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The microbiome is essential for extraction of energy and nutrition from plant-based diets and may have facilitated primate adaptation to new dietary niches in response to rapid environmental shifts. Here we use 16S rRNA sequencing to characterize the microbiota of wild western lowland gorillas and sympatric central chimpanzees and demonstrate compositional divergence between the microbiotas of gorillas, chimpanzees, Old World monkeys, and modern humans. We show that gorilla and chimpanzee microbiomes fluctuate with seasonal rainfall patterns and frugivory. Metagenomic sequencing of gorilla microbiomes demonstrates distinctions in functional metabolic pathways, archaea, and dietary plants among enterotypes, suggesting that dietary seasonality dictates shifts in the microbiome and its capacity for microbial plant fiber digestion versus growth on mucus glycans. These data indicate that great ape microbiomes are malleable in response to dietary shifts, suggesting a role for microbiome plasticity in driving dietary flexibility, which may provide fundamental insights into the mechanisms by which diet has driven the evolution of human gut microbiomes. Microbiota composition fluctuates in response to changes in environmental and lifestyle factors. Here, Hicks et al. show that the faecal microbiota of wild gorillas and chimpanzees is temporally dynamic, with shifts that correlate with seasonal rainfall patterns and periods of high and low frugivory.

The mammalian intestinal tract is colonized by trillions of beneficial commensal bacteria that are anatomically restricted to specific niches. However, the mechanisms that regulate anatomical containment remain unclear. Here, we show that interleukin-22 (IL-22)-producing innate lymphoid cells (ILCs) are present in intestinal tissues of healthy mammals. Depletion of ILCs resulted in peripheral dissemination of commensal bacteria and systemic inflammation, which was prevented by administration of IL-22. Disseminating bacteria were identified as Alcaligenes species originating from host lymphoid tissues. Alcaligenes was sufficient to promote systemic inflammation after ILC depletion in mice, and Alcaligenes-specific systemic immune responses were associated with Crohn's disease and progressive hepatitis C virus infection in patients. Collectively, these data indicate that ILCs regulate selective containment of lymphoid-resident bacteria to prevent systemic inflammation associated with chronic diseases.

Cigarette smokers have an increased risk of infectious diseases involving the respiratory tract. Some effects of smoking on specific respiratory tract bacteria have been described, but the consequences for global airway microbial community composition have not been determined. Here, we used culture-independent high-density sequencing to analyze the microbiota from the right and left nasopharynx and oropharynx of 29 smoking and 33 nonsmoking healthy asymptomatic adults to assess microbial composition and effects of cigarette smoking. Bacterial communities were profiled using 454 pyrosequencing of 16S sequence tags (803,391 total reads), aligned to 16S rRNA databases, and communities compared using the UniFrac distance metric. A Random Forest machine-learning algorithm was used to predict smoking status and identify taxa that best distinguished between smokers and nonsmokers. Community composition was primarily determined by airway site, with individuals exhibiting minimal side-of-body or temporal variation. Within airway habitats, microbiota from smokers were significantly more diverse than nonsmokers and clustered separately. The distributions of several genera were systematically altered by smoking in both the oro- and nasopharynx, and there was an enrichment of anaerobic lineages associated with periodontal disease in the oropharynx. These results indicate that distinct regions of the human upper respiratory tract contain characteristic microbial communities that exhibit disordered patterns in cigarette smokers, both in individual components and global structure, which may contribute to the prevalence of respiratory tract complications in this population.

Antibiotic disruption of the intestinal microbiota may cause susceptibility to pathogens that is resolved by progressive bacterial outgrowth and colonization. Succession is central to ecological theory but not widely documented in studies of the vertebrate microbiome. Here, we study succession in the hamster gut after treatment with antibiotics and exposure to Clostridium difficile. C. difficile infection is typically lethal in hamsters, but protection can be conferred with neutralizing antibodies against the A and B toxins. We compare treatment with neutralizing monoclonal antibodies (mAb) to treatment with vancomycin, which prolongs the lives of animals but ultimately fails to protect them from death. We carried out longitudinal deep sequencing analysis and found distinctive waves of succession associated with each form of treatment. Clindamycin sensitization prior to infection was associated with the temporary suppression of the previously dominant Bacteroidales and the fungus Saccinobaculus in favor of Proteobacteria. In mAb-treated animals, C. difficile proliferated before joining Proteobacteria in giving way to re-expanding Bacteroidales and the fungus Wickerhamomyces. However, the Bacteroidales lineages returning by day 7 were different from those that were present initially, and they persisted for the duration of the experiment. Animals treated with vancomycin showed a different set of late-stage lineages that were dominated by Proteobacteria as well as increased disparity between the tissue-associated and luminal cecal communities. The control animals showed no change in their gut microbiota. These data thus suggest different patterns of ecological succession following antibiotic treatment and C. difficile infection.

Diet strongly affects human health, partly by modulating gut microbiome composition. We used diet inventories and 16S rDNA sequencing to characterize fecal samples from 98 individuals. Fecal communities clustered into enterotypes distinguished primarily by levels of Bacteroides and Prevotella. Enterotypes were strongly associated with long-term diets, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella). A controlled-feeding study of 10 subjects showed that microbiome composition changed detectably within 24 hours of initiating a high-fat/low-fiber or low-fat/high-fiber diet, but that enterotype identity remained stable during the 10-day study. Thus, alternative enterotype states are associated with long-term diet.

