Commensal bacteria weaken the intestinal barrier by suppressing epithelial neuropilin-1 and Hedgehog signaling

Pontarollo, Giulia; Kollar, Bettina; Mann, Amrit; Khuu, My Phung; Kiouptsi, Klytaimnistra; Bayer, Franziska; Brandão, Inês; Zinina, Valeriya V.; Hahlbrock, Jennifer; Malinarich, Frano; Mimmler, Maximilian; Bhushan, Sudhanshu; Marini, Fédérico; Ruf, Wolfram; Belheouane, Meriem; Baines, John F.; Reba, Scott M.; Raker, Verena; Deppermann, Carsten; Welsch, Christoph; Bosmann, Markus; Soshnikova, Natalia; Chassaing, Benoît; Bergentall, Mattias; Sommer, Felix; Bäckhed, Fredrik; Reinhardt, Carsten

doi:10.1038/s42255-023-00828-5

Cited by 15 publications

(12 citation statements)

References 61 publications

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“…NRP1 deficiency in visceral smooth muscle cells could negatively impact GI contractility and motility 326 . Also, the viral hijack-mediated suppression of epithelial NRP1 could weaken the gut barrier function 327 . The NRP-1-mediated SARS‐CoV‐2 entry into bone marrow‐derived macrophages (BMM) could impede osteoclast differentiation and affect calcium/phosphorus metabolism in COVID‐19 patients 328 .…”

Section: Pasc: Viral-hijacked Host Cellular Factors and Consequencesmentioning

confidence: 99%

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

Naidu,

Wang,

Rao

et al. 2024

npj Sci Food

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SARS‐CoV‐2, the etiological agent of COVID-19, is devoid of any metabolic capacity; therefore, it is critical for the viral pathogen to hijack host cellular metabolic machinery for its replication and propagation. This single-stranded RNA virus with a 29.9 kb genome encodes 14 open reading frames (ORFs) and initiates a plethora of virus–host protein–protein interactions in the human body. These extensive viral protein interactions with host-specific cellular targets could trigger severe human metabolic reprogramming/dysregulation (HMRD), a rewiring of sugar-, amino acid-, lipid-, and nucleotide-metabolism(s), as well as altered or impaired bioenergetics, immune dysfunction, and redox imbalance in the body. In the infectious process, the viral pathogen hijacks two major human receptors, angiotensin-converting enzyme (ACE)-2 and/or neuropilin (NRP)-1, for initial adhesion to cell surface; then utilizes two major host proteases, TMPRSS2 and/or furin, to gain cellular entry; and finally employs an endosomal enzyme, cathepsin L (CTSL) for fusogenic release of its viral genome. The virus-induced HMRD results in 5 possible infectious outcomes: asymptomatic, mild, moderate, severe to fatal episodes; while the symptomatic acute COVID-19 condition could manifest into 3 clinical phases: (i) hypoxia and hypoxemia (Warburg effect), (ii) hyperferritinemia (‘cytokine storm’), and (iii) thrombocytosis (coagulopathy). The mean incubation period for COVID-19 onset was estimated to be 5.1 days, and most cases develop symptoms after 14 days. The mean viral clearance times were 24, 30, and 39 days for acute, severe, and ICU-admitted COVID-19 patients, respectively. However, about 25–70% of virus-free COVID-19 survivors continue to sustain virus-induced HMRD and exhibit a wide range of symptoms that are persistent, exacerbated, or new ‘onset’ clinical incidents, collectively termed as post-acute sequelae of COVID-19 (PASC) or long COVID. PASC patients experience several debilitating clinical condition(s) with >200 different and overlapping symptoms that may last for weeks to months. Chronic PASC is a cumulative outcome of at least 10 different HMRD-related pathophysiological mechanisms involving both virus-derived virulence factors and a multitude of innate host responses. Based on HMRD and virus-free clinical impairments of different human organs/systems, PASC patients can be categorized into 4 different clusters or sub-phenotypes: sub-phenotype-1 (33.8%) with cardiac and renal manifestations; sub-phenotype-2 (32.8%) with respiratory, sleep and anxiety disorders; sub-phenotype-3 (23.4%) with skeleto-muscular and nervous disorders; and sub-phenotype-4 (10.1%) with digestive and pulmonary dysfunctions. This narrative review elucidates the effects of viral hijack on host cellular machinery during SARS-CoV-2 infection, ensuing detrimental effect(s) of virus-induced HMRD on human metabolism, consequential symptomatic clinical implications, and damage to multiple organ systems; as well as chronic pathophysiological sequelae in virus-free PASC patients. We have also provided a few evidence-based, human randomized controlled trial (RCT)-tested, precision nutrients to reset HMRD for health recovery of PASC patients.

