Introduction

Diabetes mellitus is one of the leading global health emergencies, affecting all major sectors of the society, creating huge burden on global health and economy [1, 2]. As per International Diabetes Federation (IDF) Diabetes Atlas latest update, 425 million people are suffering from diabetes globally, and if the trends continue un-checked, the figure is expected to cross 629 million mark by 2045 [1]. Type 1 diabetes is characterized by autoimmune mediated destruction of pancreatic beta cells; while type 2 diabetes, the more prevalent form is defined by progressive loss of beta cells, disturbed insulin secretion and resistance to insulin [3, 4]. It is a complex metabolic disorder known to be mediated by oxidative stress led hyperglycemia [5]. Several other risk factors such as, sedentary lifestyle, genetic pre-disposition, epigenetic changes, and altered gut microbiota are associated with diabetes [2, 6]. However, pancreatic β cells dysfunction or death leading to hampered insulin secretion remains the most prominent factor for development of both type 1 and type 2 diabetes [7]. Healthy β-cells synthesize, store and secrete insulin in response to glucose, nutrients, hormones and nervous stimuli [8]. Proper functioning of β cells is vital for regulation of glucose levels and management of metabolic energy. There are multiple events responsible for apoptosis of β cells in both types of diabetes [9,10,11].

Apart from β cell apoptosis, other factors leading to death of β cells involves nuclear factor kappa B (NF-κB) mediated cytokine induced cell death. NF-κB levels are frequently observed to be elevated in diabetic patients. A recent study indicated involvement of common gene variants of NF-κB in diabetes and renal function impairment, thereby showing the association of NF-κB 1 variants in type 2 diabetic patients [12]. In another recent study it was observed that β cell de-differentiation and impaired insulin secretion which eventually leads to β cell death were promoted by NF-κB signalling pathway. Thus, modulating NF-κB signalling pathway can efficiently prevent the β cell death and provide regulated therapeutic agents for management of type 2 diabetes [13]. The transcription factor NF-κB poses major threat to health and activity of β cells and could be a potential therapeutic target for management of diabetes. Specific roles of NF-κB in type 2 diabetes and role of commensal gut microbiota and probiotics in its management has been reviewed in successive sections.

Evidently the human gut harbours a complex community of over 100 trillion bacterial cells belonging to over 1000 bacterial species [14]. Several studies have shown an association of these gut microorganisms with conditions like allergies, intestinal inflammatory diseases, cancer, diabetes, cardiovascular diseases, non-alcoholic fatty liver disease, and dyslipidaemia [2, 15,16,17,18]. Similarly, several researchers have observed that modulation of intestinal microbiota by beneficial microbes (probiotics) may facilitate the management of a number of clinical conditions [15, 19, 20]. Probiotics as defined by FAO/WHO are "live microorganisms which when administered in adequate amounts confer a health benefit on the host" [21]. Probiotics benefit the host by maintaining a healthier gut microbiota, immunomodulation and other mechanisms, and are frequently involved in host-microbe cross-talk. This cross-talk is by various secreted and non-secreted bacterial factors and cell signalling is an essential part of this interaction. Role of different cell signalling pathway in type 2 diabetes is now well established and probiotics are known to influence a vast array of host cell signalling events [22]. Given the general beneficial effect of probiotics on host health, it could prove useful in prophylactic and/or therapeutic strategies against diabetes. Hence, this review appraises modulation of NF-κB as possible intervention for management of diabetes through probiotic intervention. Our aim is to bring together the current status and possible role of probiotics in the prevention and management of diabetes through intercession of NF-κB signalling pathway.

Nuclear factor kappa B

For better understanding of the topic, it is imperative to have basic knowledge of function and regulation of NF-κB, a nuclear transcription factor found in almost all cell types [23] (Fig. 1). NF-κB performs an essential role in myriad aspects of human health including the development of both innate as well as adaptive immunity, through control over as much as 150 genes involved in a variety of cellular processes [24,25,26]. Five members of the NF-κB family including p50, p52, p65 (RelA), c-Rel, and RelB form different combinations of homo- and heterodimers with different DNA binding specificities and transactivation potential [27, 28]. Heterodimer, p50/ RelA or p52 is the commonly found active form of NF-κB. Each member of the NF-κB family has a conserved N-terminal region called the Rel-homology domain, which contains the dimerization, nuclear localization, and DNA binding domains [27, 29]. Under healthy state, inactive forms of NF-κB complexes are sequestered in the cytoplasm via non-covalent interaction with inhibitory protein, IκBα.

