Akkermansia muciniphila: a deworming partner independent of type 2 immunity.

The gut microbiota has coevolved with the host for hundreds of millions of years, playing a beneficial role in host health. Human parasitic helminths are widespread and pose a pervasive global public health issue. Although Type 2 immunity provides partial resistance to helminth infections, the composition of the gut microbiota can change correspondingly. Therefore, it raises the question of what role the gut microbiota plays during helminth infection. Akkermansia muciniphila has emerged as a notable representative of beneficial microorganisms in the gut microbiota. Recent studies indicate that A. muciniphila is not merely associated with helminth infection but is also causally linked to infection. Here, we provide an overview of the crosstalk between A. muciniphila and enteric helminth infection. Our goal is to enhance our understanding of the interplay among A. muciniphila, helminths, and their hosts while also exploring the potential underlying mechanisms.

Heterologous expression of P9 from Akkermansia muciniphila increases the GLP-1 secretion of intestinal L cells.

Glucagon-like peptide-1(GLP-1) is an incretin hormone secreted primarily from the intestinal L-cells in response to meals. GLP-1 is a key regulator of energy metabolism and food intake. It has been proven that P9 protein from A. muciniphila could increase GLP-1 release and improve glucose homeostasis in HFD-induced mice. To obtain an engineered Lactococcus lactis which produced P9 protein, mature polypeptide chain of P9 was codon-optimized, fused with N-terminal signal peptide Usp45, and expressed in L. lactis NZ9000. Heterologous secretion of P9 by recombinant L. lactis NZP9 were successfully detected by SDS-PAGE and western blotting. Notably, the supernatant of L. lactis NZP9 stimulated GLP-1 production of NCI-H716 cells. The relative expression level of GLP-1 biosynthesis gene GCG and PCSK1 were upregulated by 1.63 and 1.53 folds, respectively. To our knowledge, this is the first report on the secretory expression of carboxyl-terminal processing protease P9 from A. muciniphila in L. lactis. Our results suggest that genetically engineered L. lactis which expressed P9 may have therapeutic potential for the treatment of diabetes, obesity and other metabolic disorders.

Carrageenan as a Potential Factor of Inflammatory Bowel Diseases.

Carrageenan is a widely used food additive and is seen as a potential candidate in the pharmaceutical industry. However, there are two faces to carrageenan that allows it to be used positively for therapeutic purposes. Carrageenan can be used to create edible films and for encapsulating drugs, and there is also interest in the use of carrageenan for food printing. Carrageenan is a naturally occurring polysaccharide gum. Depending on the type of carrageenan, it is used in regulating the composition of intestinal microflora, including the increase in the population of Bifidobacterium bacteria. On the other hand, the studies have demonstrated the harmfulness of carrageenan in animal and human models, indicating a direct link between diet and intestinal inflammatory states. Carrageenan changes the intestinal microflora, especially Akkermansia muciniphilia, degrades the mucous barrier and breaks down the mucous barrier, causing an inflammatory reaction. It directly affects epithelial cells by activating the pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway. The mechanism is based on activation of the TLR4 receptor, alterations in macrophage activity, production of proinflammatory cytokines and activation of innate immune pathways. Carrageenan increases the content of Bacteroidetes bacteria, also causing a reduction in the number of short chain fatty acid (SCFA)-producing bacteria. The result is damage to the integrity of the intestinal membrane and reduction of the mucin layer. The group most exposed to the harmful effects of carrageenan are people suffering from intestinal inflammation, including Crohn disease (CD) and ulcerative colitis (UC).

Akkermansia muciniphila exoglycosidases target extended blood group antigens to generate ABO-universal blood.

Matching donor and recipient blood groups based on red blood cell (RBC) surface ABO glycans and antibodies in plasma is crucial to avoid potentially fatal reactions during transfusions. Enzymatic conversion of RBC glycans to the universal group O is an attractive solution to simplify blood logistics and prevent ABO-mismatched transfusions. The gut symbiont Akkermansia muciniphila can degrade mucin O-glycans including ABO epitopes. Here we biochemically evaluated 23 Akkermansia glycosyl hydrolases and identified exoglycosidase combinations which efficiently transformed both A and B antigens and four of their carbohydrate extensions. Enzymatic removal of canonical and extended ABO antigens on RBCs significantly improved compatibility with group O plasmas, compared to conversion of A or B antigens alone. Finally, structural analyses of two B-converting enzymes identified a previously unknown putative carbohydrate-binding module. This study demonstrates the potential utility of mucin-degrading gut bacteria as valuable sources of enzymes for production of universal blood for transfusions.