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Section: Pasc: Viral-hijacked Host Cellular Factors and Consequencesmentioning

confidence: 99%

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

Naidu,

Wang,

Rao

et al. 2024

npj Sci Food

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“…Growing evidence demonstrated that gut microbiota not only provide essential capacities for the metabolism of nutrients, but also participate in regulating the integrity and function of the intestinal barrier in a homeostatic balance ( 68 , 69 ). Therefore, gut microbiota homeostasis is vital for intestinal barrier integrity and the underlying mechanism are largely unknown ( 70–72 ). Gut microbiota provide essential capacities for the fermentation of non-digestible substrates like dietary fibers and endogenous intestinal endogenous intestinal mucus ( 73 ).…”

Section: Effects Of Astragalus Polysaccharide On Intestinal Barriermentioning

confidence: 99%

Astragalus polysaccharide: implication for intestinal barrier, anti-inflammation, and animal production

Liang,

Tao,

Wang

et al. 2024

Front. Nutr.

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Intestine is responsible for nutrients absorption and plays a key role in defending against various dietary allergens, antigens, toxins, and pathogens. Accumulating evidence reported a critical role of intestine in maintaining animal and human health. Since the use of antibiotics as growth promoters in animal feed has been restricted in many countries, alternatives to antibiotics have been globally investigated, and polysaccharides are considered as environmentally friendly and promising alternatives to improve intestinal health, which has become a research hotspot due to its antibiotic substitution effect. Astragalus polysaccharide (APS), a biological macromolecule, is extracted from astragalus and has been reported to exhibit complex biological activities involved in intestinal barrier integrity maintenance, intestinal microbiota regulation, short-chain fatty acids (SCFAs) production, and immune response regulation, which are critical for intestine health. The biological activity of APS is related to its chemical structure. In this review, we outlined the source and structure of APS, highlighted recent findings on the regulation of APS on physical barrier, biochemical barrier, immunological barrier, and immune response as well as the latest progress of APS as an antibiotic substitute in animal production. We hope this review could provide scientific basis and new insights for the application of APS in nutrition, clinical medicine and health by understanding particular effects of APS on intestine health, anti-inflammation, and animal production.

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“…Also, GM suppresses tonic Hedgehog (Hh) signaling in the small intestine, thus regulating intestinal barrier function. Hh pathway activity is mainly suppressed through Toll-like receptor (TLR2/TLR6) signaling in the intestinal epithelium, identifying intestinal epithelial neuropilin-1 (NRP1) as a microbiota-dependent Hh regulator that contributes to the stabilization of the intestinal epithelium barrier [40] .…”

Section: Purpose Of Using Germ-free Animal Modelsmentioning

confidence: 99%

What we need to know about the germ-free animal models

Aghighi,

Salami

2024

AIMSMICRO

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<abstract> <p>The gut microbiota (GM), as a forgotten organ, refers to the microbial community that resides in the gastrointestinal tract and plays a critical role in a variety of physiological activities in different body organs. The GM affects its targets through neurological, metabolic, immune, and endocrine pathways. The GM is a dynamic system for which exogenous and endogenous factors have negative or positive effects on its density and composition. Since the mid-twentieth century, laboratory animals are known as the major tools for preclinical research; however, each model has its own limitations. So far, two main models have been used to explore the effects of the GM under normal and abnormal conditions: the isolated germ-free and antibiotic-treated models. Both methods have strengths and weaknesses. In many fields of host-microbe interactions, research on these animal models are known as appropriate experimental subjects that enable investigators to directly assess the role of the microbiota on all features of physiology. These animal models present biological model systems to either study outcomes of the absence of microbes, or to verify the effects of colonization with specific and known microbial species. This paper reviews these current approaches and gives advantages and disadvantages of both models.</p> </abstract>

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Commensal bacteria weaken the intestinal barrier by suppressing epithelial neuropilin-1 and Hedgehog signaling

Cited by 15 publications

References 61 publications

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

Astragalus polysaccharide: implication for intestinal barrier, anti-inflammation, and animal production

What we need to know about the germ-free animal models

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