Interplay between microbial-derived GABA and host GABA receptor signaling collectively influence the tumorigenic function of GABA in colon cancer.

Although classically recognized as a neurotransmitter, gamma aminobutyric acid (GABA) has also been identified in colonic tumors. Moreover, the gut microbiome represents another potential source of GABA. Both GABAA and GABAB receptors have been implicated in contributing to the effects of GABA in colorectal cancer, with both pro- and anti-tumorigenic functions identified. However, their subunit composition is often overlooked. Studies to date have not addressed whether the GABA-producing potential of the microbiome changes over the course of colon tumor development or whether receptor subunit expression patterns are altered in colon cancer. Therefore, we investigated the clusters of orthologous group frequencies of glutamate decarboxylase (GAD) in feces from two murine models of colon cancer and found that the frequency of microbial GAD was significantly decreased early in the tumorigenic process. We also determined that microbial-derived GABA inhibited proliferation of colon cancer cells in vitro and that this effect of GABA on SW480 cells involved both GABAA and GABAB receptors. GABA also inhibited prostaglandin E2 (PGE2)-induced proliferation and interleukin-6 (IL-6) expression in these cells. Gene expression correlations were assessed using the "Cancer Exploration" suite of the TIMER2.0 web tool and identified that GABA receptor subunits were differentially expressed in human colon cancer. Moreover, GABAA receptor subunits were predominantly positively associated with PGE2 synthase, cyclooxygenase-2 and IL-6. Collectively, these data demonstrate decreased potential of the microbiome to produce GABA during tumorigenesis, a novel anti-tumorigenic pathway for GABA, and that GABA receptor subunit expression adds a further layer of complexity to GABAergic signaling in colon cancer.

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.

A synbiotic mixture of selected oligosaccharides and bifidobacteria assists murine gut microbiota restoration following antibiotic challenge.

BACKGROUND: Typically, animal models studying gastrointestinal microbiotas compromised in early life have employed either germ-free animals or mice treated with a cocktail of antibiotics. Such studies intend to mimic scenarios of infants born by caesarean section and/or subjected to antibiotic treatment. However, the antibiotics used in these studies are rarely prescribed to infants. Therefore, an early life model was developed in which the murine gastrointestinal microbiota was severely disrupted by clindamycin treatment. RESULTS: In this mouse model, we investigated the extent supplementation with a synbiotic mixture of prebiotics, being scGOS/lcFOS with the human milk oligosaccharide 2'-Fucosyllactose (2'-FL), in combination with or without single strain or mix of "infant type" bifidobacteria, can rescue an antibiotic-compromised microbiota. Shotgun metagenomic sequencing showed that the microbiota was severely disrupted by the clindamycin challenge. No recovery was observed 3 weeks post-challenge in the scGOS/lcFOS/2'FL group, while the group that received the synbiotic treatment of scGOS/lcFOS/2'-FL with Bifidobacterium breve NRBB01 showed partial recovery. Strikingly in the scGOS/lcFOS/2'-FL group receiving the mixture of bifidobacteria resulted in a recovery of the microbiota disruption. Histological analyses showed that the clindamycin-treated animals at the end of the experiment still suffered from mild oedema and villi/colonic crypt irregularities which was ameliorated by the synbiotic intervention. CONCLUSION: Our study demonstrates that supplementation of synbiotic mixture of scGOS/lcFOS/2'-FL in combination with a specific mix of infant-type bifidobacterial strains is able to partially revive an antibiotic-perturbed gastrointestinal microbiota. Video Abstract.

Akkermansia muciniphila reduces susceptibility to Listeria monocytogenes infection in mice fed a high-fat diet.

A high-fat (HF) diet reduces resistance to the foodborne pathogen Listeria monocytogenes. We demonstrate that short-term gavage with A. muciniphila increases resistance to oral and systemic L. monocytogenes infection in mice fed a HF diet. A. muciniphila reduced inflammation in the gut and liver of mice fed a high-fat diet prior to infection and reduced inflammatory cell infiltration in the ileum to levels similar to mice fed a low-fat (LF) diet. Akkermansia administration had minimal impacts upon the microbiota and microbial metabolites and did not affect individual taxa or impact the Bacteroidetes to Firmicutes ratio. In summary, A. muciniphila increased resistance to L. monocytogenes infection in mice fed a HF diet by moderating immune/physiological effects through specific interaction between A. muciniphila and the host gut.

Microbial bile salt hydrolase activity influences gene expression profiles and gastrointestinal maturation in infant mice.

The mechanisms by which early microbial colonizers of the neonate influence gut development are poorly understood. Bacterial bile salt hydrolase (BSH) acts as a putative colonization factor that influences bile acid signatures and microbe-host signaling pathways and we considered whether this activity can influence infant gut development. In silico analysis of the human neonatal gut metagenome confirmed that BSH enzyme sequences are present as early as one day postpartum. Gastrointestinal delivery of cloned BSH to immature gnotobiotic mice accelerated shortening of the colon and regularized gene expression profiles, with monocolonised mice more closely resembling conventionally raised animals. In situ expression of BSH decreased markers of cell proliferation (Ki67, Hes2 and Ascl2) and strongly increased expression of ALPI, a marker of cell differentiation and barrier function. These data suggest an evolutionary paradigm whereby microbial BSH activity potentially influences bacterial colonization and in-turn benefits host gastrointestinal maturation.