Fig. 1
figure 1

Regulatory circuit of NF-κB: In response to multiple triggering factors IKK phosphorylates IkBα, which is subsequently ubiquitinated and degraded by proteasome. The free NF-κB hetero-dimer translocates to the nucleus and binds to its DNA binding site

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In response to multiple triggering factors, including cytokines, viral and bacterial pathogens, inflammation and stress-inducing agents, the inactive cytoplasmic NF-κB/IκBα complex gets phosphorylated on conserved serine residues in the N-terminal portion of IκBα, followed by ubiquitinylation and proteosomal degradation resulting in breakage of non-covalent interactions and activation of NF-κB. This phosphorylation process is mediated by a multimeric IκB kinase (IKK) complex [30]. Active NF-κB translocates to the nucleus, where it binds to its DNA binding site in the promoter or enhancer regions of specific genes. Level of transcription of individual genes and the amount of transcribed product is regulated by several factors including the composition of NF-κB dimers, nature of activating stimulus and the number of consensus sites in the target genes [31, 32]. Although NF-κB is responsible for mediating immune response and homeostasis, it is better known for its pro-inflammatory potential and serves as potential target during drug therapy against infections. Excessive activation of NF-κB leads to the over-production of pro-inflammatory cytokines and chemokines resulting in chronic inflammation. NF-κB dysregulation has been widely associated with many clinical conditions, including diabetes [33].

Role of NF-κB in diabetes

NF-κB plays a mediator in development of diabetes and related complications. Activation of NF-κB is capable of triggering either pro-inflammatory or anti-inflammatory cascade [12, 34, 35]; however, in terms of β cells, the activity is reported to be predominantly pro-apoptotic [36]. NF-κB activity is suppressed in healthy β cells, however, upon oxidative stress and inflammation, NF-κB gets activated and translocate to the nucleus. Production of reactive oxygen species (ROS) intermediates play a critical role in signalling of autoimmune/inflammatory response, mediated through NF-κB. NF-κB regulates the expression of several genes involved in dysfunction and death of β cells [37]. One such study that involved the identification of novel diabetes candidate genes, gave direct evidence of role of IKK/NF-κB activation in triggering β cell death in type 1 diabetes. Recently, exhaustive bioinformatics analyses were carried out to identify core genes and pathways involved in development of type 2 diabetes [38, 39]. Role of genes viz. major histocompatibility complex class I/II and signalling pathways viz. tumor necrosis factor, cyclic adenosine monophosphate, and peroxisome proliferators-activated receptor signalling pathway in β cells death were also identified [39]. Similarly, Luo and co-workers identified the role of NF-κB and NLRP3 inflammasome activation in the development of diabetes and diabetic cardiomyopathy in a rat model. The study also revealed that activation of NLRP3 inflammasome was through NF-κB mediated pathway in high glucose treated H9c2 cells [40].

Inhibition of NF-κB has been shown to improve insulin sensitivity [41] and prevent apoptosis in both human islets [42] and in alloxan induced diabetic mice models [43]. NF-κBp50 subunit knockout conferred resistance towards streptozotocin induced diabetes in mice models [44]. Role of c-Rel and p50/p105 sub unit has also been suggested in streptozotocin induced diabetes [45, 46]. Many in vitro and in vivo studies have shown that the inhibition of NF-κB pathway provides protection against cytokine induced apoptosis of pancreatic β cells [47,48,49].

