Innate immune cells link dietary cues to normal and abnormal metabolic regulation

Abstract

A slew of common metabolic disorders, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease and steatohepatitis, are exponentially increasing in our sedentary and overfed society. While macronutrients directly impact metabolism and bioenergetics, new evidence implicates immune cells as critical sensors of nutritional cues and important regulators of metabolic homeostasis. A deeper interrogation of the intricate and multipartite interactions between dietary components, immune cells and metabolically active tissues is needed for a better understanding of metabolic regulation and development of new treatments for common metabolic diseases. Responding to macronutrients and micronutrients, immune cells play pivotal roles in interorgan communication between the microbiota, small intestine, metabolically active cells including hepatocytes and adipocytes, and the brain, which controls feeding behavior and energy expenditure. This Review focuses on the response of myeloid cells and innate lymphocytes to dietary cues, their cross-regulatory interactions and roles in normal and aberrant metabolic control.

Fig. 1 |. The gut–liver axis in metabolic regulation.

The gut–liver axis refers to the bidirectional communication network between the gastrointestinal tract and the liver, which is crucial for maintenance of metabolic health. The primary channel for gut–liver communication is the portal vein, which carries nutrients, toxins and PAMP-containing blood from the small intestine to the liver. The liver processes and responds to these substances, detoxifies harmful compounds and regulates macronutrient metabolism. The liver also produces and releases metabolites and hormones that affect gut function, motility and appetite. For example, bile acids from the liver are critical for fat digestion and absorption. The gut microbiota is also a part of the gut–liver axis, producing metabolites that affect liver function and inflammation, such as LPS and secondary bile acids. Disruptions of the gut–liver axis have been linked to inflammatory bowel disease, liver cirrhosis and the metabolic syndrome. Consumption of a calorie-dense, fast-food diet increases intestinal permeability and liver inflammation through dysbiosis and disruption of tight junctions between IECs that increase PAMP translocation to the liver, which stimulates liver macrophages and cytokine production. Other microbial and dietary factors, delivered via the portal vein, induce tolerogenic Kupffer cell (KC) death and replacement by pro-inflammatory and pro-fibrogenic monocyte-derived macrophages (MoMs), which are also involved in hepatocyte efferocytosis, lipid handling and tissue remodeling. LSEC, liver sinusoidal endothelial cell; MMPs, matrix metalloproteinases; TMA, trimethylamine; TMAO, trimethylamine-N-oxide.

Fig. 2 |. ILCs orchestrate gastrointestinal and liver physiology in response to dietary components.

ILCs respond to dietary components and metabolites. Vitamins A (retinoic acid) and D, AHR agonists (from Brassicaceae family vegetables and the microbiota), SCFAs (from bacterial fermentation of dietary fiber) and iron are required for ILC3 maintenance. By contrast, vitamin A and AHR agonists negatively affect ILC2. Energy-dense diets (HFD, ketogenic diet (KD), western diet and high-carbohydrate diet) suppress IL-22 production by ILC3. Reciprocally, IL-22 acting on IECs maintains gut homeostasis and by inducing antimicrobial peptides, such as Reg3β/γ and S100A, and mucus secretion by goblet cells. These outputs reverse dysbiosis and reduce LPS translocation across the gut barrier. IL-22 also induces peptide YY (PYY) secretion from enteroendocrine cells (EECs) to control appetite and reduces expression of fatty acid transporters and sugar metabolizing enzymes to inhibit macronutrient absorption. Additionally, a HFD induces ILC1, which may in turn inhibit ILC3.