Gut-Specific Delivery of T-Helper 17 Cells Reduces Obesity and Insulin Resistance in Mice

Hong, Chun Pyo; Park, Areum; Yang, Bo-Gie; Yun, Chang Ho; Kwak, Min Jung; Lee, Gil Woo; Kim, Junghwan; Jang, Min Seong; Lee, Eun Jung; Jeun, Eun Ji; You, Gihoon; Kim, Kwang Soon; Choi, Youngwoo; Park, Ji Hwan; Hwang, Daehee; Im, Sin Hyeog; Kim, Jihyun F.; Kim, Yoon Keun; Seoh, Ju Young; Surh, Charles D.; Kim, You-Me; Jang, Myoung Ho

doi:10.1053/j.gastro.2017.02.016

Cited by 98 publications

(97 citation statements)

References 51 publications

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“…In addition, Th17 cells are fundamental to control the replication of commensal bacteria inside the intestinal mucosa and avoid translocation of bacteria to distal tissues. A study reported that intestinal tissues from obese mice exhibit significant reductions in the proportion of Th17 cells relative to non‐obese mice . Likewise, our data show that IL‐23 deficiency in HFD‐fed mice significantly reduces Th17 cells in the MLNs and decreases IL‐17 expression in the ileum when compared with WT mice on HFD.…”

Section: Discussionsupporting

confidence: 74%

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Interleukin‐23 promotes intestinal T helper type17 immunity and ameliorates obesity‐associated metabolic syndrome in a murine high‐fat diet model

et al. 2018

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We addressed the role of interleukin-23 (IL-23) in driving the intestinal T helper type 17 (Th17) response during obesity and metabolic syndrome progression induced by a high-fat diet (HFD). Diet-induced obese and lean mice received HFD or control diet (CTD), respectively, for 20 weeks. The nutritional, metabolic and immune parameters were examined at weeks 9 and 20. Gene and protein IL-23p19 and IL-23 receptor expression was increased in the ileum of obese wild-type mice (WT) fed the HFD for 9 weeks. Mice lacking IL-23 and fed the HFD exhibited greater weight gain, higher fat accumulation, adipocyte hypertrophy and hepatic steatosis. Notably, these mice had more glucose intolerance, insulin resistance and associated metabolic alterations, such as hyperinsulinaemia and hyperlipidaemia. IL-23 deficiency also significantly reduced protein levels of IL-17, CCL20 and neutrophil elastase in the ileum and reduced Th17 cell expansion in the mesenteric lymph nodes of the HFD mice. Of importance, IL-23-deficient mice exhibited increased gut permeability and blood bacterial translocation compared with WT mice fed HFD. Finally, metagenomics analysis of gut microbiota revealed a dramatic outgrowth of Bacteroidetes over Firmicutes phylum with the prevalence of Bacteroides genera in the faeces of IL-23-deficient mice after HFD. In summary, IL-23 appears to maintain the Th17 response and neutrophil migration into the intestinal mucosa, minimizing the gut dysbiosis and protecting against obesity and metabolic disease development in mice.

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Section: Discussionsupporting

confidence: 74%

“…More recently, it was reported that the prevalence of Th17 lymphocytes in the adipose tissue is associated with the progression of obesity in humans . However, another study found a decrease in the proportion of retinoic acid‐related orphan receptor γt‐expressing CD4 + T cells after 30 days of a high‐fat diet (HFD) …”

Section: Introductionmentioning

confidence: 99%

Interleukin‐23 promotes intestinal T helper type17 immunity and ameliorates obesity‐associated metabolic syndrome in a murine high‐fat diet model

et al. 2018

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“…To this end, emerging evidence indicates that the non-regulatory counterparts to p T regs , i.e. T H 17 cells, are purged from SI-LP in DIO mice 14 and that reintroducing ex vivo differentiated gut tropic T H 17 cells curtail obesity development, hence improving insulin sensitivity 15 .…”

Section: Discussionmentioning

confidence: 99%

“…The impact of this predominantly colonic cell subset on host metabolism also remains unknown. Still, mounting evidence points towards the importance of intestinal IL-17 for controlling metabolic homeostasis 14, 15 . IL-17 + p T regs may therefore be leveraged as a ‘dual hit’ strategy to curb immunometabolic dysfunction and gastrointestinal disturbances based on the immune-regulatory capacity of p T regs concomitant with the metabolic benefits of gut-delivered IL-17.…”

Section: Introductionmentioning

confidence: 99%

Lysates ofMethylococcus capsulatusBath induce a lean-like microbiota, intestinal FoxP3⁺RORγt⁺IL-17⁺Tregs and improve metabolism