Effect of inulin, galacto-oligosaccharides, and polyphenols on the gut microbiota, with a focus on Akkermansia muciniphila.

Inulins, galacto-oligosaccharides (GOS) and polyphenols are considered to stimulate the growth of Akkermansia muciniphila (A. muciniphila) in the gut. We performed a meta-analysis of six microbiome studies (821 stool samples from 451 participants) to assess the effects of inulin, GOS, and polyphenols on the abundance of A. muciniphila in the gut. The intervention of GOS increased the relative abundance of A. muciniphila in healthy participants. Additionally, metabolic pathways associated with carbohydrate metabolism and short-chain fatty acid release were enriched following the GOS intervention. Furthermore, after the GOS intervention, the coexisting microbial communities of A. muciniphila, such as Eubacterium hallii and Bacteroides, exhibited an enhanced correlation with A. muciniphila. In conclusion, our findings suggest that GOS may promote the growth of A. muciniphila in the gut by modulating the gut microbiota composition.

Integrative metagenomic analysis reveals distinct gut microbial signatures related to obesity.

Obesity is a metabolic disorder closely associated with profound alterations in gut microbial composition. However, the dynamics of species composition and functional changes in the gut microbiome in obesity remain to be comprehensively investigated. In this study, we conducted a meta-analysis of metagenomic sequencing data from both obese and non-obese individuals across multiple cohorts, totaling 1351 fecal metagenomes. Our results demonstrate a significant decrease in both the richness and diversity of the gut bacteriome and virome in obese patients. We identified 38 bacterial species including Eubacterium sp. CAG:274, Ruminococcus gnavus, Eubacterium eligens and Akkermansia muciniphila, and 1 archaeal species, Methanobrevibacter smithii, that were significantly altered in obesity. Additionally, we observed altered abundance of five viral families: Mesyanzhinovviridae, Chaseviridae, Salasmaviridae, Drexlerviridae, and Casjensviridae. Functional analysis of the gut microbiome indicated distinct signatures associated to obesity and identified Ruminococcus gnavus as the primary driver for function enrichment in obesity, and Methanobrevibacter smithii, Akkermansia muciniphila, Ruminococcus bicirculans, and Eubacterium siraeum as functional drivers in the healthy control group. Additionally, our results suggest that antibiotic resistance genes and bacterial virulence factors may influence the development of obesity. Finally, we demonstrated that gut vOTUs achieved a diagnostic accuracy with an optimal area under the curve of 0.766 for distinguishing obesity from healthy controls. Our findings offer comprehensive and generalizable insights into the gut bacteriome and virome features associated with obesity, with the potential to guide the development of microbiome-based diagnostics.

Structural characteristics of gut microbiota in longevity from Changshou town, Hubei, China.

The gut microbiota (GM) and its potential functions play a crucial role in maintaining host health and longevity. The aim of this study was to investigate the potential relationship between GM and longevity. We collected fecal samples from 92 healthy volunteers (middle-aged and elderly: 43-79 years old; longevity: ≥ 90 years old) from Changshou Town, Zhongxiang City, Hubei, China. In addition, we collected samples from 30 healthy middle-aged and elderly controls (aged 51-70 years) from Wuhan, Hubei. The 16S rDNA V3 + V4 region of the fecal samples was sequenced using high-throughput sequencing technology. Diversity analysis results showed that the elderly group with longevity and the elderly group with low body mass index (BMI) exhibited higher α diversity. However, no significant difference was observed in ß diversity. The results of the microbiome composition indicate that Firmicutes, Proteobacteria, and Bacteroidota are the core phyla in all groups. Compared to younger elderly individuals, Akkermansia and Lactobacillus are significantly enriched in the long-lived elderly group, while Megamonas is significantly reduced. In addition, a high abundance of Akkermansia is a significant characteristic of elderly populations with low BMI values. Furthermore, the functional prediction results showed that the elderly longevity group had higher abilities in short-chain fatty acid metabolism, amino acid metabolism, and xenobiotic biodegradation. Taken together, our study provides characteristic information on GM in the long-lived elderly population in Changshou Town. This study can serve as a valuable addition to the current research on age-related GM. KEY POINTS: • The gut microbiota of elderly individuals with longevity and low BMI exhibit higher alpha diversity • Gut microbiota diversity did not differ significantly between genders in the elderly population • Several potentially beneficial bacteria (e.g., Akkermansia and Lactobacillus) are enriched in long-lived individuals.

