Faculty Bibliography

OBJECTIVE:This study was undertaken to investigate the gut microbiome in progressive multiple sclerosis (MS) and how it relates to clinical disease. METHODS:We sequenced the microbiota from healthy controls and relapsing-remitting MS (RRMS) and progressive MS patients and correlated the levels of bacteria with clinical features of disease, including Expanded Disability Status Scale (EDSS), quality of life, and brain magnetic resonance imaging lesions/atrophy. We colonized mice with MS-derived Akkermansia and induced experimental autoimmune encephalomyelitis (EAE). RESULTS:Microbiota β-diversity differed between MS patients and controls but did not differ between RRMS and progressive MS or differ based on disease-modifying therapies. Disease status had the greatest effect on the microbiome β-diversity, followed by body mass index, race, and sex. In both progressive MS and RRMS, we found increased Clostridium bolteae, Ruthenibacterium lactatiformans, and Akkermansia and decreased Blautia wexlerae, Dorea formicigenerans, and Erysipelotrichaceae CCMM. Unique to progressive MS, we found elevated Enterobacteriaceae and Clostridium g24 FCEY and decreased Blautia and Agathobaculum. Several Clostridium species were associated with higher EDSS and fatigue scores. Contrary to the view that elevated Akkermansia in MS has a detrimental role, we found that Akkermansia was linked to lower disability, suggesting a beneficial role. Consistent with this, we found that Akkermansia isolated from MS patients ameliorated EAE, which was linked to a reduction in RORγt+ and IL-17-producing γδ T cells. INTERPRETATION/CONCLUSIONS:Whereas some microbiota alterations are shared in relapsing and progressive MS, we identified unique bacteria associated with progressive MS and clinical measures of disease. Furthermore, elevated Akkermansia in MS may be a compensatory beneficial response in the MS microbiome. ANN NEUROL 2021.

[This corrects the article DOI: 10.1371/journal.pntd.0002880.].

OBJECTIVE:To understand the role of gut microbiome in influencing the pathogenesis of neuromyelitis optica spectrum disorders (NMOSDs) among patients of south Indian origin. METHODS:T cells were sorted in 12 healthy controls, and in 12 patients with AQP4+ NMOSD, RNA was extracted and immune gene expression was analyzed using the NanoString nCounter human immunology kit code set. RESULTS:correlated with expression of inflammatory genes associated with both innate and adaptive immunities and particularly involved in plasma cell differentiation, B cell chemotaxis, and Th17 activation. CONCLUSION/CONCLUSIONS:associated with AQP4+ NMOSD among Indian patients. It is possible that this organism may be causally related to the immunopathogenesis of this disease in susceptible individuals.

Alzheimer's disease (AD) affects an estimated 5.8 million Americans, and advanced age is the greatest risk factor. AD patients have altered intestinal microbiota. Accordingly, depleting intestinal microbiota in AD animal models reduces amyloid-beta (Aβ) plaque deposition. Age-related changes in the microbiota contribute to immunologic and physiologic decline. Translationally relevant dietary manipulations may be an effective approach to slow microbiota changes during aging. We previously showed that calorie restriction (CR) reduced brain Aβ deposition in the well-established Tg2576 mouse model of AD. Presently, we investigated whether CR alters the microbiome during aging. We found that female Tg2576 mice have more substantial age-related microbiome changes compared to wildtype (WT) mice, including an increase in Bacteroides, which were normalized by CR. Specific gut microbiota changes were linked to Aβ levels, with greater effects in females than in males. In the gut, Tg2576 female mice had an enhanced intestinal inflammatory transcriptional profile, which was reversed by CR. Furthermore, we demonstrate that Bacteroides colonization exacerbates Aβ deposition, which may be a mechanism whereby the gut impacts AD pathogenesis. These results suggest that long-term CR may alter the gut environment and prevent the expansion of microbes that contribute to age-related cognitive decline.

Gut-dwelling Prevotella copri (P. copri), the most prevalent Prevotella species in the human gut, have been associated with diet and disease. However, our understanding of their diversity and function remains rudimentary because studies have been limited to 16S and metagenomic surveys and experiments using a single type strain. Here, we describe the genomic diversity of 83 P. copri isolates from 11 human donors. We demonstrate that genomically distinct isolates, which can be categorized into different P. copri complex clades, utilize defined sets of polysaccharides. These differences are exemplified by variations in susC genes involved in polysaccharide transport as well as polysaccharide utilization loci (PULs) that were predicted in part from genomic and metagenomic data. Functional validation of these PULs showed that P. copri isolates utilize distinct sets of polysaccharides from dietary plant, but not animal, sources. These findings reveal both genomic and functional differences in polysaccharide utilization across human intestinal P. copri strains.

