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

Abstract

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...

Type 2 diabetes influences bacterial tissue compartmentalisation in human obesity

“…4j), which suggests that environmental bacteria-and/or their fragments-that are present in food and water can accumulate in the MAT and may affect blood glucose regulation. This observation is well-aligned with a recent report that investigated the positive impact on gut immunity and host metabolism of a related environmental bacterium 29 .…”