Akkermansia muciniphila: a potential candidate for ameliorating metabolic diseases.

Metabolic diseases are comprehensive disease based on obesity. Numerous cumulative studies have shown a certain correlation between the fluctuating abundance of Akkermansia muciniphila and the occurrence of metabolic diseases. A. muciniphila, a potential probiotic candidate colonized in the human intestinal mucus layer, and its derivatives have various physiological functions, including treating metabolic disorders and maintaining human health. This review systematically explicates the abundance change rules of A. muciniphila in metabolic diseases. It also details the high efficacy and specific molecules mechanism of A. muciniphila and its derivatives in treating obesity, type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease.

The role of morphine- and fentanyl-induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota-gut-brain axis.

Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis.

The secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation.

Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc_1409, a previously uncharacterised A. muciniphila-secreted protein. Amuc_1409 increased intestinal stem cell (ISC) proliferation and regeneration in ex vivo intestinal organoids and in vivo models of radiation- or chemotherapeutic drug-induced intestinal injury and natural aging with male mice. Mechanistically, Amuc_1409 promoted E-cadherin/ß-catenin complex dissociation via interaction with E-cadherin, resulting in the activation of Wnt/ß-catenin signaling. Our results demonstrate that Amuc_1409 plays a crucial role in intestinal homeostasis by regulating ISC activity in an E-cadherin-dependent manner and is a promising biomolecule for improving and maintaining gut health.

An orally active carbon monoxide-releasing molecule enhances beneficial gut microbial species to combat obesity in mice.

Carbon monoxide (CO), a gaseous signaling molecule, has shown promise in preventing body weight gain and metabolic dysfunction induced by high fat diet (HFD), but the mechanisms underlying these effects are largely unknown. An essential component in response to HFD is the gut microbiome, which is significantly altered during obesity and represents a target for developing new therapeutic interventions to fight metabolic diseases. Here, we show that CO delivered to the gut by oral administration with a CO-releasing molecule (CORM-401) accumulates in faeces and enriches a variety of microbial species that were perturbed by a HFD regimen. Notably, Akkermansia muciniphila, which exerts salutary metabolic effects in mice and humans, was strongly depleted by HFD but was the most abundant gut species detected after CORM-401 treatment. Analysis of bacterial transcripts revealed a restoration of microbial functional activity, with partial or full recovery of the Krebs cycle, ß-oxidation, respiratory chain and glycolysis. Mice treated with CORM-401 exhibited normalization of several plasma and fecal metabolites that were disrupted by HFD and are dependent on Akkermansia muciniphila's metabolic activity, including indoles and tryptophan derivatives. Finally, CORM-401 treatment led to an improvement in gut morphology as well as reduction of inflammatory markers in colon and cecum and restoration of metabolic profiles in these tissues. Our findings provide therapeutic insights on the efficacy of CO as a potential prebiotic to combat obesity, identifying the gut microbiota as a crucial target for CO-mediated pharmacological activities against metabolic disorders.

Lycium barbarum L. Balanced intestinal flora with YAP1/FXR activation in drug-induced liver injury.

Drug-induced liver injury (DILI) is a common and severe adverse drug reaction that can result in acute liver failure. Previously, we have shown that Lycium barbarum L. (wolfberry) ameliorated liver damage in acetaminophen (APAP)-induced DILI. Nevertheless, the mechanism needs further clarification. Herein, we utilized APAP-induced DILI mice to investigate how wolfberry impacts the gut-liver axis to mitigate liver damage. We showed that the abundance of Akkermansia muciniphila (A. muciniphila) was decreased, and intestinal microbiota was disrupted, while the expression levels of YAP1 and FXR-mediated CYP7A1 were reduced in the liver of DILI mice. Furthermore, wolfberry increased the abundance of A. muciniphila and the number of goblet cells in the intestines, while decreasing AST, ALT, and total bile acids (TBA) levels in the serum. Interestingly, A. muciniphila promoted YAP1 and FXR expression in hepatocytes, leading to the inhibition of CYP7A1 expression and a decrease in TBA content. Notably, wolfberry did not exert the beneficial effects mentioned above after the removal of intestinal bacteria by antibiotics (ATB)-containing water. Additionally, Yap1 knockout downregulated FXR expression and enhanced CYP7A1 expression in the liver of hepatocyte-specific Yap1 knockout mice. Therefore, wolfberry stimulated YAP1/FXR activation and reduced CYP7A1 expression by promoting the balance of intestinal microbiota, thereby suppressing the overproduction of bile acids.

