Intestinal glucose absorption is predominantly mediated by sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2). Expression of these glucose transporters is influenced by diet, inflammation and insulin sensitivity, and is increased in patients with type 2 diabetes (1). Overexpression may increase intestinal glucose absorption and exacerbate postprandial hyperglycaemia. Chronic low-grade inflammation, common in metabolic diseases, upregulates these transporters (2) and the SARS-CoV-2 receptors, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2) (3), potentially worsening glucose metabolism and increasing susceptibility to COVID-19. We hypothesised that dietary phytochemicals, known to regulate glucose metabolism and inflammation, may counteract high glucose- and inflammation-induced changes in transporter and viral receptor expression. We initially screened various phytochemicals, pharmaceuticals and plant extracts for their effects on the expression of ACE2 or TMPRSS2 in differentiated Caco-2/TC7 human intestinal epithelial cells. Genistein, apigenin, artemisinin and sulforaphane were the most promising compounds for downregulating TMPRSS2, and thus were used in subsequent experiments. The cells were stimulated with glucose or pro-inflammatory cytokines interleukin-1 beta (IL-1β) and tumour necrosis factor-alpha (TNF-α), with and without the phytochemicals. ACE2, TMPRSS2, SGLT1 and GLUT2 mRNA was measured by droplet digital PCR, while interleukin-8 (IL-8) and ACE2 proteins were assessed using ELISA, with significant changes detected by ANOVA. To assess whether effects observed in Caco-2/TC7 cells were relevant to human tissues, we examined gene expression in human gut tissues from patients with and without inflammatory bowel disease using transcriptomic datasets. In Caco-2/TC7 cells, high glucose (25 mM) increased expression of SGLT1 (p < 0.05) and TMPRSS2 (p < 0.01), while exposure to pro-inflammatory cytokines upregulated ACE2 (p < 0.001), TMPRSS2 (p < 0.001) and SGLT1 (p < 0.001). Although none of the phytochemicals decreased inflammation-induced IL-8 secretion, genistein normalised inflammation-induced increases in SGLT1 (p < 0.01) and TMPRSS2 (p < 0.001). The regulation of SGLT1 gene expression followed the same pattern as TMPRSS2, implying a common mechanism. In the human transcriptome data, we observed a correlation between TMPRSS2 and SGLT1 (r > 0.5, p < 0.05), which was enhanced by inflammation. High glucose and inflammation upregulate ACE2, SGLT1 and TMPRSS2 in intestinal cells, potentially increasing the risk of type 2 diabetes and SARS-CoV-2 infection in humans via a gut-mediated mechanism. The association between TMPRSS2 and SGLT1 gene expression, which is particularly evident in inflammatory conditions, suggests a common regulatory pathway that warrants further investigation. These findings suggest a possible relationship between elevated SGLT1 and new-onset diabetes in COVID-19 patients and may help to explain why individuals with metabolic diseases are more likely to develop severe COVID-19. Furthermore, our results provide mechanistic evidence for nutrition-based interventions, such as genistein, to potentially alleviate postprandial glycaemic response and COVID-19 pathophysiology.