The role of NF-κB and its associated target genes is very well documented in the pathogenesis of insulin resistance and type 2 diabetes. Two independent studies, one using the selective transgenic expression and the other using IKKβ knockout in the liver [50, 51] offered adequate evidence to support the key role of NF-κB in development of insulin resistance. Over expression of IKKβ led to the activation of NF-κB, which mimics the effects of high fat diet or obesity induced insulin resistance in experimental mice model. Tumor necrosis factor α (TNF α), a pro-inflammatory cytokine, one of the best characterized inducer of NF-κB is also known to induce insulin resistance through serine phosphorylation of insulin receptor substrate 1 (IRS1). Members of TNF family induce rapid transcription of genes involved in cell survival, inflammation, proliferation and differentiation, mediated through activation of NF-κB [52]. Furthermore, there are various evidences that TNF α is highly induced in the adipose tissues of obese human and animal subjects, while the neutralization of TNF α can reverse insulin resistance, indicating towards involvement of NF-κB activation in insulin resistance [53]. The type and level of polymorphism in NF-κB gene determines the level of complications. For instance, a study conducted to investigate the correlation between NF-κB gene polymorphism and their susceptibility to diabetic nephropathy revealed that a NF-κB1 gene, -94 ATG insertion/deletion polymorphism in Asian Indian subjects with previous history of diabetes mellitus might be associated with an increased risk of nephropathy development [54]. Romzova and co-workers reported increase in homozygous AA genotype of IκBα (NF-κB inhibitor) gene in human subjects with type 2 diabetes suggesting role of NF-κB polymorphism in pathogenesis of type 2 diabetes [55]. Variation in the NF-κB1 was independently responsible as a risk factor for the development of type 2 diabetes in elderly Caucasian subjects [12]. Chronic exposure to glucose and free fatty acids also induces β cell apoptosis. Although high glucose does not induce NF-κB, indicating that the glucose induced β cell apoptosis is primarily independent of NF-κB. However, few studies linked higher glucose concentration to aggravated NF-κB expression in pancreatic cells [56].

Although, majority of studies have demonstrated apoptotic effect of NF-κB in pancreatic β cells, it has been earlier reported that NF-κB has both protective and destructive effects which depends on pathophysiology and on the tissue. Blockage or knockout of NF-κB gene resulted in reduced expression of insulin secretion pathway genes and marginal decrease in the count of endocrine cells in adult pancreas [57]. In another such study, A20 was identified as an NF-kB dependent antiapoptotic gene in β cells that protected β cells from TNF induced apoptosis [58].

NF-κB is involved in the expression of GLUT2 (Glucose transporter 2), which contributes to insulin secretion by β cells [59]. Reports generated from various cell and animal studies suggest that an inhibition of GLUT2 transcription factor might have certain deleterious effects, ultimately leading to the development of insulin resistance and type 2 diabetes [34]. The appropriate control and regulation of NF-κB activity, by means of gene modification as well as pharmacological strategies would provide a potential approach for the management of NF-κB related human diseases including diabetes. Keeping this in mind, several research groups have explored different compounds for modulating NF-κB signalling in different clinical conditions including diabetes. Free phenolic extracts from cereal grains, and plumbagin, a vitamin K3 analogue inhibited Lipopolysaccharide (LPS) induced NF-κB under in vitro cell line conditions [60, 61]. Lycopene inhibited promoter binding activity of NF-κB and intracellular ROS production in human hepatoma Hep 1 cells [62]. Pyrrolidine dithiocarbamate, an anti-oxidant is known to inhibit DNA binding and nuclear translocation of NF-κB in neurons. However, DDTC, another NF-κB inhibiting thiocarbamate has been shown to have negative health effects [63]. NF-κB modulation by probiotic strains can be a safe, dietary intervention for possible management of diabetes.

Management of NF-κB by probiotics

Substantial evidence proves that certain probiotic strains can modulate immune response exerting metabolic changes in the host [59]. Potential sites where probiotics and their metabolites can influence NF-κB are depicted in Fig. 2. In particular, the NF-kB signalling can be modulated by probiotics and their active biological molecules at different sites with probiotic induced effects reported on inhibition of different processes viz. induction through TLRs, transcriptional activation, phosphorylation, ubiquitination and proteasomal degradation of IkBα, nuclear translocation, and DNA binding of the p50/p65 isoforms (Table 1).