The role of Akkermansia muciniphila in colorectal cancer: A double-edged sword of treatment or disease progression?

Colorectal cancer (CRC) is the second most cancer-related death worldwide. In recent years, probiotics have been used to reduce the potential risks of CRC and tumors with various mechanisms. Different bacteria have been suggested to play different roles in the progression, prevention, or treatment of CRC. Akkermansia muciniphila is considered a next-generation probiotic for preventing and treating some diseases. Therefore, in this review article, we aimed to describe and discuss different mechanisms of A. muciniphila as an intestinal microbiota or probiotic in CRC. Some studies suggested that the abundance of A. muciniphila was higher or increased in CRC patients compared to healthy individuals. However, the decreased abundance of A. muciniphila was associated with severe symptoms of CRC, indicating that A. muciniphila did not play a role in the development of CRC. In addition, A. muciniphila administration elevates gene expression of proliferation-associated molecules such as S100A9, Dbf4, and Snrpd1, or markers for cell proliferation. Some other studies suggested that inflammation and tumorigenesis in the intestine might promoted by A. muciniphila. Overall, the role of A. muciniphila in CRC development or inhibition is still unclear and controversial. Various methods of bacterial supplementation, such as viability, bacterial number, and abundance, could all influence the colonization effect of A. muciniphila administration and CRC progression. Overall, A. mucinipila has been revealed to modulate the therapeutic potential of immune checkpoint inhibitors. Preliminary human data propose that oral consumption of A. muciniphila is safe, but its efficacy needs to be confirmed in more human clinical studies.

Lacidophilin tablets alleviate constipation through regulation of intestinal microflora by promoting the colonization of Akkermansia sps.

Constipation is a major health problem worldwide that requires effective and safe treatment options. Increasing evidence indicates that disturbances in gut microbiota may be a risk factor for constipation. Administration of lacidophilin tablets shows promising therapeutic potential in the treatment of inflammatory bowel disease owing to their immunomodulatory properties and regulation of the gut microbiota. The focus of this study was on investigating the ability of lacidophilin tablets to relieve constipation by modulating the gut microbiome. Rats with loperamide hydrochloride induced constipation were treated with lacidophilin tablets via intragastric administration for ten days. The laxative effect of lacidophilin tablets was then evaluated by investigating the regulation of intestinal microflora and the possible underlying molecular mechanism. Our results reveal that treatment with lacidophilin tablets increased the intestinal advancement rate, fecal moisture content, and colonic AQP3 protein expression. It also improved colonic microflora structure in the colonic contents of model rats mainly by increasing Akkermansia muciniphila and decreasing Clostridium_sensu_stricto_1. Transcriptome analysis indicated that treatment with lacidophilin tablets maintains the immune response in the intestine and promotes recovery of the intestinal mechanical barrier in the constipation model. Our study shows that lacidophilin tablets improve constipation, possibly by promoting Akkermansia colonization and by modulating the intestinal immune response.

Akkermansia muciniphila in infectious disease: A new target for this next-generation probiotic?

The common gastrointestinal commensal Akkermansia muciniphila is a mucin-degrading bacterium that is greatly reduced in individuals consuming a high-fat diet. Increasing evidence from a variety of clinical and pre-clinical studies suggests that oral supplementation with Akkermansia can improve metabolic health and moderate systemic inflammation. We and others have demonstrated a role for Akkermansia administration in protection against infectious disease and the outcome from sepsis. Very recent studies have indicated the molecular mechanisms by which A. muciniphila may interact with the host to influence systemic immune-regulation and control of microbial pathogenesis. Here we consider recent studies which demonstrate the efficacy of this potential next-generation probiotic in animal models of Salmonella Typhimurium, Listeria monocytogenes and Clostridioides difficile as well as influenza virus and phlebovirus. The potential mechanisms by which A. muciniphila may influence local and systemic immune responses are discussed.

Xylooligosaccharides ameliorate insulin resistance by increasing Akkermansia muciniphila and improving intestinal barrier dysfunction in gestational diabetes mellitus mice.

