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The restoration of CD4⁺ T cells, especially T-helper type 17 (Th17) cells, remains incomplete in the gut mucosa of most human immunodeficiency virus type 1 (HIV-1)–infected individuals despite sustained antiretroviral therapy (ART). Herein, we report an increase in the absolute number of CXCR3⁺ T cells in the duodenal mucosa during ART. The frequencies of Th1 and CXCR3⁺ CD8⁺ T cells were increased and negatively correlated with CCL20 and CCL25 expression in the mucosa. In ex vivo analyses, we showed that interferon γ, the main cytokine produced by Th1 and effector CD8⁺ T cells, downregulates the expression of CCL20 and CCL25 by small intestine enterocytes, while it increases the expression of CXCL9/10/11, the ligands of CXCR3. Interleukin 18, a pro-Th1 cytokine produced by enterocytes, also contributes to the downregulation of CCL20 expression and increases interferon γ production by Th1 cells. This could perpetuate an amplification loop for CXCR3-driven Th1 and effector CD8⁺ T cells recruitment to the gut, while impairing Th17 cells homing through the CCR6-CCL20 axis in treated HIV-1–infected individuals.

Circadian rhythmicity is a defining feature of mammalian metabolism that synchronizes metabolic processes to day-night light cycles. Here, we show that the intestinal microbiota programs diurnal metabolic rhythms in the mouse small intestine through histone deacetylase 3 (HDAC3). The microbiota induced expression of intestinal epithelial HDAC3, which was recruited rhythmically to chromatin, and produced synchronized diurnal oscillations in histone acetylation, metabolic gene expression, and nutrient uptake. HDAC3 also functioned noncanonically to coactivate estrogen-related receptor α, inducing microbiota-dependent rhythmic transcription of the lipid transporter gene Cd36 and promoting lipid absorption and diet-induced obesity. Our findings reveal that HDAC3 integrates microbial and circadian cues for regulation of diurnal metabolic rhythms and pinpoint a key mechanism by which the microbiota controls host metabolism.

The glycolytic activity of Paneth cells provides lactate, which is required by self-renewing intestinal stem cells for oxidative metabolism to activate p38 MAP kinase, ensuring regeneration of a mature crypt. Metabolism and gut regeneration Small intestine crypts are regenerated throughout life thanks to self-renewing stem cells located at the bottom of crypts. Differentiated Paneth cells provide the signalling molecules that modulate the regenerative properties of these stem cells. The influence of metabolism on the self-renewal of the crypt has not been studied in great detail. Burgering and colleagues now show that, whereas intestinal stem cells rely on mitochondrial activity for their metabolic needs, Paneth cells use glycolysis, a process that provides the lactate that is required by the stem cells for their oxidative metabolism. This activates the p38 MAP kinase to ensure regeneration of a mature crypt. The findings suggest that the metabolism of certain intestinal cells has an important role in supporting stem cell function. The small intestinal epithelium self-renews every four or five days. Intestinal stem cells (Lgr5 + crypt base columnar cells (CBCs)) sustain this renewal and reside between terminally differentiated Paneth cells at the bottom of the intestinal crypt 1 . Whereas the signalling requirements for maintaining stem cell function and crypt homeostasis have been well studied, little is known about how metabolism contributes to epithelial homeostasis. Here we show that freshly isolated Lgr5 + CBCs and Paneth cells from the mouse small intestine display different metabolic programs. Compared to Paneth cells, Lgr5 + CBCs display high mitochondrial activity. Inhibition of mitochondrial activity in Lgr5 + CBCs or inhibition of glycolysis in Paneth cells strongly affects stem cell function, as indicated by impaired organoid formation. In addition, Paneth cells support stem cell function by providing lactate to sustain the enhanced mitochondrial oxidative phosphorylation in the Lgr5 + CBCs. Mechanistically, we show that oxidative phosphorylation stimulates p38 MAPK activation by mitochondrial reactive oxygen species signalling, thereby establishing the mature crypt phenotype. Together, our results reveal a critical role for the metabolic identity of Lgr5 + CBCs and Paneth cells in supporting optimal stem cell function, and we identify mitochondria and reactive oxygen species signalling as a driving force of cellular differentiation.

Human gut microbiota senses its environment and responds by releasing metabolites, some of which are key regulators of human health and disease. In this study, we characterize gut-associated bacteria in their ability to decarboxylate levodopa to dopamine via tyrosine decarboxylases. Bacterial tyrosine decarboxylases efficiently convert levodopa to dopamine, even in the presence of tyrosine, a competitive substrate, or inhibitors of human decarboxylase. In situ levels of levodopa are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson’s disease. Finally, the higher relative abundance of bacterial tyrosine decarboxylases at the site of levodopa absorption, proximal small intestine, had a significant impact on levels of levodopa in the plasma of rats. Our results highlight the role of microbial metabolism in drug availability, and specifically, that abundance of bacterial tyrosine decarboxylase in the proximal small intestine can explain the increased dosage regimen of levodopa treatment in Parkinson’s disease patients. The gut microbiota can impact the bioavailability of therapeutic drugs. Here, the authors show that bacterial tyrosine decarboxylases (TDC) decrease the levels of levodopa, the primary treatment in Parkinson’s disease, by conversion to dopamine, and suggest TDC as a potential predictive biomarker for treatment.