Fig. 2
figure 2

Schematic illustration of signalling pathways involved in activation of NF-κB and their probable regulation by probiotics: Probiotic mediated regulation of NF-κB can take place at several steps viz. inactivation of IKK, inhibition of IkBα phosphorylation and ubiquitination, inhibition of IkBα degrading proteasomes, suppression of translocation of NF-κB dimer to the nucleus and transcription inhibition

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Table 1 A list of studies suggesting NF-κB regulatory potential of established probiotic strains
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Various pathogens interact with different toll like receptors (TLRs) to activate NF-κB leading to inflammation. Probiotic bacteria such as L. casei suppresses the Shigella flexneri induced transcription of inflammatory cytokines, adhesion molecules and chemokines in intestinal epithelial cells by inhibiting NF-κB activation [64]. Several other studies supported NF-κB down-regulating potential of L. reuteri, L. rhamnosus GG (LGG), B. infantis and L. salivarius expressed through suppressed TNF α or Salmonella Typhimurium induced IL 8 gene expression and secretion by intestinal epithelial cells [65,66,67]. Inhibition of pathogen recognition associated TLRs is one of the mechanism identified for inhibiting NF-κB [68, 69]. Among other, down regulation of the transcriptional activity of NF-κB via targeting NF-κB signalling pathway is the most reported mechanism. Different steps in NF-κB signalling pathway can act as potential targets for anti-inflammatory probiotics and several other commensals to weaken its transcription. In this line, Kaci et al. (2011) documented the NF-κB suppressing activity of commensal Streptococcus salivarius K12 in human intestinal epithelial cells. Cell free supernatants (< 3 kDa fraction) of S. salivarius and S. vestibularis strains markedly inhibited TNF α induced NF-κB activation in different in vitro models viz. THP-1 reporter cells, Caco-2/kB-seap-7 cells suggesting role of an active microbial metabolite modulating the inflammatory response [70]. In another similar study, S. salivarius K12 was reported to attenuate NF-κB activation, suggesting preventive role of this bacterium in inflammation [71]. Bifidobacterium lactis was observed to suppress NF-κB activation in TNF α, IL 1β and LPS induced HT-29 cells [72]. In contrast, conditioned media from bifidobacteria were reported to stimulate NF-κB in HT-29 cells, while inhibiting the same in Caco-2 cells co-cultured with pro-inflammatory cytokines and bifidobacteria conditioned media. However, under similar conditions TNF α induced NF-κB activation was restrained in the two cell lines only by Colinsella aerofasciens [73]. In another study, LGG pre-feeding prevented TNF α induced intestinal activation of NF-κB [74]. A study carried out by Johnson-Henry et al. (2005) demonstrated probiotics induced downregulation of pro-inflammatory Th1 response with a simultaneous shift towards an improved Th2 response in mice infected with Citrobacter rodentium [75]. This response was attributed to downregulation of NF-κB mediated pathways by probiotic L. helveticus R0052 and L. rhamnosus R0011. Recently, peptides belonging to microbial anti-inflammatory molecule (MEM) secreted by Faecalibacterium prausnitzii were shown to inhibit NF-κB under in vitro epithelial cell culture model and displayed anti-inflammatory properties in colitis model. In transgenic mice models, MEM administration inhibited Th1, Th2 and Th17 immune response through mechanism affecting NF-κB activation [76]. Pre-incubation with yeasts induced NF-κB mediated downregulation in expression of pro-inflammatory chemokines [77]. Another study which evaluated the suppression of Salmonella enteric infection in mice, showed an association of probiotic bacteria with reduced mRNA expression of a group of genes (RelB, Myd88, IKKα, Jun, Irak2) regulated through NF-κB signal transduction pathway as a part of cytokine response [78].

Effects of probiotics on NF-κB transcriptional activity in the nucleus is modulated through PPAR gamma dependent pathway in a strain and dose dependent manner [59]. PPAR gamma forms complex with nuclear RelA and enhances its nuclear export, thereby diminishing NF-κB transcription [79]. B. thetaiotaomicron induced nuclear export of the RelA subunit of NF-κB associated with PPAR. In another study, L. crispatus M247 was able to produce hydrogen peroxide which acts as a signal transducing molecule thereby helping in the activation of PPAR gamma leading to suppression in NF-κB activity. Other non-hydrogen peroxide producing Lactobacillus strains were unable to activate the PPAR gamma mechanism [80].

