Serotonin reduction in post-acute sequelae of viral infection.

Post-acute sequelae of COVID-19 (PASC, "Long COVID") pose a significant global health challenge. The pathophysiology is unknown, and no effective treatments have been found to date. Several hypotheses have been formulated to explain the etiology of PASC, including viral persistence, chronic inflammation, hypercoagulability, and autonomic dysfunction. Here, we propose a mechanism that links all four hypotheses in a single pathway and provides actionable insights for therapeutic interventions. We find that PASC are associated with serotonin reduction. Viral infection and type I interferon-driven inflammation reduce serotonin through three mechanisms: diminished intestinal absorption of the serotonin precursor tryptophan; platelet hyperactivation and thrombocytopenia, which impacts serotonin storage; and enhanced MAO-mediated serotonin turnover. Peripheral serotonin reduction, in turn, impedes the activity of the vagus nerve and thereby impairs hippocampal responses and memory. These findings provide a possible explanation for neurocognitive symptoms associated with viral persistence in Long COVID, which may extend to other post-viral syndromes.

A microbiome-dependent gut-brain pathway regulates motivation for exercise.

Exercise exerts a wide range of beneficial effects for healthy physiology1. However, the mechanisms regulating an individual's motivation to engage in physical activity remain incompletely understood. An important factor stimulating the engagement in both competitive and recreational exercise is the motivating pleasure derived from prolonged physical activity, which is triggered by exercise-induced neurochemical changes in the brain. Here, we report on the discovery of a gut-brain connection in mice that enhances exercise performance by augmenting dopamine signalling during physical activity. We find that microbiome-dependent production of endocannabinoid metabolites in the gut stimulates the activity of TRPV1-expressing sensory neurons and thereby elevates dopamine levels in the ventral striatum during exercise. Stimulation of this pathway improves running performance, whereas microbiome depletion, peripheral endocannabinoid receptor inhibition, ablation of spinal afferent neurons or dopamine blockade abrogate exercise capacity. These findings indicate that the rewarding properties of exercise are influenced by gut-derived interoceptive circuits and provide a microbiome-dependent explanation for interindividual variability in exercise performance. Our study also suggests that interoceptomimetic molecules that stimulate the transmission of gut-derived signals to the brain may enhance the motivation for exercise.

ß-Hydroxybutyrate suppresses colorectal cancer.

Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed1. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body ß-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.

Microbial memories.

The microbiota impedes pathogen invasion of the intestinal ecosystem, a phenomenon termed colonization resistance. In an upcoming issue of Cell, Stacy et al. describe host-initiated metabolite pathways that functionally alter the microbiota after primary infection, thereby augmenting colonization resistance to subsequent infection.

Small molecules, big effects: microbial metabolites in intestinal immunity.

The mammalian intestine is host to a vast number of microbial organisms. The immune system must balance tolerance with innate and adaptive defense mechanisms to maintain homeostasis with the microbial community. Interestingly, microbial metabolites have been shown to play a role in shaping the host immune response, thus assisting with adaptations that have significant implications for human health and disease. New investigations have uncovered roles for metabolites in modulating almost every aspect of the immune system. In this minireview, we survey these recent findings, which taken together reveal nuanced interactions that we are just beginning to understand.

MAIT cells are imprinted by the microbiota in early life and promote tissue repair.

How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T (MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)-producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1-, IL-18-, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury.

New Approaches to Microbiome-Based Therapies.

Over the last decade, our understanding of the composition and functions of the gut microbiota has greatly increased. To a large extent, this has been due to the development of high-throughput genomic analyses of microbial communities, which have identified the critical contributions of the microbiome to human health. Consequently, the intestinal microbiota has emerged as an attractive therapeutic target. The large majority of microbiota-targeted therapies aim at engineering the intestinal ecosystem by means of probiotics or prebiotics. Recently, a novel therapeutic approach has emerged which focuses on molecules that are secreted, modulated, or degraded by the microbiome and act directly on the host. Here, we discuss the advantages and challenges associated with the metabolite-based "postbiotic" approach, highlighting recent progress and the areas that need intensive attention and investigation over the next 5 years. The time is ripe for postbiotic therapies to be developed in the near future.

CD8+ T Cells Lack Local Signals To Produce IFN-γ in the Skin during Leishmania Infection.

Resolution of leishmaniasis depends upon parasite control and limiting inflammation. CD4+ Th1 cells are required to control parasites, whereas CD8+ T cells play a dual role: they promote Th1 cell differentiation but can also increase inflammation at the site of infection as a consequence of cytolysis. Although CD8+ T cells taken from leishmanial lesions are cytolytic, in this study, we showed that only a few CD8+ T cells produced IFN-γ. Correspondingly, only low levels of IL-12 and/or IL-12 mRNA were present in lesions from infected mice, as well as patients. Addition of IL-12 increased IFN-γ production by CD8+ T cells isolated from leishmanial lesions, suggesting that a lack of IL-12 at the site of infection limits IFN-γ production by CD8+ T cells. To determine whether CD8+ T cells could promote resistance in vivo if IL-12 was present, we administered IL-12 to Leishmania-infected RAG mice reconstituted with CD8+ T cells. IL-12 treatment increased the ability of CD8+ T cells to make IFN-γ, but CD8+ T cells still failed to control the parasites. Furthermore, despite the ability of CD8+ T cells to promote immunity to secondary infections, we also found that CD8+ T cells from immune mice were unable to control Leishmania in RAG mice. Taken together, these results indicate that lesional CD8+ T cells fail to make IFN-γ because of a deficit in IL-12 but that, even with IL-12, CD8+ T cells are unable to control Leishmania in the absence of CD4+ T cells.