Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism

Jensen, Benjamin Anderschou Holbech; Holm, Jacob Bak; Larsen, Ida Søgaard; Burg, Nicole von; Derer, Stefanie; Sonne, Si Brask; Pærregaard, Simone I.; Damgaard, Mads V.; Indrelid, Stine; Rivollier, Aymeric; Agrinier, Anne Laure; Sulek, Karolina; Arnoldussen, Yke Jildouw; Fjære, Even; Marette, André; Angell, Inga Leena; Rudi, Knut; Treebak, Jonas T.; Madsen, Lise; Åkesson, Caroline Piercey; Agace, William W.; Sina, Christian; Kleiveland, C; Kristiansen, Karsten; Lea, Tor

doi:10.1038/s41467-021-21408-9

Cited by 26 publications

(27 citation statements)

References 73 publications

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“…Here, Th17/Tregs ratio was reversed, yet Tregs decreased upon SR1001 treatment. We speculated that this result was caused by SR1001 administration because of the complexity of Tregs 32 . Effects of SR1001 on Tregs and the complicated interrelationship between RORγt and Tregs require more investigations.…”

Section: Discussionmentioning

confidence: 99%

RORγt inhibitor SR1001 alleviates acute pancreatitis by suppressing pancreatic IL‐17‐producing Th17 and γδ‐T cells in mice with ceruletide‐induced pancreatitis

Wang

Jing

et al. 2021

Basic Clin Pharma Tox

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The management of acute pancreatitis (AP) remains a challenge to clinicians worldwide for limited effective interventions. Retinoid orphan receptor gamma t (RORγt) is a therapeutic target for several diseases; however, it is unclear whether inhibiting RORγt can ameliorate AP. The relative expression of RORγt, IL‐17 and IL‐23 in the peripheral blood mononuclear cells of AP patients was measured by RT‐PCR. An AP mouse model was induced by ceruletide, and SR1001 was injected before ceruletide administration. RORγt+ cells, T helper 17 cells (Th17), regulatory T cells (Tregs) and γδ T cells were assessed in the pancreas and spleen by flow cytometry. Higher RORγt expression in patients indicated the potential role of RORγt in AP progression. Analyses of the IL‐17/IL‐23 axis confirmed its role. SR1001 significantly alleviated AP histologically in the mouse model. Serum levels of amylase, IL‐6, TNFalpha, IL‐17 and IL‐23 decreased upon SR1001 treatment. SR1001 selectively decreased the number of RORγt+, Th17, Tregs and γδ T cells in the pancreas but not the spleen. Collectively, these results showed that SR1001 exerted therapeutic effects on AP by suppressing IL‐17‐secreting Th17 and γδ T cells in the pancreas. Thus, SR1001 may be a promising drug for the treatment of AP in the clinic.

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Section: Discussionmentioning

confidence: 99%

RORγt inhibitor SR1001 alleviates acute pancreatitis by suppressing pancreatic IL‐17‐producing Th17 and γδ‐T cells in mice with ceruletide‐induced pancreatitis

Wang

Jing

et al. 2021

Basic Clin Pharma Tox

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“…Fresh feces were collected at baseline prior to EtOH feeding as well as at the termination of the study, and DNA was extracted using the NucleoSpin 96 soil kit (Macherey-Nagel, Düren, Germany) following the manufacturer's instructions. Baseline samples were processed as previously described (Jensen et al, 2021). Briefly, 30 ng DNA and 16S rRNA fusion primers were added for PCR followed by purification with Agencourt AMPure XP beads (Beckman Coulter, Indianapolis, IN).…”

Section: Fecal Microbiota Composition Analysis and Bioinformaticsmentioning

confidence: 99%

“…To determine the potential mechanisms underlying the beneficial effects of hBD-2 on EtOH-associated liver injury, we first analyzed the immunomodulatory effects of hBD-2, specifically focusing on well-known cytokines that play an important role in ALD pathogenesis and innate immunity. We measured the expression of liver and small intestine IL-22, a hepatoprotective cytokine which also exerts beneficial effects in the gut (Wang et al, 2014), and IL-17A, a cytokine with pleiotropic effects including gut microbial defense (Hong et al, 2017;Jensen et al, 2021). In Cohort 1, liver and intestinal IL-22 and IL-17A protein levels were unchanged following either EtOH feeding or hBD-2 administration (Figures 4A,B).…”