Presence of reactive oxygen species was also observed to suppress degradation of IκBα [81]. Role of probiotics in modulating inflammatory responses by inducing local generation of ROS has been reported [82]. ROS can oxidize and inactivate key regulatory enzymes. In one such study, LGG induced ROS exhibited increased oxidation of the Ubc12 enzyme in intestinal epithelia. Ubc12 is responsible for the ubiquitination of the inhibitory molecule IκBα, therefore IκBα is not targeted for proteasomal degradation keeping NF-κB inactive in the cytosol. Pre-treatment of Caco-2 cells with LGG inhibited nuclear translocation of the NF-κB p65 resulting in decreased production of TNF α [83]. L. reuteri was shown to inhibit IκB phosphorylation in the intestine during LPS exposure which in turn inhibited the translocation of free NF-κB to the nucleus, thereby inhibiting the later anti-inflammatory response [84]. L. paracasei attenuated the LPS induced secretion of TNF α and IL 1β, concurrently with or before LPS challenge and the effect was due to decrease in IκB phosphorylation and NF-κB nuclear translocation [69]. Further investigators proposed the role of various probiotics which acts after the subsequent NF-κB translocation into the nucleus and is preceded by proteolytic degradation of IκBα. To elucidate whether probiotics could suppress NF-κB activation, inhibition of IκBα degradation was tested in human myeloid leukemia‐derived cells and results indicated that the probiotic could suppresses TNF induced IκBα degradation [85].

Activation of cytosolic NF-κB is followed by its translocation inside the nucleus. Blockage or inhibition of NF-κB nuclear translocation is another intervention point where probiotics can act. In order to study the effect of microbial metabolites on nuclear translocation of active NF-κB, THP-1 cells were stimulated with LPS in presence or absence of Streptococcus thermophilus and B. breve conditioned medium filtrate fractions (< 3 kDa), which significantly inhibited nuclear translocation of active NF-κB subunits [86]. Lactococcus lactis subsp. cremoris strains also inhibited NF-κB nuclear translocation in RAW264.7 cells along with notable suppression in expression of TNF-α, IFN-γ, IL-6, iNOS, and MIP-2 [87]. In another study, pre-treatment of HT-29 cells with LGG attenuated LPS induced NF-κB nuclear translocation along with blockage of LPS induced IκBα degradation [77]. LGG reduced the nuclear translocation of NF-κB by reducing the p65 subunit, necessary for the nuclear translocation [88]. L. reuteri was found to block nuclear translocation of RelA by preventing IκBα degradation in response to TNF stimulation [89]. Another study showed that L. casei suppresses S. flexneri induced transcription of inflammatory chemokines, cytokines and various adhesion molecules by manipulating the ubiquitin pathway to stabilise IκBα and thereby inhibit NF-κB nuclear translocation [23]. The activation of NF-κB was inhibited, thereby inhibiting p65 nuclear translocation and reversal of IκBα degradation when the Raw264.7 cells were treated with L. casei 3260 [90].

In another study binding of p50/p65 isoforms of NF-κB in presence of pro-inflammatory stimulus and bacterial conditioned media was studied. Pre-treatment of intestinal epithelial cells and macrophages (RAW 264.7) with conditioned media from several different Gram positive and Gram negative commensal bacteria, followed by pro-inflammatory stimulation with TNF α inhibited the binding of the p50/p65 subunits. The study depicted that pre-treatment with conditioned medium inhibits the chymotrypsin like activity of the proteasome responsible for release and activation of p50/p65 subunit of NF-κB, thus inhibiting its DNA binding activity [91]. Probiotic treatment was also shown to reduce NF-kB binding activity in high fat diet fed mice [92]. Many studies revealed that the binding activity of NF-κB was limited due to blocking of degradation of IκBα subunit which is a key step in the activation of NF-κB [91]. L. reuteri secretes various factors promoting Bcl-2 and Bcl-xL (anti-apoptotic protein) production in human myeloid leukemia derived cells by inhibiting NF-κB activation. These secreted proteins inhibit NF-κB activation through inhibition of IκB Ubiquitination [85].

