Biology subjects

Myhill, L. J.

Publications and source records attributed to Myhill, L. J..

6 recordsLinked to original sources

bioRxiv2025

Transglutaminase 2 predicts parasitic worm-mediated protection against hepatic steatosis in obese mice

Parasitic worm infection can mitigate high fat diet-induced chronic inflammation in obese mice by reducing hepatic fat accumulation and improving insulin sensitivity. However, the molecular alterations during infection-mediated regulation of hepatic steatotic events in obesity remain poorly understood. Here, we integrated proteomic and metabolomic analyses of infected obese mice, a functional deworming and interleukin-4c (IL-4c) treated animal model, and an obese patient cohort before and after bariatric surgery to uncover molecular targets/pathways indicative of the regulation of hepatic steatosis by gut Heligmosomoides polygyrus bakeri (H. p. bakeri) helminth infection. Proteomic analysis identified alterations in several molecules related to metabolism and showed elevated levels of transglutaminase 2 (TGM2) proportionate with an infection-regulated lipid load in diet-induced obese (DIO) mice. The role of TGM2 as a reliable predictor of hepatic steatosis was validated using deworming experiments which revealed a decrease in the liver tissue levels of Tgm2 following removal of H. p. bakeri. Further validation showing increase in Tgm2 levels in IL-4c treated mice confirmed its relevance as a general response indicator of type 2 immune response induced by helminth infection. Assessment of circulating TGM2 levels in matched obese patients before and after bariatric surgery revealed no change, indicating that differential expression of TGM2 is a unique functional response to regulation of hepatic steatosis by H. p. bakeri infection. Together, our data show that TGM2 is a unique predictive marker of improvement in hepatic lipid profile and provides additional evidence that parasitic worm infection protects against hepatic steatosis in DIO mice. These findings pave the way for novel therapeutic opportunities to resolve hepatic steatosis and prevent its progression to severe forms of metabolic dysfunction-associated steatotic liver disease, based on TGM2 coupled with mimetics of H. p. bakeri-derived products. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/689654v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1cae718org.highwire.dtl.DTLVardef@9ec0aorg.highwire.dtl.DTLVardef@1679b1corg.highwire.dtl.DTLVardef@f86bc9_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2025

Dietary fibre promotes chronic whipworm infection through direct and time-dependent modulation of innate immunity

Dietary fibre regulates the microbiome and gut health but increases murine whipworm (Trichuris muris) infection through unclear mechanisms. We show that mice fed inulin-supplemented diets exhibit dysregulated innate antimicrobial defences and altered tryptophan metabolism during T. muris infection. Inhibiting tryptophan catabolism or neutralizing IL-27 and IL-18 in inulin-fed mice restored infection resistance. Notably, inulin led to chronic infection even in microbiota-depleted mice. Removing inulin within a critical immune development window rapidly restored anti-helminth immunity, indicating direct, time-dependent modulation of mucosal immune responses. Our findings reveal a previously unrecognized, direct influence of dietary fibre on mucosal immunity to parasitic infection, independent of the microbiome, highlighting the complex interplay between diet timing and host defence.

microbiology↗

bioRxiv2024

Gut microbial-mediated polyphenol metabolism is restrained by parasitic whipworm infection and associated with altered immune function in mice

Polyphenols are phytochemicals commonly found in plant-based diets which have demonstrated immunomodulatory and anti-inflammatory properties. However, the interplay between polyphenols and pathogens at mucosal barrier surfaces has not yet been elucidated in detail. Here, we show that proanthocyanidin (PAC) polyphenols interact with gut parasites to influence immune function and gut microbial-derived metabolites in mice. PAC intake inhibited mastocytosis during infection with the small intestinal roundworm Heligmosomoides polygyrus, and induced a type-1, interferon-driven mucosal immune response during infection with the large intestinal whipworm Trichuris muris. PAC also induced alterations in mesenteric lymph node T-cell populations that were dependent on infection model, with a Th2/Treg bias during H. polygyrus infection, and a Th1 bias during T. muris infection. In the absence of infection, PAC intake promoted the expansion of Turicibacter sp. within the gut microbiota, increased faecal short chain fatty acids, and enriched phenolic metabolites such as phenyl-{gamma}-valerolactones in the caecum. However, these putatively beneficial effects were reduced in PAC-fed mice infected with T. muris, suggesting concomitant parasite infection can attenuate gut microbial-mediated PAC catabolism. Collectively, our results suggest an inter-relationship between a phytonutrient and infection, whereby PAC may augment parasite-induced inflammation (most prominently with the caecum dwelling T. muris), and infection may abrogate the beneficial effects of health-promoting phytochemicals.

