gained genes presumably important for this new ecological niche. Finally, S. macedonicus carries a reduced number of putative SBSEC virulence factors, which suggests a diminished pathogenic potential.

Anti-inflammatory properties of Streptococcus salivarius, a commensal bacterium of the oral cavity and digestive tract.

Streptococcus salivarius is one of the first colonizers of the human oral cavity and gut after birth and therefore may contribute to the establishment of immune homeostasis and regulation of host inflammatory responses. The anti-inflammatory potential of S. salivarius was first evaluated in vitro on human intestinal epithelial cells and human peripheral blood mononuclear cells. We show that live S. salivarius strains inhibited in vitro the activation of the NF-κB pathway on intestinal epithelial cells. We also demonstrate that the live S. salivarius JIM8772 strain significantly inhibited inflammation in severe and moderate colitis mouse models. These in vitro and in vivo anti-inflammatory properties were not found with heat-killed S. salivarius, suggesting a protective response exclusively with metabolically active bacteria.

Recommended minimal standards for description of new taxa of the genera Bifidobacterium, Lactobacillus and related genera.

Minimal standards for the description of new cultivable strains that represent novel genera and species belonging to the genera Bifidobacterium, Lactobacillus and related genera are proposed in accordance with Recommendation 30b of the Bacteriological Code (1990 Revision): the description of novel species should be based on phenotypic, genotypic and ecological characteristics to ensure a rich polyphasic characterization. Concerning genotypic characterization, in addition to DNA G+C content (mol%) data, the description should be based on DNA-DNA hybridization (DDH), 16S rRNA gene sequence similarities and at least two housekeeping gene (e.g. hsp60 and recA) sequence similarities. DDH might not be needed if the 16S rRNA gene sequence similarity to the closest known species is lower than 97 %. This proposal has been endorsed by members of the Subcommittee on the Taxonomy of Bifidobacterium, Lactobacillus and related organisms of the International Committee on the Systematics of Prokaryotes.

Bioluminescence imaging study of spatial and temporal persistence of Lactobacillus plantarum and Lactococcus lactis in living mice.

Lactic acid bacteria, especially lactobacilli, are common inhabitants of the gastrointestinal tract of mammals, for which they have received considerable attention due to their putative health-promoting properties. In this study, we describe the development and application of luciferase-expressing Lactobacillus plantarum and Lactococcus lactis strains for noninvasive in vivo monitoring in the digestive tract of mice. We report for the first time the functional in vitro expression in Lactobacillus plantarum NCIMB8826 and in Lactococcus lactis MG1363 of the click beetle luciferase (CBluc), as well as Gaussia and bacterial luciferases, using a combination of vectors, promoters, and codon-optimized genes. We demonstrate that a CBluc construction is the best-performing luciferase system for the noninvasive in vivo detection of lactic acid bacteria after oral administration. The persistence and viability of both strains was studied by bioluminescence imaging in anesthetized mice and in mouse feces. In vivo bioluminescence imaging confirmed that after a single or multiple oral administrations, L. lactis has shorter survival times in the mouse gastrointestinal tract than L. plantarum, and it also revealed the precise gut compartments where both strains persisted. The application of luciferase-labeled bacteria has significant potential to allow the in vivo and ex vivo study of the interactions of lactic acid bacteria with their mammalian host.

Chronic ingestion of cadmium and lead alters the bioavailability of essential and heavy metals, gene expression pathways and genotoxicity in mouse intestine.

Chronic ingestion of environmental heavy metals such as lead (Pb) and cadmium (Cd) causes various well-documented pathologies in specific target organs following their intestinal absorption and subsequent accumulation. However, little is known about the direct impact of the non-absorbed heavy metals on the small intestine and the colon homeostasis. The aim of our study was to compare the specific bioaccumulation and retention of Cd and Pb and their effect on the essential metal balance in primary organs, with those occurring specifically in the gastrointestinal tract of mice. Various doses of Cd (5, 20 and 100 mg l(-1)) and Pb (100 and 500 mg l(-1)) chloride salts were provided in drinking water for subchronic to chronic exposures (4, 8 and 12 weeks). In contrast to a clear dose- and time-dependent accumulation in target organs, results showed that intestines are poor accumulators for Cd and Pb. Notwithstanding, changes in gene expression of representative intestinal markers revealed that the transport-, oxidative- and inflammatory status of the gut epithelium of the duodenum, ileum and colon were specifically affected by both heavy metal species. Additionally, in vivo comet assay used to evaluate the impact of heavy metals on DNA damage showed clear genotoxic activities of Cd, on both the upper and distal parts of the gastrointestinal tract. Altogether, these results outline the resilience of the gut which balances the various effects of chronic Cd and Pb in the intestinal mucosa. Collectively, it provides useful information for the risk assessment of heavy metals in gut homeostasis and further disease's susceptibility.