Jensen

Holm

Larsen

et al. 2019

Preprint

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58Interactions between host and gut microbial communities may be modulated by diets and play 59 pivotal roles in securing immunological homeostasis and health. Here we show that intake of feed 60 based on whole-cell lysates of the non-commensal bacterium Methylococcus capsulatus Bath 61 (McB) as protein source reversed high fat high sucrose-induced changes in the gut microbiota to a 62 state resembling that of lean, low fat diet-fed mice, both under mild thermal stress (T22°C) and at 63 thermoneutrality (T30°C). McB feeding selectively upregulated triple positive (Foxp3 + RORγt + IL-64 17 + ) regulatory T cells in the small intestine and colon, and enhanced mucus production and 65 glycosylation status suggesting improved gut health. Mice receiving McB lysates further exhibited 66 improved glucose regulation, reduced body and liver fat along with diminished hepatic immune 67 infiltration. Collectively, these data points towards profound whole-body effects elicited by the 68McB lysate suggesting that it may serve as a potent modulator of immunometabolic homeostasis. 69 70 Introduction: 71 72Gut microbes shape intestinal immunity 1 and increase the bioavailability of otherwise indigestible 73 nutrients 2 . A well-balanced community structure is therefore essential for immunometabolic 74 homeostasis, whereas aberrant gut microbiota compositions associate with numerous diseases, both 75 within and outside the gastrointestinal tract 3 . 76While therapeutic implications of rebalancing a mistuned gut microbiota appear promising, 77 inconsistent response rates in relation to both probiotics and fecal transfer studies, with occasional 78 adverse events, emphasize the complexity of such approaches. One example relates to the otherwise 79 promising probiotic candidate Akkermansia muciniphila 4 , where negative effects have been seen in 80 immunocompromised recipients 5,6 . Similarly, Prevotella copri aids in metabolizing fibers in healthy 81 individuals 7 and protects against bacterial invasion in high fiber, chow-fed mice 8 , yet associates 82 with insulin resistance in prediabetic obese individuals and precipitates glucoregulatory 83 impairments in diet-induced obese (DIO) mice 9 . 84 85 An alternative to administering viable microbes is to utilize whole cell lysates, or selected cell 86 components, of non-living bacteria. Apart from alleviating global energy demands, if used as a 87 nutrient source, such components may also potently affect host physiology as recently reported for 88A. muciniphila 10 and Bifidobacterium bifidum 11 . In the latter example, cell surface polysaccharides 89 of B. bifidum were used to induce peripheral immune-tolerance via generation of regulatory T cells 90 (Tregs). The authors reported a pronounced increase in Foxp3 + RORγt + Tregs (pTregs), specifically in 91 lamina propria (LP) of the large intestine (LI) 11 . This cell type is believed to be induced by 92 commensal microbes and has emerged as a potent Treg subset, exhibiting increased lineage stability 93 and enhanced immunosuppressive cap...

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“…For instance, Th17 cells maintain metabolic homeostasis in the gut. Hong et al reported that the number of Th17 cells was decreased in the gut of mice on a high-fat diet (14). The transfer of Th17 cells to obese mice restored the metabolic disturbance, indicating that Th17 cells play a beneficial role in the host.…”

Section: Editorial On Nutritionmentioning

confidence: 99%

The day will come to treat HCC in a drugstore?

Miura¹

2017

Hepatobiliary Surg. Nutr.

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Gut-Specific Delivery of T-Helper 17 Cells Reduces Obesity and Insulin Resistance in Mice

Cited by 98 publications

References 51 publications

Interleukin‐23 promotes intestinal T helper type17 immunity and ameliorates obesity‐associated metabolic syndrome in a murine high‐fat diet model

Interleukin‐23 promotes intestinal T helper type17 immunity and ameliorates obesity‐associated metabolic syndrome in a murine high‐fat diet model

Lysates ofMethylococcus capsulatusBath induce a lean-like microbiota, intestinal FoxP3⁺RORγt⁺IL-17⁺Tregs and improve metabolism

The day will come to treat HCC in a drugstore?

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Gut-Specific Delivery of T-Helper 17 Cells Reduces Obesity and Insulin Resistance in Mice

Cited by 98 publications

References 51 publications

Interleukin‐23 promotes intestinal T helper type17 immunity and ameliorates obesity‐associated metabolic syndrome in a murine high‐fat diet model

Interleukin‐23 promotes intestinal T helper type17 immunity and ameliorates obesity‐associated metabolic syndrome in a murine high‐fat diet model

Lysates ofMethylococcus capsulatusBath induce a lean-like microbiota, intestinal FoxP3+RORγt+IL-17+Tregs and improve metabolism

The day will come to treat HCC in a drugstore?

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Lysates ofMethylococcus capsulatusBath induce a lean-like microbiota, intestinal FoxP3⁺RORγt⁺IL-17⁺Tregs and improve metabolism