Section: Human Beta Defensin 2 Led To Favorable Immunomodulatory Changes In a Cohort-dependent Mannermentioning

confidence: 99%

Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice

et al. 2022

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Alcohol-associated liver disease (ALD) is a prevalent liver disorder and significant global healthcare burden with limited effective therapeutic options. The gut-liver axis is a critical factor contributing to susceptibility to liver injury due to alcohol consumption. In the current study, we tested whether human beta defensin-2 (hBD-2), a small anti-microbial peptide, attenuates experimental chronic ALD. Male C57Bl/6J mice were fed an ethanol (EtOH)-containing diet for 6 weeks with daily administration of hBD-2 (1.2 mg/kg) by oral gavage during the final week. Two independent cohorts of mice with distinct baseline gut microbiota were used. Oral hBD-2 administration attenuated liver injury in both cohorts as determined by decreased plasma ALT activity. Notably, the degree of hBD-2-mediated reduction of EtOH-associated liver steatosis, hepatocellular death, and inflammation was different between cohorts, suggesting microbiota-specific mechanisms underlying the beneficial effects of hBD-2. Indeed, we observed differential mechanisms of hBD-2 between cohorts, which included an induction of hepatic and small intestinal IL-17A and IL-22, as well as an increase in T regulatory cell abundance in the gut and mesenteric lymph nodes. Lastly, hBD-2 modulated the gut microbiota composition in EtOH-fed mice in both cohorts, with significant decreases in multiple genera including Barnesiella, Parabacteroides, Akkermansia, and Alistipes, as well as altered abundance of several bacteria within the family Ruminococcaceae. Collectively, our results demonstrated a protective effect of hBD-2 in experimental ALD associated with immunomodulation and microbiota alteration. These data suggest that while the beneficial effects of hBD-2 on liver injury are uniform, the specific mechanisms of action are associated with baseline microbiota.

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“…Although the mechanisms involved in postbiotics bioactivity have not been fully understood, studies have reported various functions of postbiotics, including anti-inflammatory, antihypertensive and antioxidant activity [ 86 , 87 , 88 ]. For example, Benjamin at al found that whole-cell lysates of the non-commensal bacterium Methylococcus capsulatus Bath could improve glucose regulation, diminish hepatic immune infiltration, and change the gut microbiome composition in diet-induced obese mice [ 89 ]. Several properties of postbiotics, including their clear chemical structures, stability, and safety dose parameters grant them the potential to become the new generation of health products [ 90 , 91 ].…”

Section: Microorganisms From Other Origins and Kingdoms Beyond Fecal mentioning

confidence: 99%

Human Gut Microbiome and Liver Diseases: From Correlation to Causation

Mao

et al. 2021

Microorganisms

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The important role of human gut microbiota in liver diseases has long been recognized as dysbiosis and the translocation of certain microbes from the gut to liver. With the development of high-throughput DNA sequencing, the complexity and integrity of the gut microbiome in the whole spectrum of liver diseases is emerging. Specific patterns of gut microbiota have been identified in liver diseases with different causes, including alcoholic, non-alcoholic, and virus induced liver diseases, or even at different stages, ranging from steatohepatitis, fibrosis, cirrhosis, to hepatocellular carcinoma. At the same time, the mechanism of how microbiota contributes to liver diseases goes beyond the traditional function of the gut–liver axis which could lead to liver injury and inflammation. With the application of proteomics, metabolomics, and modern molecular technologies, more microbial metabolites and the complicated interaction of microbiota with host immunity come into our understanding in the liver pathogenesis. Germ-free animal models serve as a workhorse to test the function of microbiota and their derivatives in liver disease models. Here, we review the current evidence on the relationship between gut microbiota and liver diseases, and the mechanisms underlying this phenotype. In addition to original liver diseases, gut microbiota might also affect liver injury in systemic disorders involving multiple organs, as in the case of COVID-19 at a severe state. A better understanding of the gut microbial contribution to liver diseases might help us better benefit from this guest–host relationship and pave the way for novel therapies.

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Lysates of Methylococcus capsulatus Bath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+ Tregs and improve metabolism

Cited by 26 publications

References 73 publications

RORγt inhibitor SR1001 alleviates acute pancreatitis by suppressing pancreatic IL‐17‐producing Th17 and γδ‐T cells in mice with ceruletide‐induced pancreatitis

RORγt inhibitor SR1001 alleviates acute pancreatitis by suppressing pancreatic IL‐17‐producing Th17 and γδ‐T cells in mice with ceruletide‐induced pancreatitis

Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice

Human Gut Microbiome and Liver Diseases: From Correlation to Causation

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