Little is known regarding the effects of xylooligosaccharides (XOS) on insulin resistance (IR) in gestational diabetes mellitus (GDM). We aimed to investigate this issue and its mechanism. Sixty female mice were randomly allotted to 4 groups (n = 15): control, high fat diet (HFD), GDM, and GDM + XOS. The control mice were fed an AIN-93 diet, while the mice in the other groups were fed 45% HFD. After pregnancy, mice in GDM and GDM + XOS groups were intraperitoneally injected with 30 mg kg-1 streptozocin for 3 days from the first day of pregnancy. Mice in the GDM + XOS group were then fed an HFD containing 2% XOS. Fasting glucose and insulin levels were monitored. The fecal Akkermansia muciniphila (Akk. muciniphila) and Bifidobacterium were measured by qPCR. The Chiu scores were calculated from hematoxylin-eosin (HE)-stained ileal tissues. Phosphorylated Akt in the liver and occludin and ZO-1 in the intestinal tissues were determined by western blotting. XOS reduced (p < 0.05) fasting blood glucose and insulin and HOMA-IR, and increased (p < 0.05) Akt phosphorylation in the livers of GDM mice. Moreover, XOS decreased (p < 0.05) TNFα, IL-1ß, IL-15 and LPS in the serum, increased (p < 0.05) fecal Akk. muciniphila abundance, lowered (p < 0.05) Chiu's scores, and enhanced (p < 0.05) occludin and ZO-1 expression. XOS ameliorate IR by increasing Akk. muciniphila and improving intestinal barrier dysfunction in GDM mice.

Unveiling the immunomodulatory effect of the novel probiotic Akkermansia muciniphila and its protective effect in vitro.

Akkermansia muciniphila, a bacterium found in the human microbiota, has gained interest due to its potential health benefits. Previous studies have linked its absence to inflammatory disorders, while also suggesting its role in maintaining a healthy gut barrier. However, there is limited information on its specific effects on the immune system. Therefore, the aim of this research was to analyze the in vitro response triggered by A. muciniphila employing RAW 264.7 macrophages. The study focused on investigating the production of cytokines and nitric oxide, along with evaluating the expression of inflammatory surface cellular markers. Additionally, we assessed its potential to protect against intestinal infections, using Salmonella enterica serovar Enteritidis as a model. Our findings reveal a modulation effect of A. muciniphila with pro-inflammatory features, including the release of pro-inflammatory cytokines and upregulation of CD40 and CD80 surface markers, in contrast with previous reported data. Importantly, A. muciniphila could protect against Salmonella infection by promoting macrophage activation, appearing as a promising probiotic candidate for the control of intestinal infections.

Akkermansia muciniphila and Parabacteroides distasonis synergistically protect from colitis by promoting ILC3 in the gut.

Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the gastrointestinal tract. The etiology of IBD remains elusive, but the disease is suggested to arise from the interaction of environmental and genetic factors that trigger inadequate immune responses and inflammation in the intestine. The gut microbiome majorly contributes to disease as an environmental variable, and although some causative bacteria are identified, little is known about which specific members of the microbiome aid in the intestinal epithelial barrier function to protect from disease. While chemically inducing colitis in mice from two distinct animal facilities, we serendipitously found that mice in one facility showed remarkable resistance to disease development, which was associated with increased markers of epithelial barrier integrity. Importantly, we show that Akkermansia muciniphila and Parabacteroides distasonis were significantly increased in the microbiota of resistant mice. To causally connect these microbes to protection against disease, we colonized susceptible mice with the two bacterial species. Our results demonstrate that A. muciniphila and P. distasonis synergistically drive a protective effect in both acute and chronic models of colitis by boosting the frequency of type 3 innate lymphoid cells in the colon and by improving gut epithelial integrity. Altogether, our work reveals a combined effort of commensal microbes in offering protection against severe intestinal inflammation by shaping gut immunity and by enhancing intestinal epithelial barrier stability. Our study highlights the beneficial role of gut bacteria in dictating intestinal homeostasis, which is an important step toward employing microbiome-driven therapeutic approaches for IBD clinical management. IMPORTANCE: The contribution of the gut microbiome to the balance between homeostasis and inflammation is widely known. Nevertheless, the etiology of inflammatory bowel disease, which is known to be influenced by genetics, immune response, and environmental cues, remains unclear. Unlocking novel players involved in the dictation of a protective gut, namely, in the microbiota component, is therefore crucial to develop novel strategies to tackle IBD. Herein, we revealed a synergistic interaction between two commensal bacterial strains, Akkermansia muciniphila and Parabacteroides distasonis, which induce protection against both acute and chronic models of colitis induction, by enhancing epithelial barrier integrity and promoting group 3 innate lymphoid cells in the colonic mucosa. This study provides a novel insight on how commensal bacteria can beneficially act to promote intestinal homeostasis, which may open new avenues toward the use of microbiome-derived strategies to tackle IBD.