Probiotics Lactobacillus strains are known to prevent damage from inflammatory response during autoimmune diseases as well as bacterial infections. In one such study, L. brevis G-101 was shown to inhibit phosphorylation of both Akt (alpha serine/threonine protein kinase) and IRAK1 (Interleukin-1 receptor-associated kinase-1) via the traditional MyD88 pathway, preventing the activation of NF-κB [93]. Investigators studied the role of intracellular events of anti-proliferative activity of L. plantarum JSA22 through the signalling cascade involving an overall decrease in NF-κB activation in colon fibroblast cells when stimulated with S. Typhimurium. The study indicated that L. plantarum JSA22 promotes intestinal epithelial cells survival through inhibition of Akt factor, which is pro-apoptotic in nature, through the inactivation of p38. The phosphorylation levels of Akt and p38 were estimated with or without probiotics. A significant decrease was observed in both the proteins under study when the host cells were infected with L. plantarum JSA22 or even L. rhamnosus GG [94]. In contrast, LGG and their soluble factors (p75 and p40) were reported to prevent epithelial cell apoptosis through activating anti-apoptotic Akt and inhibiting pro-apoptotic p38/MAPK [59].

The effect of eukaryotic probiotic Saccharomyces boulardii on NF-κB DNA binding was studied and mechanism of IκBα degradation was observed. The expression of NF-κB regulated gene was evaluated by transient transfection of THP-1 cells with a NF-κB responsive luciferase reporter gene. S. boulardii inhibited IκBα degradation and reduced both NF-κB DNA binding and NF-κB reporter gene up-regulation in LPS stimulated THP-1 cells. S. boulardii also exerts an anti-inflammatory effect that blocks NF-κB activation in intestinal epithelial cells and monocytes [95]. β-glucan from Saccharomyces cerevisiae was reported to induce sheep β-defensin 1 expression in ovine ruminal epithelial cells mediated through activation of NF-κB. β-defensins play a key role in innate and adaptive immunity [96].

The efficacy of probiotics against diabetes has also been proven in experimental in vivo models. For instance, Bifidobacterium spp. reduced blood glucose levels and increased the expressions of insulin receptor β, insulin receptor substrate 1, protein kinase B (Akt/PKB). Increased Akt suppress IκBα degradation in adipose tissue of diabetic mice [97]. Authors also reported that feeding of probiotic induced the adiponectin expression and decreased both macrophage chemoattractant protein-1 (MCP-1) and interleukin 6 (IL 6) expression in the test organism. An in vivo study showed that B. infantis was responsible for the generation and function of Treg to suppress LPS induced NF-κB activation [98]. Furthermore, the implication of probiotic action has also been reported through production of short chain fatty acids (SCFA) in large intestine. SCFA are established as histone deacetylase inhibitors and affects the expression of various genes, which are directly and indirectly involved in glucose metabolism and pathogenesis of diabetes [99]. For example, probiotic generated SCFA, such as butyrate is reported to downregulate NF-κB activation through blocking cullin-1 neddylation, a critical step in the ubiquitination system which leads to NF-κB suppression [100]. Orally administered probiotic cocktail consisting of L. acidophilus, L. plantarum, B. lactis and B. breve reduced colonic expression of NF-κB, TLR-4 and iNOS in dextran sulfate sodium (DSS) induced acute colitis mice model [101].

Probiotics also have potential to enhance the immunocompetence to prevent spontaneous autoimmune response in diabetic subjects. Probiotic containing kefir improved the phagocytic capacity of peritoneal macrophages and increased concentration of IL 10, TNF α, IL 17 and IL 1β in diabetic mice challenged with LPS [102]. Likewise, Bernini et al. [103] studied the effects of B. lactis HN019 on inflammatory state and nitro-oxidative stress in patients with and without the metabolic syndrome. The study revealed that probiotic intervention decreased homocysteine, hydroperoxides, IL 6 levels and increased adiponectin and nitric oxide metabolites in metabolic syndrome group. The mechanism behind could involve the attenuation of pro-inflammatory Th1 and Th17 cytokines and generation of regulatory T cells that produce IL 10 like cytokines in the process of immune tolerance [104, 105]. Intestinal gut microbiota is known to regulate Th17 cell homeostasis and govern the outcome of metabolic disorders [106]. Moreover, changes in the level of NF-κB expression by T lymphocyte cells have a direct impact on the differentiation and activation of T helper and T regulatory lymphocytes. The application of probiotics could change the expression of NF-κB in immunopositive cells leading to impact on physiological disease outcomes [107].