Group 3 innate lymphoid cells are shown to process and present antigen and to control CD4 + T-cell responses to intestinal commensal bacteria through an MHC-class-II-dependent mechanism. Immune response to intestinal bacteria The recently characterized innate lymphoid cells (ILCs) can be classified functionally into three groups. Group 1 ILCs produce interferon-γ, group 2 cells express interleukin (IL)-5, IL-13 and amphiregulin, and group 3 ILCs produce IL-17A and IL-22. The function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses are largely unknown. A study in mice now shows that group 3 ILCs process and present antigen and control CD4 + T-cell responses to intestinal commensal bacteria through an MHC-class-II-dependent mechanism. This finding may be relevant to the pathogenesis of chronic human diseases associated with inflammatory host immune responses to commensal bacteria. Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis 3 , 8 , 11 , 12 , 13 . Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 . However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4 + T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt + ) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORγt + ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4 + T-cell responses. Consistent with this, selective deletion of MHCII in murine RORγt + ILCs resulted in dysregulated commensal bacteria-dependent CD4 + T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4 + T cells that limit pathological adaptive immune cell responses to commensal bacteria.

This work identifies a role for intestinal epithelial cell (IEC)-intrinsic expression of histone deacetylase 3 in regulating commensal-bacteria-dependent gene expression and intestinal homeostasis; IEC-specific HDAC3 deficiency gives rise to Paneth cell abnormalities, impaired intestinal barrier function, and increased DSS-induced intestinal inflammation in commensal-bacteria-containing, but not germ-free, mice. HDAC3 role in intestinal homeostasis Epigenetic mechanisms alter the transcriptional response to environmental cues and thus represent a mechanism that can link host genetic predisposition and environmental triggers in the pathogenesis of inflammatory bowel disease (IBD). This study identifies a previously unrecognized role for intestinal epithelial cell (IEC)-intrinsic expression of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3) in regulating intestinal barrier function and susceptibility to commensal-driven inflammation. IEC-specific HDAC3 deficiency in mice is shown to give rise to Paneth-cell abnormalities, rectal prolapse, increased susceptibility to dextran sodium sulphate-induced colitis and increased barrier permeability in commensal-containing but not germ-free animals. The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria 1 , 2 , 3 , 4 , 5 , 6 . However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3 ΔIEC mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3 ΔIEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3 ΔIEC mice showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation of HDAC3 ΔIEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis and intestinal barrier function were largely restored in the absence of commensal bacteria. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, these data indicate that HDAC3 is a critical factor that integrates commensal-bacteria-derived signals to calibrate epithelial cell responses required to establish normal host–commensal relationships and maintain intestinal homeostasis.

The innate and adaptive immune systems in the intestine cooperate to maintain the integrity of the intestinal barrier and to regulate the composition of the resident microbiota. However, little is known about the crosstalk between the innate and adaptive immune systems that contribute to this homeostasis. We find that CD4+ T cells regulate the number and function of barrier-protective innate lymphoid cells (ILCs), as well as production of antimicrobial peptides (AMPs), Reg3γ and Reg3β. RAG1−/− mice lacking T and B cells had elevated ILC numbers, interleukin-22 (IL-22) production, and AMP expression, which were corrected by replacement of CD4+ T cells. Major histocompatibility class II−/− (MHCII−/−) mice lacking CD4+ T cells also had increased ILCs, IL-22, and AMPs, suggesting that negative regulation by CD4+ T cells occurs at steady state. We utilized transfers and genetically modified mice to show that reduction of IL-22 is mediated by conventional CD4+ T cells and is T-cell receptor dependent. The IL-22-AMP axis responds to commensal bacteria; however, neither the bacterial repertoire nor the gross localization of commensal bacteria differed between MHCII+/− and MHCII−/− littermates. These data define a novel ability of CD4+ T cells to regulate intestinal IL-22-producing ILCs and AMPs.

The article in review, 'The Korean Nuclear Imbroglio: Can India be a Muted Spectator?', written by Sitakanta Mishra, brings to light the strategic environment of the region of North Asia and the Korean Peninsula. The region in question is increasingly characterised, for good reasons, by the impact it has to endure due to the nuclearisation of North Korea. Efforts to denuclearise North Korea has only, till now, achieved nothing more than a stalemate. This has raised concerns all over the world as North Korea progresses in the path of nuclearisation under the direction of an authoritarian regime to which the world has limited access. At a time, such as this, it is impractical to focus on approaches to manage the crisis without properly understanding and recognising North Korea’s security concerns which prompted it to become a nuclear power. Only after grasping the full picture should the focus be on how to contain North Korea when it is engaging in activities which reflects an increase in its nuclear capabilities, thereby challenging the preservation of stability in not only the region of North Asia but the whole of Asia and the world. The strategic environment in the region is largely dictated by the dynamics of deterrence employed by both U.S-ROK and North Korea, which may have contributed to the ongoing crisis. The article then proceeds to highlight the need for a reevaluation of the Korean crisis from a non-western standpoint. Sitakanta Mishra attempts to usher in an Asian nation’s perspective by raising an important question as to what role should India, being a nuclear power itself and an aspiring superpower, play in this strategic narrative to resolve the worrisome nuclear crisis of North Korea.

The development and severity of inflammatory bowel diseases (IBD) and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria1–6. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3ΔIEC mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defense. Critically, conventionally-housed HDAC3ΔIEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3ΔIEC mice exhibited significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 plays a central role in maintaining intestinal homeostasis. Rederivation of HDAC3ΔIEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis, and intestinal barrier function were largely restored in the absence of commensal bacteria. While the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be elucidated, these data indicate that HDAC3 is a critical factor that integrates commensal bacteria-derived signals to calibrate epithelial cell responses required to establish normal host-commensal relationships and maintain intestinal homeostasis.