Placebo-resistant gut bacteria: Akkermansia muciniphila spp. and Familial Mediterranean fever disease.

Introduction: Despite numerous investigations into the impact of drugs/probiotics on the gut microbiota composition in Familial Mediterranean Fever (FMF) patients, the question as to whether there exists a significant bacterial diversity(ies) independent of the placebo effect that can be reliably considered in clinical and nutritional trials remains unresolved. Methods: This study represents the in augural analysis of the placebo's influence on the gut microbiota of both healthy individuals and FMF afflicted men, utilizing previously collected data from PhyloChip™ DNA microarray experiments. A total of 15 healthy and 15 FMF male volunteers, aged 18 to 50, participated in this partially randomized placebo trial, which is accessible through the GEO Series accession number GSE111835. Results and Discussion: Key findings from current investigations include i. the anticipated divergence in gut bacteria resistance to placebo between healthy and FMF individuals, ii. the minor impact of placebo on gut bacterial diversities in healthy individuals, with Enterobacteriaceae diversities identified as placebo-resistant among "healthy" gut bacteria, and iii. the comprehensive influence of placebo on all bacterial phyla in the gut microbiome of FMF patients, extending to nearly all bacterial genera, except for the resilience of gut Akkermansia muciniphila spp. to placebo in FMF patients. This study underscores the susceptibility of Faecalibacterium, Blautia, and Clostridium genera to placebo. Consequently, this investigation holds significance for the proper design of placebo-controlled trials and establishes a foundation for further exploration of the gut-brain axis. Furthermore, it contributes valuable insights to discussions regarding proposals for probiotic therapies, particularly focusing on Faecalibacterium spp., Blautia spp., and Clostridium spp.

Mechanism of 2'-fucosyllactose degradation by human-associated Akkermansia.

Among the first microorganisms to colonize the human gut of breastfed infants are bacteria capable of fermenting human milk oligosaccharides (HMOs). One of the most abundant HMOs, 2'-fucosyllactose (2'-FL), may specifically drive bacterial colonization of the intestine. Recently, differential growth has been observed across multiple species of Akkermansia on various HMOs including 2'-FL. In culture, we found growth of two species, A. muciniphila MucT and A. biwaensis CSUN-19,on HMOs corresponded to a decrease in the levels of 2'-FL and an increase in lactose, indicating that the first step in 2'-FL catabolism is the cleavage of fucose. Using phylogenetic analysis and transcriptional profiling, we found that the number and expression of fucosidase genes from two glycoside hydrolase (GH) families, GH29 and GH95, vary between these two species. During the mid-log phase of growth, the expression of several GH29 genes was increased by 2'-FL in both species, whereas the GH95 genes were induced only in A. muciniphila. We further show that one putative fucosidase and a ß-galactosidase from A. biwaensis are involved in the breakdown of 2'-FL. Our findings indicate that the plasticity of GHs of human-associated Akkermansia sp. enables access to additional growth substrates present in HMOs, including 2'-FL. Our work highlights the potential for Akkermansia to influence the development of the gut microbiota early in life and expands the known metabolic capabilities of this important human symbiont.IMPORTANCEAkkermansia are mucin-degrading specialists widely distributed in the human population. Akkermansia biwaensis has recently been observed to have enhanced growth relative to other human-associated Akkermansia on multiple human milk oligosaccharides (HMOs). However, the mechanisms for enhanced growth are not understood. Here, we characterized the phylogenetic diversity and function of select genes involved in the growth of A. biwaensis on 2'-fucosyllactose (2'-FL), a dominant HMO. Specifically, we demonstrate that two genes in a genomic locus, a putative ß-galactosidase and α-fucosidase, are likely responsible for the enhanced growth on 2'-FL. The functional characterization of A. biwaensis growth on 2'-FL delineates the significance of a single genomic locus that may facilitate enhanced colonization and functional activity of select Akkermansia early in life.