Targeting gut microbiota and metabolism as the major probiotic mechanism - An evidence-based review

The role of probiotics in regulating intestinal flora to enhance host immunity has recently received widespread attention. Altering the human gut microbiota may increase the predisposition to several disease phenotypes such as gut inflammation and metabolic disorders. The intestinal microbiota converts dietary nutrients into metabolites that serve as biologically active molecules in modulating regulatory functions in the host. Probiotics, which are active microorganisms, play a versatile role in restoring the composition of the gut microbiota, helping to improve host immunity and prevent intestinal disease phenotypes. This comprehensive review provides firsthand information on the gut microbiota and their influence on human health, the dietary effects of diet on the gut microbiota, and how probiotics alter the composition and function of the human gut microbiota, along with their corresponding effects on host immunity in building a healthy intestine. We also discuss the implications of probiotics in some of the most important human diseases. In summary, probiotics play a significant role in regulating the gut microbiota, boosting overall immunity, increasing the abundance of beneficial bacteria, and helping ameliorate the symptoms of multiple diseases. 

Effects of Probiotics on Gut Microbiota: An Overview

The ribotoxic stress response (RSR) is a signaling pathway in which the p38- and c-Jun N-terminal kinase (JNK)–activating mitogen-activated protein kinase kinase kinase (MAP3K) ZAKα senses stalling and/or collision of ribosomes. Here, we show that reactive oxygen species (ROS)–generating agents trigger ribosomal impairment and ZAKα activation. Conversely, zebrafish larvae deficient for ZAKα are protected from ROS-induced pathology. Livers of mice fed a ROS-generating diet exhibit ZAKα-activating changes in ribosomal elongation dynamics. Highlighting a role for the RSR in metabolic regulation, ZAK-knockout mice are protected from developing high-fat high-sugar (HFHS) diet-induced blood glucose intolerance and liver steatosis. Finally, ZAK ablation slows animals from developing the hallmarks of metabolic aging. Our work highlights ROS-induced ribosomal impairment as a physiological activation signal for ZAKα that underlies metabolic adaptation in obesity and aging. Editor’s summary Under conditions of food scarcity, metabolic flexibility was historically important for humans to optimize storage and access to energy when food was not readily available. By contrast, the constant access to high-calorie foods in modern societies has become a liability, contributing to the rise in obesity and metabolic diseases. Reactive oxygen species are thought to contribute to the metabolic dysregulation associated with obesity and aging, but the underlying process was not well understood. Snieckute et al. have now identified a mechanism linking reactive oxygen species, a protein called ZAKα, and resulting changes in ribosome function, which then contribute to the observed metabolic changes across multiple model animal species. —Yevgeniya Nusinovich Reactive oxygen species cause activation of ZAKα and changes in ribosomal dynamics, resulting in metabolic dysregulation. INTRODUCTION When ribosomes stall and/or collide during mRNA translation, ribosomal surveillance mechanisms are activated. These pathways signal the presence of ribotoxic stress and coordinate the resolution of nonproductive ribosomes. The ribosome-binding and stress-sensing MAP3 kinase ZAKα is at the nexus of the ribotoxic stress response (RSR) that culminates in the activation of and signaling through the stress-associated MAP kinases p38 and JNK. The RSR pathway is nonessential, and little is known about the in vivo conditions in which translational problems occur and the contexts in which the RSR is physiologically important. RATIONALE Reactive oxygen species (ROS) activate p38 and JNK and impair ribosomal translation. We rationalized that these responses may be coupled, and that ROS, which is associated with a range of physiological and pathological biological transitions, is a source of RSR activation in vivo. ZAK knockout (KO) mice display a mild metabolic phenotype with leanness and decreased adiposity, suggesting that the RSR is involved in metabolic regulation. Further, p38 and JNK are involved in metabolic transitions such as the emergence of insulin resistance and liver steatosis in obesity. In the context of obesity and metabolic regulation, activation of these kinases is driven by elusive metabolic stress signals that could be mediated by any of the 21 known p38- and JNK-directed MAP3 kinases. We thus sought to investigate the potential links among ROS, RSR signaling, and metabolic regulation using cellular, zebrafish, and mouse models. RESULTS We confirmed that ROS activates the RSR in cellular models, associated with both stalling and collision of ribosomes. In vitro translation reactions highlighted that these effects are primarily mediated by effects on soluble translation factors, including transfer RNAs. When exposed to a pathological burst of ROS, developing zebrafish larvae deficient for the zakα gene were strongly protected against early lethality, likely due to prevention of RSR-induced programmed cell death. ZAK KO mice fed a high-fat high-sugar (HFHS) diet, which is associated with rapid weight gain and ROS-driven pathology in rodents, were protected against early manifestations of metabolic maladaptation, including blood glucose intolerance and liver steatosis. These phenotypes were accompanied by deregulated RSR signaling in ZAK KO mouse livers. In HFHS-fed mice, highly translated liver mRNAs displayed increased stalling and queuing of ribosomes, indicating the presence of known ZAKα-activating structures. Finally, aging in male mice is also associated with increased ROS production and metabolic deterioration manifested as impaired blood glucose intolerance, stochastic liver steatosis, and whitening of brown adipose tissue. ZAK KO mice were protected against all of these hallmarks of metabolic aging. CONCLUSION Our study uncovers ROS as a physiologically relevant source of translational aberrations and RSR activation. Furthermore, impaired ribosomes constitute at least a portion of the metabolic stress signals that drive unwanted metabolic maladaptation in obesity and aging. The strong protection against these reactions offered by Zak gene deletion in mice warrants investigation of the ZAKα kinase as a potential drug target for metabolic conditions such as nonalcoholic steatohepatitis, hypertension, and dyslipidemia. Additional work will be needed to unravel the tissue-specific contributions of RSR signaling to the above phenotypes and to identify other physiologically relevant sources of ribotoxic stress. The ribotoxic stress response drives metabolic maladaptation in obesity and aging. ROS are a physiologically relevant source of translational impairment and activation of the stress kinases ZAKα, p38, and JNK. In obese and aging mice, this RSR drives metabolic maladaptation manifested by blood glucose intolerance, liver steatosis, and whitening of brown adipose tissue (BAT). [Figure created with BioRender.]

