Inflammatory Pathways Triggered by the Aging Gut Microbiome Converge on NF-κB

While more knowledge is always a good thing in the long run, it is unclear as to what exactly can be done about age-related chronic inflammation in the near term with a better map of the regulatory processes that initiate, sustain, and suppress inflammation. The state of knowledge today strongly suggests that excessive, unwanted inflammation and necessary, important inflammation both run through the same systems of signaling between and within cells. Therapies based on interfering in more critical portions of that signaling can reduce inflammation, and indeed a number of such drugs already exist, but they have the serious side-effect of also interfering in the vital activities of the immune system. It seems likely that the practical way forward is to remove the causes of inflammation rather than suppressing the mechanisms of inflammation. In the case of inflammation provoked by the aging of the gut microbiome, there are comparatively simple approaches that can reset the balance of populations and reduce the presence of inflammatory microbes, such as fecal microbiota transplantation. It only remains to bring them into common medical practice.

Of the distinct niches colonized by our microbiota within or on us, the gastrointestinal tract harbours the most complex microbiota, consisting of bacteria, fungi, viruses, archaea, and protozoa, and acts as a hotspot for host-microbe interactions. The host through evolution and adaptation has developed diverse mechanisms to distinguish between the microbial symbionts and pathogens and respond accordingly by balancing between tolerance and inflammation. The first step of this interaction is mediated by pattern recognition receptors (PRRs), which sense microorganisms through conserved molecular structures. Several families of PRRs have now been well studied, including the Toll-like receptors (TLRs), the nucleotide-binding oligomerization (NOD)-like receptors (NLRs), the C-type lectin receptors, and the RIG-I-like receptors (RLRs).

Once the microbial signatures are recognized by the host, usually a transcriptional response follows, which determines the outcome of this interaction and is critical for maintaining the balance between homeostasis and inflammation. It is at this stage that members of the nuclear factor kappa B (NF-κB), play a crucial balancing act by maintaining tolerance towards the endogenous symbionts, hence establishing homeostasis while activating inflammatory pathways in response to abnormal changes in the microbiome, "dysbiosis", or pathogenic invasion. Most of the cellular PRRs such as TLRs, NLRs and RLRs after sensing microbial signatures follow distinct pathways, which ultimately converge to stimulate NF-κB, suggesting NF-κB's central role in host response to microbes.

The balance in NF-κB response to microbial signatures becomes crucial for host health particularly during ageing and is often linked to ageing associated diseases. Ageing is associated with an overall decline in host organ functions, which changes host requirements and the dynamics between the host and its microbiota, leading to alterations in microbiome composition and diversity. These age-related microbiota transmutations can either be beneficial with the enrichment of health associated microbes and promote healthy ageing or may lead to severe imbalances leading to a potentially detrimental condition, termed dysbiosis. Ageing-associated dysbiosis usually triggers host immune responses, particularly the innate arm of it, since adaptive immunity typically declines with age, a phenomenon termed immunosenescence. This elevated basal level of innate immune responses during ageing leads to sustained inflammation, a condition known as inflammaging, which contributes to increased risk of developing age-related diseases. NF-κB signaling is a central player in this process as it integrates microbial cues via PRRs and in turn orchestrates innate immune responses.


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