Lipids entering the gastrointestinal tract include dietary lipids (triacylglycerols, cholesteryl esters and phospholipids) and endogenous lipids from bile (phospholipids and cholesterol) and from shed intestinal epithelial cells (enterocytes). Here, we comprehensively review the digestion, uptake and intracellular re-synthesis of intestinal lipids as well as their packaging into pre-chylomicrons in the endoplasmic reticulum, their modification in the Golgi apparatus and the exocytosis of the chylomicrons into the lamina propria and subsequently to lymph. We also discuss other fates of intestinal lipids, including intestinal HDL and VLDL secretion, cytosolic lipid droplets and fatty acid oxidation. In addition, we highlight the applicability of these findings to human disease and the development of therapeutics targeting lipid metabolism. Finally, we explore the emerging role of the gut microbiota in modulating intestinal lipid metabolism and outline key questions for future research.The small intestine is a key site for the absorption of nutrients, including lipids. In this Review, the physiology and biochemistry of intestinal fat absorption during health and disease is discussed, including insights into enterocyte biology and clinical disorders of intestinal fat absorption.

Tissue resident memory CD8 + T (T RM ) cells offer rapid and long-term protection at sites of reinfection 1 . Tumour-infiltrating lymphocytes with characteristics of T RM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses 2 , 3 . Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting T RM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8 + T cell populations. We found that memory CD8 +  T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate–cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where T RM cells interface with dietary cholesterol and maintain a heightened state of activation 4 , and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of T RM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8 + T cell formation in the context of acute infections and enhance antitumour immunity. A study describes the metabolic adaptations supporting differentiation, survival and function of tissue-resident memory CD8 + T cells and how to leverage them to enhance immunity against pathogens and tumours.

Key studies published in 2020 demonstrate that an impaired intestinal barrier precedes clinical diagnosis of inflammatory bowel disease (IBD) by years. Furthermore, studies identify novel regulators of the intestinal barrier, including intestinal macrophages and diurnal variations of diet–microbiome interactions, which could be future therapeutic strategies for IBD.Key advancesIntestinal barrier dysfunction precedes and predicts the development of Crohn’s disease7,8.Macrophages in the distal colon in mice sense water and fungal metabolite absorption by intestinal enterocytes and regulate the intestinal barrier of the colon9.The small intestinal barrier in mice is regulated by diurnal variations in the diet–microbiome–enterocyte MHC-II–IL-10 axis in intraepithelial lymphocytes10.

Distinct populations of lymphocytes act sequentially during development to direct maturation of the mammalian gut microbiota. How innate and adaptive immunity shapes the microbiota Mammalian intestines are colonized by trillions of bacteria that help to maintain immunologic and metabolic health under homeostatic conditions, but that can induce effector T cell responses and inflammation under adverse conditions. Ronald Germain and colleagues use histocytochemistry to investigate the role of two major lymphoid-cell populations in the maintenance of immune homeostasis in the small intestine. They show that effector T helper 17 cells regulate the number of bacteria present in the small intestine, whereas regulatory T cells suppress the induction of the pro-inflammatory cytokine IL-23 by CCR2 + monocytes in response to stimuli from commensal bacteria. This process leads to downregulation of IL-22 production by group 3 innate lymphoid cells (ILC3s) and subsequent activation of intestinal epithelial cells. In the absence of this adaptive immune effect, ILC3s remain constitutively activated after weaning, and the persistent production of IL-22 results in inflammation and abnormal lipid metabolism. The mammalian gut is colonized by numerous microorganisms collectively termed the microbiota, which have a mutually beneficial relationship with their host 1 , 2 , 3 . Normally, the gut microbiota matures during ontogeny to a state of balanced commensalism marked by the absence of adverse inflammation 4 , 5 . Subsets of innate lymphoid cells (ILCs) and conventional T cells are considered to have redundant functions in containment and clearance of microbial pathogens 6 , 7 , but how these two major lymphoid-cell populations each contribute to shaping the mature commensal microbiome and help to maintain tissue homeostasis has not been determined. Here we identify, using advanced multiplex quantitative imaging methods, an extensive and persistent phosphorylated-STAT3 signature in group 3 ILCs and intestinal epithelial cells that is induced by interleukin (IL)-23 and IL-22 in mice that lack CD4 + T cells. By contrast, in immune-competent mice, phosphorylated-STAT3 activation is induced only transiently by microbial colonization at weaning. This early signature is extinguished as CD4 + T cell immunity develops in response to the expanding commensal burden. Physiologically, the persistent IL-22 production from group 3 ILCs that occurs in the absence of adaptive CD4 + T-cell activity results in impaired host lipid metabolism by decreasing lipid transporter expression in the small bowel. These findings provide new insights into how innate and adaptive lymphocytes operate sequentially and in distinct ways during normal development to establish steady-state commensalism and tissue metabolic homeostasis.

Satiety and other core physiological functions are modulated by sensory signals arising from the surface of the gut. Luminal nutrients and bacteria stimulate epithelial biosensors called enteroendocrine cells. Despite being electrically excitable, enteroendocrine cells are generally thought to communicate indirectly with nerves through hormone secretion and not through direct cell-nerve contact. However, we recently uncovered in intestinal enteroendocrine cells a cytoplasmic process that we named neuropod. Here, we determined that neuropods provide a direct connection between enteroendocrine cells and neurons innervating the small intestine and colon. Using cell-specific transgenic mice to study neural circuits, we found that enteroendocrine cells have the necessary elements for neurotransmission, including expression of genes that encode pre-, post-, and transsynaptic proteins. This neuroepithelial circuit was reconstituted in vitro by coculturing single enteroendocrine cells with sensory neurons. We used a monosynaptic rabies virus to define the circuit's functional connectivity in vivo and determined that delivery of this neurotropic virus into the colon lumen resulted in the infection of mucosal nerves through enteroendocrine cells. This neuroepithelial circuit can serve as both a sensory conduit for food and gut microbes to interact with the nervous system and a portal for viruses to enter the enteric and central nervous systems.