ROS-induced ribosome impairment underlies ZAKα-mediated metabolic decline in obesity and aging

The intestine is the primary colonisation site for carbapenem-resistant Enterobacteriaceae (CRE) and serves as a reservoir of CRE that cause invasive infections (e.g. bloodstream infections). Broad-spectrum antibiotics disrupt colonisation resistance mediated by the gut microbiota, promoting the expansion of CRE within the intestine. Here, we show that antibiotic-induced reduction of gut microbial populations leads to an enrichment of nutrients and depletion of inhibitory metabolites, which enhances CRE growth. Antibiotics decrease the abundance of gut commensals (including Bifidobacteriaceae and Bacteroidales) in ex vivo cultures of human faecal microbiota; this is accompanied by depletion of microbial metabolites and enrichment of nutrients. We measure the nutrient utilisation abilities, nutrient preferences, and metabolite inhibition susceptibilities of several CRE strains. We find that CRE can use the nutrients (enriched after antibiotic treatment) as carbon and nitrogen sources for growth. These nutrients also increase in faeces from antibiotic-treated mice and decrease following intestinal colonisation with carbapenem-resistant Escherichia coli. Furthermore, certain microbial metabolites (depleted upon antibiotic treatment) inhibit CRE growth. Our results show that killing gut commensals with antibiotics facilitates CRE colonisation by enriching nutrients and depleting inhibitory microbial metabolites. 

pdf/antibiotics-promote-intestinal-growth-of-carbapenem-29lua0nhza.pdf

Antibiotics promote intestinal growth of carbapenem-resistant Enterobacteriaceae by enriching nutrients and depleting microbial metabolites

The extracellular matrix (ECM) is a critical non-cellular component of multicellular organisms containing a variety of proteins, glycoproteins, and proteoglycans which have been implicated in a wide variety of essential biological processes, including development, wound healing, and aging. Due to low solubility, many ECM proteins have been underrepresented in previous proteomic datasets. Using an optimized three-step decellularization and ECM extraction method involving chaotrope extraction and digestion via hydroxylamine hydrochloride, we have generated coverage of the matrisome across 25 organs. We observe that the top 100 most abundant proteins from the ECM fractions of all tissues are generally present in all tissues, indicating that tissue matrices are principally composed of a shared set of ECM proteins. However, these proteins vary up to 4000-fold between tissues, resulting in highly unique matrix profiles even with the same primary set of proteins. A data reduction approach was used to reveal related networks of expressed ECM proteins across varying tissues, including basement membrane and collagen subtypes. 

Mass Spectrometry-Based Atlas of Extracellular Matrix Proteins across 25 Mouse Organs

Infections by multidrug-resistant Enterobacteriaceae (MRE) are life-threatening to patients. The intestinal microbiome protects against MRE colonization, but antibiotics cause collateral damage to commensals and open the way to colonization and subsequent infection. Despite the significance of this problem, the specific commensals and mechanisms that restrict MRE colonization remain largely unknown. Here, by performing a multi-omic prospective study of hospitalized patients combined with mice experiments, we find that Lactobacillus is key, though not sufficient, to restrict MRE gut colonization. Lactobacillus rhamnosus and murinus increase the levels of Clostridiales bacteria, which induces a hostile environment for MRE growth through increased butyrate levels and reduced nutrient sources. This mechanism of colonization resistance, an interaction between Lactobacillus spp. and Clostridiales involving cooperation between microbiota members, is conserved in mice and patients. These results stress the importance of exploiting microbiome interactions for developing effective probiotics that prevent infections in hospitalized patients. 

/pdf/lactobacillus-supports-clostridiales-to-restrict-gut-2wo8rjrb.pdf

Lactobacillus supports Clostridiales to restrict gut colonization by multidrug-resistant Enterobacteriaceae

Mass spectrometry-based draft of the mouse proteome

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Lactobacillus supports Clostridiales to restrict gut colonization by multidrug-resistant Enterobacteriaceae

Mass spectrometry-based draft of the mouse proteome