Macedovicin, the second food-grade lantibiotic produced by Streptococcus macedonicus ACA-DC 198.

Streptococcus macedonicus ACA-DC 198 was found to produce a second lantibiotic named macedovicin in addition to macedocin. Macedovicin was purified to homogeneity and mass spectrometric analysis identified a peptide of approximately 3.4 kDa. Partial N-terminal sequence analysis and tandem mass spectrometry revealed that macedovicin was identical to bovicin HJ50 and thermophilin 1277 produced by Streptococcus bovis and Streptococcus thermophilus, respectively. Macedovicin inhibits a broad spectrum of lactic acid bacteria, several food spoilage species (e.g. Clostridium spp.) and oral streptococci. We determined the complete biosynthetic gene cluster of macedovicin. Even though the gene clusters of macedovicin, thermophilin 1277 and bovicin HJ50 were almost identical at the nucleotide level, there were important differences in their predicted genes and proteins. Bovicin HJ50-like lantibiotics were also found to be encoded by Streptococcus suis strains SC84 and D12, Enterococcus columbae PLCH2, Clostridium perfringens JGS1721 and several Bacillus strains. All these lantibiotics contained a number of conserved amino acids that may be important for their biosynthesis and activity, while phylogenetic analysis supported their dispersion by horizontal gene transfer. In conclusion, the production of multiple bacteriocins may enhance the bio-protective potential of S. macedonicus during food fermentation.

Emerging issues in probiotic safety: 2023 perspectives.

Probiotics are used for both generally healthy consumers and in clinical settings. However, theoretical and proven adverse events from probiotic consumption exist. New probiotic strains and products, as well as expanding use of probiotics into vulnerable populations, warrants concise, and actionable recommendations on how to work toward their safe and effective use. The International Scientific Association for Probiotics and Prebiotics convened a meeting to discuss and produce evidence-based recommendations on potential acute and long-term risks, risks to vulnerable populations, the importance for probiotic product quality to match the needs of vulnerable populations, and the need for adverse event reporting related to probiotic use. The importance of whole genome sequencing, which enables determination of virulence, toxin, and antibiotic resistance genes, as well as clear assignment of species and strain identity, is emphasized. We present recommendations to guide the scientific and medical community on judging probiotic safety.

What is the context? Probiotics, available to healthy consumers as both dietary supplements and foods, are also used by some patient populations. The goal of this paper is to determine if any new factors have emerged that would impact current views about probiotic safety for both these populations.What is new? The authors conclude that established practices are sensibly addressing factors important to the safety of traditional probiotics used by the general population. They also make recommendations regarding emerging safety considerations. Probiotics targeted for patient populations should undergo stringent testing to meet quality standards appropriate for that population, preferably verified by an independent third party. The safety of probiotics derived from species without a history of safe use must be considered on a case-by-case basis. Research is needed to address some gaps, for example which best animal models to use for safety assessment of live microbes, the possibility of antibiotic resistance gene transfer via transformation, and potential impact of probiotic-induced changes in microbiomes, interactions with drugs, and probiotic colonization.What is the impact? Probiotics of sufficient quality for patient populations are being developed and should be used accordingly. Long-term safety assessments for probiotics should be consistent with, and not more stringent than, current regulatory requirements for biologic drugs, including fecal microbial transplants. Rigor in collecting and reporting data on adverse events is needed. The authors confirm the need for understanding the entire genetic makeup of a probiotic as a cornerstone for assessing its safety.

Small intestine vs. colon ecology and physiology: Why it matters in probiotic administration.

Research on gut microbiota has generally focused on fecal samples, representing luminal content of the large intestine. However, nutrient uptake is restricted to the small intestine. Abundant immune cell populations at this anatomical site combined with diminished mucus secretion and looser junctions (partly to allow for more efficient fluid and nutrient absorption) also results in intimate host-microbe interactions despite more rapid transit. It is thus crucial to dissect key differences in both ecology and physiology between small and large intestine to better leverage the immense potential of human gut microbiota imprinting, including probiotic engraftment at biological sensible niches. Here, we provide a detailed review unfolding how the physiological and anatomical differences between the small and large intestine affect gut microbiota composition, function, and plasticity. This information is key to understanding how gut microbiota manipulation, including probiotic administration, may strain-dependently transform host-microbe interactions at defined locations.

Complete genome sequence of the dairy isolate Streptococcus macedonicus ACA-DC 198.

The species Streptococcus macedonicus is associated with the food environment, especially with fermented dairy products. Here we present the complete 2.1-Mb genome sequence of strain ACA-DC 198, which was isolated from naturally fermented Greek kasseri cheese.

Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) has been linked to a loss of tolerance towards the resident microflora. Therapeutic use of probiotics is known to be strain specific, but precise mechanisms remain unclear. The role of NOD2 signalling and the protective effect of Lactobacillus peptidoglycan (PGN) and derived muropeptides in experimental colitis were evaluated. METHODS: The anti-inflammatory capacity of lactobacilli and derived bacterial compounds was evaluated using the 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis model. The role of NOD2, MyD88 and interleukin 10 (IL-10) in this protection was studied using Nod2(-/-), MyD88(-/-) and Il10-deficient mice, while induction of regulatory dendritic cells (DCs) was monitored through the expansion of CD103(+) DCs in mesenteric lymph nodes or after adoptive transfer of bone marrow-derived DCs. The development of regulatory T cells was investigated by following the expansion of CD4(+)FoxP3(+) cells. High-performance liquid chromatography and mass spectrometry were used to analyse the PGN structural differences. RESULTS: The protective capacity of strain Lactobacillus salivarius Ls33 was correlated with a local IL-10 production and was abolished in Nod2-deficient mice. PGN purified from Ls33 rescued mice from colitis in an IL-10-dependent manner and favoured the development of CD103(+) DCs and CD4(+)Foxp3(+) regulatory T cells. In vitro Ls33 PGN induced IL-10-producing DCs able to achieve in vivo protection after adoptive transfer in a NOD2-dependent way. This protection was also correlated with an upregulation of the indoleamine 2,3-dioxygenase immunosuppressive pathway. The protective capacity was not obtained with PGN purified from a non-anti-inflammatory strain. Structural analysis of PGNs highlighted in Ls33 the presence of an additional muropeptide, M-tri-Lys. The synthesised ligand protected mice from colitis in a NOD2-dependent but MyD88-independent manner. CONCLUSIONS: The results indicated that PGN and derived muropeptides are active compounds in probiotic functionality and might represent a useful therapeutic strategy in IBD.

Oral supplementation with selected Lactobacillus acidophilus triggers IL-17-dependent innate defense response, activation of innate lymphoid cells type 3 and improves colitis.

Live biotherapeutic products constitute an emerging therapeutic approach to prevent or treat inflammatory bowel diseases. Lactobacillus acidophilus is a constituent of the human microbiota with probiotic potential, that is illustrated by improvement of intestinal inflammation and antimicrobial activity against several pathogens. In this study, we evaluated the immunomodulatory properties of the L. acidophilus strain BIO5768 at steady state and upon acute inflammation. Supplementation of naïve mice with BIO5768 heightened the transcript level of some IL-17 target genes encoding for protein with microbicidal activity independently of NOD2 signaling. Of these, the BIO5768-induced expression of Angiogenin-4 was blunted in monocolonized mice that are deficient for the receptor of IL-17 (but not for NOD2). Interestingly, priming of bone marrow derived dendritic cells by BIO5768 enhanced their ability to support the secretion of IL-17 by CD4+ T cells. Equally of importance, the production of IL-22 by type 3 innate lymphoid cells is concomitantly heightened in response to BIO5768. When administered alone or in combination with Bifidobacterium animalis spp. lactis BIO5764 and Limosilactobacillus reuteri, BIO5768 was able to alleviate at least partially intestinal inflammation induced by Citrobacter rodentium infection. Furthermore, BIO5768 was also able to improve colitis induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). In conclusion, we identify a new potential probiotic strain for the management of inflammatory bowel diseases, and provide some insights into its IL-17-dependent and independent mode of action.

Perspective: Leveraging the Gut Microbiota to Predict Personalized Responses to Dietary, Prebiotic, and Probiotic Interventions.

Humans often show variable responses to dietary, prebiotic, and probiotic interventions. Emerging evidence indicates that the gut microbiota is a key determinant for this population heterogeneity. Here, we provide an overview of some of the major computational and experimental tools being applied to critical questions of microbiota-mediated personalized nutrition and health. First, we discuss the latest advances in in silico modeling of the microbiota-nutrition-health axis, including the application of statistical, mechanistic, and hybrid artificial intelligence models. Second, we address high-throughput in vitro techniques for assessing interindividual heterogeneity, from ex vivo batch culturing of stool and continuous culturing in anaerobic bioreactors, to more sophisticated organ-on-a-chip models that integrate both host and microbial compartments. Third, we explore in vivo approaches for better understanding of personalized, microbiota-mediated responses to diet, prebiotics, and probiotics, from nonhuman animal models and human observational studies, to human feeding trials and crossover interventions. We highlight examples of existing, consumer-facing precision nutrition platforms that are currently leveraging the gut microbiota. Furthermore, we discuss how the integration of a broader set of the tools and techniques described in this piece can generate the data necessary to support a greater diversity of precision nutrition strategies. Finally, we present a vision of a precision nutrition and healthcare future, which leverages the gut microbiota to design effective, individual-specific interventions.