Another key mechanism involves modulation of gut microbiota to improve insulin sensitivity in diabetic condition. The composition of gut microflora has direct impact on energy metabolism, immunity, inflammation and metabolic dysfunction. Altered microbial population enhance gut permeability and activates LPS induced downstream signalling of MAPK, JNK and P38 molecules which eventually activates NF-κB in epithelial cells, immune cells and metabolically active tissues [97]. Probiotics have proven efficacy in the treatment of dysbiosis and its complications. The transplantation of butyrate producing probiotic Faecalibacterium prausnitzii has been proposed to improve symptoms of metabolic syndrome like obesity and diabetes using such mechanism [108]. Besides, other probiotic species such as, L. rhamnosus, L. acidophilus and B. bifidum have also been reported to influence gut microbiota, intestinal permeability and insulin sensitivity in mice subjected to high fat diet [109].

In contrast to the available reports supporting the NF-κB inhibitory potential of probiotic strains, few reports documented NF-κB induction by probiotics. The ability of L. plantarum JSA22 to activate the innate response via the NF-κB dependent manner was evaluated based on the assessment of NF-κB nuclear translocation. The results indicated that co-infection of cells with L. plantarum JSA22 and S. Typhimurium, significantly induced NF-κB dependent gene activation in intestinal epithelial cells [94]. In a co-culture model (intestinal epithelial cells and macrophages) of the undeveloped small intestine, members of Lactobacillus spp. influenced NF-kB p65 nuclear translocation in both intestinal epithelial cells and underlying macrophages in a strain dependent manner. LGG and PCS 20 strains significantly increased NF-kB p65 translocation; however no significant induction was reported with PCS 26. This nuclear translocation was linked to the ability of commensal microbiome to train the early immune system against pathogens [110].

Apart from their role in prevention of diabetes, probiotics also play a major role in improvement of metabolic diseases including alcoholic fatty liver disease (AFLD) and non-alcoholic fatty liver disease (NAFLD). Hepatic fat accumulation is associated with hepatic insulin resistance in obesity and type 2 diabetes. Increasing evidence suggest that intervention of probiotics could reduce the risk of metabolic syndrome associated NAFLD. One such study conducted by Li et al. documented VSL#3 mediated inhibition of TNF α, thereby leading to an improvement in NAFLD in ob/ob mice models. The results were also consistent with patients of nonalcoholic steatohepatitis (NASH), where enhanced β oxidation of fatty acids was reported in hepatic cells. It was proposed earlier that VSL#3 might tend to normalize the abnormalities in fatty acid β oxidation in ob/ob mice, which may further improve NASH in this mice model. On evaluation of the effects of probiotic VSL#3 therapy on peroxisomal and mitochondrial fatty acid oxidation, results showed that VSL#3 and/or anti TNF antibodies restored the hepatic fatty acid β-oxidation levels towards normal [111]. Furthermore, probiotic B. adolescentis had protective effect on high-fat diet induced NAFLD mice model through reduction of expression of MyD88 mRNA and activation of nuclear factor NF-κB [112].

Prospects/conclusion

Growing burden of diabetes and sub-optimal performance of available treatment strategies highlights the requirement for novel therapeutic strategies. Pancreatic beta cells play a central role in diabetes pathogenesis. Preserving beta cells via management of NF-κB can be a promising strategy for the management of diabetes. The correlation established between gut microbiota and NF-kB supports that the probiotic mediated NF-kB targeted therapy can be explored for possible management of diabetes and other related metabolic and inflammation driven disorders. Many Lactobacillus strains have been shown to regulate NF-κB expression under in vitro and in vivo conditions. Emerging leads from available data reflects NF-κB as a promising biotherapeutic target against diabetes, which can be modulated with dietary intervention involving probiotics. Selective probiotics strains may possibly be harnessed to regulate NF-κB for maintaining health and protecting against diabetes.