microbiology↗

bioRxiv2022

Dietary non-starch polysaccharides impair immunity to enteric nematode infection

The influence of diet on immune function and resistance to enteric infection and disease is becoming ever more established. Highly processed, refined diets can lead to inflammation and gut microbiome dysbiosis, whilst health-promoting dietary components such as phytonutrients and fermentable fibres are thought to promote a healthy microbiome and balanced mucosal immunity. Chicory (Cichorium intybus) is a leafy green vegetable rich in fibres and bioactive compounds that may promote gut health. Unexpectedly, we here show that incorporation of chicory into semisynthetic AIN93G diets renders mice susceptible to infection with enteric helminths. Mice fed a high level of chicory leaves (10% dry matter) had a more diverse gut microbiota, but a diminished type-2 immune response to infection with the intestinal roundworm Heligmosomoides polygyrus. Furthermore, the chicory-supplemented diet significantly increased burdens of the caecum-dwelling whipworm Trichuris muris, concomitant with a highly skewed type-1 immune environment in caecal tissue. The chicory-supplemented diet was rich in non-starch polysaccharides, particularly uronic acids (the monomeric constituents of pectin). In accordance, mice fed pectin-supplemented AIN93G diets had higher T. muris burdens and reduced IgE production and expression of genes involved in type-2 immunity. Importantly, treatment of pectin-fed mice with exogenous IL-25 restored type-2 responses and was sufficient to allow T. muris expulsion. Collectively, our data suggest that increasing levels of fermentable, non-starch polysaccharides in refined diets compromises immunity to helminth infection in mice. This diet-infection interaction may inform new strategies for manipulating the gut environment to promote resistance to enteric parasites.

immunology↗

bioRxiv2021

Garlic-derived organosulfur compounds regulate metabolic and immune pathways in macrophages and attenuate intestinal inflammation in mice

ScopeGarlic is a source of bioactive phytonutrients that may have anti-inflammatory or immunomodulatory properties. The mechanism(s) underlying the bioactivity of these compounds and their ability to regulate responses to enteric infections remains unclear. Methods and ResultsWe investigated if a garlic-derived preparation (PTSO-PTS) containing two organosulfur metabolites, propyl-propane thiosulfonate (PTSO) and propyl-propane thiosulfinate (PTS), regulated inflammatory responses in murine macrophages and intestinal epithelial cells (IEC) in vitro, as well as in a model of enteric parasite-induced inflammation. PTSO-PTS decreased lipopolysaccharide-induced secretion of TNF, IL-6 and IL-27 in macrophages. RNA-sequencing demonstrated that PTSO-PTS strongly suppressed pathways related to immune and inflammatory signaling. PTSO-PTS induced the expression of a number of genes involved in antioxidant responses in IEC during exposure to antigens from the parasite Trichuris muris. In vivo, PTSO-PTS did not affect T. muris establishment or intestinal T-cell responses but significantly altered caecal transcriptomic responses. Notably, a reduction in T. muris-induced expression of Tnf, Saa2 and Nos2 was observed. ConclusionGarlic-derived organosulfur compounds exert anti-inflammatory effects in macrophages and IEC, and regulate gene expression during intestinal infection. These compounds and related organic molecules may thus hold potential as functional food components to improve gut health in humans and animals.

immunology↗

bioRxiv2021

Dietary Proanthocyanidins Exert Localized Immunomodulatory Effects in Porcine Pulmonary and Gastrointestinal Tissues during Ascaris suum-induced Type 2 inflammation

Bioactive dietary components may considerably influence intestinal health and resistance to enteric disease. Proanthocyanidins (PAC) are dietary polyphenols with putative health-promoting activity that have been increasingly studied for their anti-inflammatory and immunomodulatory effects. However, whether dietary PAC can regulate type-2 immune function and inflammation at mucosal surfaces remains unclear. Here, we investigated whether diets supplemented with purified PAC modulated pulmonary and intestinal mucosal immune responses during infection with the helminth parasite Ascaris suum in pigs. A. suum infection induced a type 2-biased immune response in lung and intestinal tissues, characterized by pulmonary granulocytosis, increased Th2/Th1 T cell ratios in tracheal-bronchial lymph nodes, intestinal eosinophilia, and modulation of genes involved in mucosal barrier function and immunity. We observed that PAC had only minor effects on pulmonary immune responses, regardless of concurrent A. suum infection. However, RNA-sequencing of intestinal tissues revealed that dietary PAC significantly enhanced transcriptional responses related to immune function, antioxidant responses, and cellular stress activity, both in uninfected and A. suum-infected animals. A. suum infection and dietary PAC both induced distinct changes in gut microbiota composition, primarily in the jejunum and colon, respectively. Notably, PAC substantially increased Limosilactobacillus reuteri abundance in the colon of both naive and A. suum-infected animals. Thus, dietary PAC may have distinct beneficial effects on intestinal health during infection with mucosal pathogens, whilst having limited activity to modulate naturally-induced type-2 pulmonary inflammation. Our results shed further light on the mechanisms underlying the health-promoting properties of PAC-rich foods, and may aid in the design of novel dietary supplements to regulate mucosal inflammatory responses in the gastrointestinal tract.

immunology↗