The functional interactions between the gut microbiota and the host are important for host physiology, homeostasis, and sustained health. We compared the skeletal muscle of germ-free mice that lacked a gut microbiota to the skeletal muscle of pathogen-free mice that had a gut microbiota. Compared to pathogen-free mouse skeletal muscle, germ-free mouse skeletal muscle showed atrophy, decreased expression of insulin-like growth factor 1, and reduced transcription of genes associated with skeletal muscle growth and mitochondrial function. Nuclear magnetic resonance spectrometry analysis of skeletal muscle, liver, and serum from germ-free mice revealed multiple changes in the amounts of amino acids, including glycine and alanine, compared to pathogen-free mice. Germ-free mice also showed reduced serum choline, the precursor of acetylcholine, the key neurotransmitter that signals between muscle and nerve at neuromuscular junctions. Reduced expression of genes encoding Rapsyn and Lrp4, two proteins important for neuromuscular junction assembly and function, was also observed in skeletal muscle from germ-free mice compared to pathogen-free mice. Transplanting the gut microbiota from pathogen-free mice into germ-free mice resulted in an increase in skeletal muscle mass, a reduction in muscle atrophy markers, improved oxidative metabolic capacity of the muscle, and elevated expression of the neuromuscular junction assembly genes Rapsyn and Lrp4 Treating germ-free mice with short-chain fatty acids (microbial metabolites) partly reversed skeletal muscle impairments. Our results suggest a role for the gut microbiota in regulating skeletal muscle mass and function in mice.

Recent studies suggest that closely related species can accumulate substantial genetic and phenotypic differences despite ongoing gene flow, thus challenging traditional ideas regarding the genetics of speciation. Baboons (genus Papio) are Old World monkeys consisting of six readily distinguishable species. Baboon species hybridize in the wild, and prior data imply a complex history of differentiation and introgression. We produced a reference genome assembly for the olive baboon (Papio anubis) and whole-genome sequence data for all six extant species. We document multiple episodes of admixture and introgression during the radiation of Papio baboons, thus demonstrating their value as a model of complex evolutionary divergence, hybridization, and reticulation. These results help inform our understanding of similar cases, including modern humans, Neanderthals, Denisovans, and other ancient hominins.

Developmental programming by reduced maternal nutrition alters function in multiple offspring physiological systems, including lipid metabolism. We have shown that intrauterine growth restriction (IUGR) leads to offspring cardiovascular dysfunction with an accelerated aging phenotype in our nonhuman primate, baboon model. We hypothesized age-advanced pericardial fat and blood lipid changes. In pregnancy and lactation, pregnant baboons ate ad lib (control) or 70% ad lib diet (IUGR). We studied baboon offspring pericardial lipid deposition with magnetic resonance imaging at 5-6 years (human equivalent 20-24 years), skinfold thickness, and serum lipid profile at 8-9 years (human equivalent 32-36 years), comparing values with a normative life-course baboon cohort, 4-23 years. Increased pericardial fat deposition occurred in IUGR males but not females. Female but not male total cholesterol, low-density lipoprotein, and subcutaneous fat were increased with a trend of triglycerides increase. When comparing IUGR changes to values in normal older baboons, the increase in male apical pericardial fat was equivalent to advancing age by 6 years and the increase in female low-density lipoprotein to an increase of 3 years. We conclude that reduced maternal diet accelerates offspring lipid changes in a sex-dimorphic manner. The interaction between programming and accelerated lipogenesis warrants further investigation.

Antibiotic exposure in children has been associated with the risk of inflammatory bowel disease (IBD). Antibiotic use in children or in their pregnant mother can affect how the intestinal microbiome develops, so we asked whether the transfer of an antibiotic-perturbed microbiota from mothers to their children could affect their risk of developing IBD. Here we demonstrate that germ-free adult pregnant mice inoculated with a gut microbial community shaped by antibiotic exposure transmitted their perturbed microbiota to their offspring with high fidelity. Without any direct or continued exposure to antibiotics, this dysbiotic microbiota in the offspring remained distinct from controls for at least 21 weeks. By using both IL-10-deficient and wild-type mothers, we showed that both inoculum and genotype shape microbiota populations in the offspring. Because IL10(-/-) mice are genetically susceptible to colitis, we could assess the risk due to maternal transmission of an antibiotic-perturbed microbiota. We found that the IL10(-/-) offspring that had received the perturbed gut microbiota developed markedly increased colitis. Taken together, our findings indicate that antibiotic exposure shaping the maternal gut microbiota has effects that extend to the offspring, with both ecological and long-term disease consequences.